Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[C:22]#[CH:23].C1(C)C=CC(S(O)(=O)=[O:31])=CC=1>C(#N)C>[C:22]([C:3]1[C:4]([C:20]#[N:21])=[N:5][N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:17])([F:16])[F:18])=[CH:9][C:8]=2[Cl:19])[C:2]=1[NH2:1])(=[O:31])[CH3:23]
Reactant: C#Cc1c(C#N)nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: CC(=O)c1c(C#N)nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-4-ethynylpyrazole (0.318 g) in acetonitrile (10 ml) was added p-toluenesulphonic acid (0.455 g) and the mixture was stirred at room temperature for 1.5 hours and then evaporated to dryness. The residue was taken up in ether and washed with saturated aqueous sodium hydrogen carbonate solution (5 ml). The aqueous layer was twice extracted with ether. The combined organic layers were dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with hexane:ether (1:1). Combination and evaporation of suitable fractions gave a yellow solid which was further purified by reverse phase high performance chromatography on C18 silica eluted with acetonitrile:water:methanol (60:30:10). Appropriate fractions were combined and evaporated to give, after recrystallisation from propan-2-ol, the title compound as a white solid, m.p. 192.3-192.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.[BH4-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(C=O)cc2)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Cl)c(OCCOc2ccc(CO)cc2)c(Cl)c1
Reaction time: 3 h

Procedure:
To a solution of the aldehyde from Step 2 (1 eq.) in a mixture of THF/MeOH (2/1, 0.21M) was added portion wise sodium borohydride (1.5 eq.). The mixture was stiffed 3 h at room temperature, quenched slowly with 1N HCl and finally concentrated in vacuo. The residual aqueous phase was extracted with diethylether twice. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Stirring the residue in 10% Et2O/Hex for 4 h followed by filtration afforded the desired alcohol as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=O)=[CH:4][CH:3]=1.Cl.[O:13]([NH2:15])[CH3:14]>>[CH3:14][O:13][N:15]=[CH:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: O=CCCc1ccc(F)cc1
Reactant: CON
Agent: Cl
Product: CON=CCCc1ccc(F)cc1
Yield: 97 %

Procedure:
Reaction of 3-(4-fluorophenyl)-propionaldehyde (Dickinson, R. P.; Dack, K. N.; Steele, J.; Tute, M. S. Bioorg. Med. Chem. Lett., 6, 14, 1996, 1691-1696) with methoxylamine hydrochloride as described in the preparation of compound 1-A gave the title oxime ether as a clear oil (97% yield), bp 65-75° C./1.5 torr (bulb to bulb distillation, air bath temperature). 1HNMR indicated a 6:4 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.51 and 2.65 (2H, 2 m, CH2), 2.8 (2H, m, CH2), 3.84 and 3.88 (3H, 2 s, OCH3), 6.67 (t, J=5.5 Hz, CH), 7.0 (2H, m, aromatics), 7.16 (2H, m, aromatics), 7.40 (t, J=4.2 Hz, CH).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:21])[C:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:22]([C:9]1[C:10](=[O:21])[N:11]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12]2[C:7]([CH:8]=1)=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2-c2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2-c2ccccc2)c1O
Temperature: 25 °C
Yield: 45.1 %

Procedure:
A mixture of 3-benzyl-5-hydroxy-2-oxo-1-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (25 mg, 0.065 mmol), β-alanine (767 mg, 8.6 mmol) and NaOMe solution (13 mL, 6.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 13 mg of the title compound. MS: (+) m/z 444.25 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[O:15]=[S:16]1(=[O:39])[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]O)[CH:31]=3)=[C:25]([CH3:38])[CH:24]=2)[CH2:18][CH2:17]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[O:15]=[S:16]1(=[O:39])[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:1][C:2]4[CH:3]=[CH:4][C:5]([CH:8]5[CH2:10][CH:9]5[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=4)[CH:31]=3)=[C:25]([CH3:38])[CH:24]=2)[CH2:18][CH2:17]1
Reactant: Cc1cc(OC2CCS(=O)(=O)CC2)cc(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1CC1c1ccc(OCc2cccc(-c3c(C)cc(OC4CCS(=O)(=O)CC4)cc3C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.156 g, 0.813 mmol), {4′-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-2′,6′-dimethylbiphenyl-3-yl}methanol (0.395 g, 0.739 mmol) and tributylphosphine (0.298 g, 1.47 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.372 g, 1.47 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Hexane (15 mL) was added to the reaction mixture and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-40:60) to give the title compound (0.396 g, yield 91%) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[NH:20][NH2:21]>C(Cl)Cl>[NH:21]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[NH:20][C:19]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)NN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (100 mL) and benzyl chloroformate (103 mL) were added to ethyl carbazate (50.0 g) in methylene chloride (400 mL) at 0° C., followed by stirring at room temperature for 18 hours. The reaction mixture was partitioned by use of saturated aqueous sodium hydrogencarbonate and chloroform. The organic layer was washed with brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give benzyl ethyl hydrazine-1,2-dicarboxylate as an oily product (31.7 g, 27.7%).
Reaction SMILES: [Br-:1].[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br-:1].[CH2:2]([P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Decane bromide (7.0 g) and 10 g of triphenylphosphine were stirred at 120° C. under a nitrogen atmosphere for 8 hours. The mixture was recrystallized from acetone-ether to give 14.4 g of colorless, crystalline decyltriphenylphosphonium bromide. IRν max (CHCl3): 2920, 2850, 1440, 1120, 1000, 680 cm-1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>CN(C=O)C.C1COCC1.O>[CH2:15]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Cl:1])[CH:14]=[CH2:13]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(C=O)cc1Cl
Temperature: 65 °C
Yield: 85.6 %

Procedure:
To a solution of 3-chloro-4-hydroxybenzaldehyde (5.0 g, 31.9 mmol) in DMF/THF 1:3 (120 mL) is added NaH (1.67 g of a 55% dispersion in mineral oil, 38.3 mmol) in four portions. The mixture is stirred at it for 1 h before allylbromide (9.66 g, 79.8 mmol) is added. The reaction mixture is heated to 65° C. for 18 h, diluted with water (250 mL) and extracted with diethyl ether (3×250 mL). The organic extracts are washed with water (250 mL), combined and concentrated. The remaining oil is chromatographed on silic gel with heptane/EA 4:1 to afford 4-allyloxy-3-chlorobenzaldehyde (5.37 g) as an almost colourless oil. LC: tR=0.95 min. The above 4-allyloxy-3-chloro-benzaldehyde (5.37 g, 27.3 mmol) is dissolved in acetone (100 mL) and water (10 mL) and treated with a 2.5% solution of OsO4 in tert.-butanol (1.71 mL, 0.137 mmol OsO4). N-methyl morpholine-N-oxide (3.87 g, 32.8 mmol) is added and the reaction mixture is stirred at it for 20 h before it is diluted with EA (300 mL) and washed with 10% aq. citric acid solution (200 mL) and water (2×150 mL). The washings are extracted with EA (300 mL) and the combined organic extracts are dried over MgSO4, filtered and concentrated to furnish the title compound (6.02 g) as beige foam which was used in the following steps without further purification. LC: tR=0.67 min.
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([CH3:41])([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:22][CH2:21]3)[N:17]=[C:16]([NH2:33])[N:15]=2)=[CH:9][CH:8]=1)C>O1CCCC1.O.[K]>[NH2:33][C:16]1[N:15]=[C:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:41])([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:4]([OH:42])=[O:3])=[CH:8][CH:9]=2)[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:21]2)[N:17]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(Oc2cc(N3CCN(Cc4ccccc4)CC3)nc(N)n2)cc1)Oc1ccccc1
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Product: CC(Cc1ccc(Oc2cc(N3CCN(Cc4ccccc4)CC3)nc(N)n2)cc1)(Oc1ccccc1)C(=O)O
Reaction time: 20 h

Procedure:
3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionic acid ethyl ester was dissolved in tetrahydrofuran (THF)/alcohol solvent in the presence of an excess of aqueous potassium hydrate, the reaction is allowed to proceed for about 20 h. After most of the solve was removed in vacuo, the aqueous solution was acidified to pH 6, the white product was precipitated, then filtered through celite, rac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionic acid (11 g, 95%) was collected.
Reaction SMILES: [CH:1]1([N:7]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][C:27]([CH2:29][CH2:30][S:31]([N:34]1[CH2:39][CH2:38][NH2+:37][CH2:36][CH2:35]1)(=[O:33])=[O:32])=[O:28].[Cl-]>>[CH3:25][O:26][C:27](=[O:28])[CH2:29][CH2:30][S:31]([N:34]1[CH2:35][CH2:36][N:37]([CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C@H:18]3[CH2:19][CH2:20][C@H:21]([CH3:24])[CH2:22][CH2:23]3)=[O:9])=[N:15][CH:14]=2)[CH2:38][CH2:39]1)(=[O:32])=[O:33]
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(C=O)s2)C2CCCCC2)CC1
Reactant: COC(=O)CCS(=O)(=O)N1CC[NH2+]CC1
Agent: [Cl-]
Product: COC(=O)CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)[C@H]3CC[C@H](C)CC3)s2)CC1

Procedure:
Prepared in 60% (342 mg) yield as described in general procedure (B) from trans-1-cyclohexyl-3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea (349 mg, 1.0 mmol) and 4-(2-methoxycarbonyl-ethanesulfonyl)-piperazin-1-ium; chloride (273 mg, 1.0 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:26])([F:25])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][N:14]=2)[CH2:11][O:10]1.[Cl-].[NH4+].[N-:29]=[N+:30]=[N-:31].[Na+].N#N>CO>[N:29]([CH2:11][C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:10])[C:12]([F:26])([F:25])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][N:14]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1ccc(C2(C(F)(F)c3ccc(OCC(F)(F)F)cn3)CO2)c(F)c1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: [N-]=[N+]=NCC(O)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCC(F)(F)F)cn1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a magnetically stirred mixture of 2-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)-5-(2,2,2-trifluoroethoxy)pyridine (775 mg, 2.033 mmol) and ammonium chloride (326 mg, 6.10 mmol) in MeOH (6.776 mL) was added sodium azide (396 mg, 6.10 mmol) in a 20 mL vial under a N2 atmosphere. The reaction mixture was stirred at 50° C. for 16 h. The reaction was cooled to rt, then volatiles were removed under a gentle stream of N2. Et2O was added to the resulting residue and stirred rapidly for 5 min, then filtered to remove solids. The volatiles were removed by rotary evaporation and the resulting oil was carried on without further purification.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:16]=[C:9]2[N:10]=[C:11]([Br:15])[C:12]([Br:14])=[CH:13][C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[C:3]([C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([CH3:17])[CH2:5][N:6]1[CH:16]=[C:9]2[N:10]=[C:11]([Br:15])[C:12]([Br:14])=[CH:13][C:8]2=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2nc(Br)c(Br)cc2n1
Product: CC(C#N)(Cn1cc2nc(Br)c(Br)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5,6-dibromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (60 mg, described in Example 195) and 4-trifluoromethylthiobenzoyl chloride (28 μL), the title compound was isolated as a white solid (44 mg, 47%). MS (ES): M/Z [M+H]=562. 1H NMR: (400 MHz, DMSO-d6): 1.68 (s, 3H), 5.13 (d, J=13.2 Hz, 1H), 5.18 (d, J=13.2 Hz, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H), 8.74 (s, 1H), 8.79 (s, 1H) and 9.04 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: [K+].[Br-].CC[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][C@@H:25]([C@@H:95]([OH:113])/[CH:96]=[CH:97]/[CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH2:110]CC)[CH2:26][O:27][C@@H:28]1[O:33][C@H:32]([CH2:34][OH:35])[C@@H:31]([O:36][C@@H:37]2[O:42][C@H:41]([CH2:43][OH:44])[C@H:40]([O:45][C@@H:46]3[O:51][C@H:50]([CH2:52][OH:53])[C@H:49]([OH:54])[C@H:48]([O:55][C@@H:56]4[O:61][C@H:60]([CH2:62][OH:63])[C@H:59]([OH:64])[C@H:58]([OH:65])[C@H:57]4[OH:66])[C@H:47]3[NH:67][C:68]([CH3:70])=[O:69])[C@H:39]([O:71][C@@:72]3([C:89]([OH:91])=[O:90])[O:77][C@@H:76]([C@H:78]([OH:83])[C@H:79]([OH:82])[CH2:80][OH:81])[C@H:75]([NH:84][C:85]([CH3:87])=[O:86])[C@@H:74]([OH:88])[CH2:73]3)[C@H:38]2[OH:92])[C@H:30]([OH:93])[C@H:29]1[OH:94])=[O:23]>>[CH3:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][C@H:25]([C@H:95]([OH:113])/[CH:96]=[CH:97]/[CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH3:110])[CH2:26][O:27][C@@H:28]1[O:33][C@H:32]([CH2:34][OH:35])[C@@H:31]([O:36][C@@H:37]2[O:42][C@H:41]([CH2:43][OH:44])[C@H:40]([O:45][C@@H:46]3[O:51][C@H:50]([CH2:52][OH:53])[C@H:49]([OH:54])[C@H:48]([O:55][C@@H:56]4[O:61][C@H:60]([CH2:62][OH:63])[C@H:59]([OH:64])[C@H:58]([OH:65])[C@H:57]4[OH:66])[C@H:47]3[NH:67][C:68]([CH3:70])=[O:69])[C@H:39]([O:71][C@@:72]3([C:89]([OH:91])=[O:90])[O:77][C@@H:76]([C@H:78]([OH:83])[C@H:79]([OH:82])[CH2:80][OH:81])[C@H:75]([NH:84][C:85]([CH3:87])=[O:86])[C@@H:74]([OH:88])[CH2:73]3)[C@H:38]2[OH:92])[C@H:30]([OH:93])[C@H:29]1[OH:94])=[O:23]
Reactant: CCCCCCCCCCCCCCC/C=C/[C@H](O)[C@@H](CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@]3(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H]2O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCCCC
Agent: [Br-]
Agent: [K+]
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@]3(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H]2O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCC

Procedure:
IR spectroscopic examination of KBr pellets shows the typical band of the ester at 1750 cm-1. Chromatographic analysis of the product carried out in the same way as in Example 1 shows the presence of a unitary compound with an Rf of 0.72 and the absence of GM1 ganglioside and its internal ester (Rf 0.65 and 0.75, respectively). Hydrolysis with Na2CO2 as described in Example 1 produces the ganglioside GM1.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C[O-].[Na+].C(O)C>Cl>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([C:8]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:13]=2[OH:21])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)c1ccccc1S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(C(=O)c2sc3ccccc3c2O)cc1

Procedure:
A mixture of 4-cyanophenacyl bromide (3.0 g), methyl thiosalicylate (2.25 g), sodium methoxide (1.52 g) and ethanol (100 ml) was boiled under reflux for 3.5 hours. The mixture was cooled and diluted with 2M hydrochloric acid (100 ml). A precipitate was collected by filtration and recrystallized from ethanol to give 2-(4-cyanobenzoyl)-3-hydroxybenzo[b]thiophene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([O:14][CH3:15])[C@H:10]([NH:16]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][N:39]=2)=[N:35][C:34]=1[C:45](O)=[O:46])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][N:39]=2)=[N:35][C:34]=1[C:45]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([NH2:16])[CH2:9][CH2:8]1)=[O:46]
Reactant: CO[C@@H]1CCN(c2c(N)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ncccc2F)nc1C(=O)O
Product: COC1CCN(c2c(NC(=O)c3nc(-c4ncccc4F)sc3N)cnn2C)CCC1N

Procedure:
Following the procedure Example 101, reacting tert-butyl ((4R,5R)-1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-methoxyazepan-4-yl)carbamate and 5-((tert-butoxycarbonyl)amino)-2-(3-fluoro-pyridin-2-yl)thiazole-4-carboxylic acid gave racemic 323 (35.8 mg, 24% over two steps). 1H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 8.43 (d, J=4.6 Hz, 1H), 7.89-7.78 (m, 1H), 7.66 (s, 2H), 7.62 (s, 1H), 7.48 (dt, J=8.3, 4.1 Hz, 1H), 3.65 (s, 3H), 3.28 (d, J=7.5 Hz, 5H), 3.26-2.95 (m, 8H), 2.07 (dd, J=10.6, 4.4 Hz, 1H), 1.92 (dd, J=10.6, 7.4 Hz, 1H), 1.79-1.55 (m, 2H). LCMS (ES+) m/z 461 (M+1)
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[C:4]([CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH2:17][C@H:18]([N:20]1C(=O)C2=CC=CC=C2C1=O)[CH3:19])=[O:5])[CH3:2].O.NN>C(O)C>[CH2:31]([N:3]([CH2:1][CH3:2])[C:4]([CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH2:17][C@H:18]([NH2:20])[CH3:19])=[O:5])[CH3:32]
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)N3C(=O)c4ccccc4C3=O)c[nH]c12
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)N)c[nH]c12
Temperature: 85 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
(R)-7-Diethylaminocarbonylmethyloxy-3-(2-phthalimidopropyl)indole 10.27 g was suspended in 100 ml of ethanol, and 2.5 ml of hydrazine monohydrate was added thereto. The suspension was heated to reflux in an oil bath of 85° C. For 3 hours. After cooling down, the resulting deposited insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate and a sodium hydroxide aqueous solution were added to the residue and distributed in liquid-liquid, and the organic layer was further washed with a sodium hydroxide aqueous solution and dried. The solution was evaporated under reduced pressure. The resulting residue was slowly crystallized, and dried under reduced pressure, whereby 6.90 g of the title compound was obtained in the form of a pale brownish white substance.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][C:28](=O)[NH:27][C:26]=4[CH:32]=3)[CH2:17][CH2:16]2)[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][NH:27][C:26]=4[CH:32]=3)[CH2:19][CH2:20]2)[N:3]=1
Reactant: Cc1ccc2c(OCCN3CCC(Cc4ccc5c(c4)NC(=O)CO5)CC3)cccc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc2c(OCCN3CCC(Cc4ccc5c(c4)NCCO5)CC3)cccc2n1
Yield: 54.6 %

Procedure:
The title compound (0.228 g, 54%) was prepared by reduction of 6-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one (0.431 g, 1 mmol) with lithium aluminium hydride as described in Example 3.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:3]=1.[CH3:15][N:16]([CH3:33])[C:17]1[CH:18]=[C:19]([C:23]2[C:24]3[N:25]([N:29]=[C:30]([NH2:32])[N:31]=3)[CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1>>[CH3:15][N:16]([CH3:33])[C:17]1[CH:18]=[C:19]([C:23]2[C:24]3[N:25]([N:29]=[C:30]([NH:32][CH:11]4[CH2:12][CH2:13][N:8]([C:4]5[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=5)[CH2:9][CH2:10]4)[N:31]=3)[CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Reactant: CN(C)c1cccc(-c2cccn3nc(N)nc23)c1
Product: Cc1cc(N2CCC(Nc3nc4c(-c5cccc(N(C)C)c5)cccn4n3)CC2)ncn1

Procedure:
Prepared in analogy to example 1h employing 1-(6-methylpyrimidin-4-yl)piperidin-4-one (see example 93b) and 8-(3-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (prepared in analogy to example 66a-c). The title compound was obtained as white foam.