Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])OC2=O)[NH:3]1.Cl.[CH3:21][C:22]1[S:23][CH:24]=[C:25]([CH2:27][O:28][NH2:29])[N:26]=1>>[CH3:21][C:22]1[S:23][CH:24]=[C:25]([CH2:27][O:28][NH:29][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:8][CH2:7][C:4]2[NH:3][C:2](=[O:1])[NH:6][N:5]=2)[N:26]=1
Reactant: O=c1[nH]nc(Cn2c(=O)oc(=O)c3ccccc32)[nH]1
Reactant: Cc1nc(CON)cs1
Agent: Cl
Product: Cc1nc(CONC(=O)c2ccccc2NCc2n[nH]c(=O)[nH]2)cs1

Procedure:
Starting materials: 1-(5-Oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (see preparation 7E) and O-(2-methyl-thiazol-4-ylmethyl)-hydroxylamine hydrochloride (see preparation 12).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([Cl:17])[C:15]=1[OH:16])[C:9](OC)=[O:10].Cl>>[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([Cl:17])[C:15]=1[OH:16])[C:9]([NH:1][CH2:2][CH2:3][OH:4])=[O:10]
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Reactant: NCCO
Agent: Cl
Product: O=C(NCCO)c1cc(Cl)c(O)c(Cl)c1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A 2 L, 3 necked, round bottom flask was charged with 2-aminoethanol (240 gm; 3.93 moles) and heated to 80° C. Methyl 3,5-dichloro-4-hydroxybenzoate (432 gm; 1.96 moles ) was added in portions through a powder funnel. The resulting amber solution was heated to 145° C. and the liberated methanol distilled into a Dean Stark trap. The reaction requires about 3.5 hrs. Upon completion, the solution was cooled to 90°-100° C. and dissolved in 1.95 L H2O. The aqueous solution was cooled to 25° C., placed in an ice bath and made slightly acidic with concentrated hydrochloric acid (196 ml; 2.35 moles). The product precipitated and filtration afforded a white solid. After drying at 50° C. in a vacuum oven, the product darkened slightly. The crude material (384.4 gm; 78.8%) was ground and passed through a No. 20 mesh screen to produce 3,5-dichloro-4-hydroxy-N-(2-hydroxyethyl)benzamide as a cream colored solid (m.p. 174°-178° C.) which is suitable for use in the next step.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[N:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[OH:13][C@H:14]([CH2:19][O:20][C@@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[C:15](OC)=[O:16]>C1(C)C=CC=CC=1>[OH:13][C@@H:14]([CH2:19][O:20][C@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:33])[CH3:32])[CH:25]([CH3:26])[CH3:27])[C:15]([NH:12][C:9]1[CH:8]=[N:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:16]
Reactant: Cc1cnc(N)cn1
Reactant: COC(=O)[C@H](O)CO[C@@H](C)CO[Si](C(C)C)(C(C)C)C(C)C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1cnc(NC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
Trimethylaluminium (2M solution in toluene) (5.98 mL, 11.96 mmol) was added to 5-methylpyrazin-2-amine (1.305 g, 11.96 mmol) in toluene (20 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (R)-methyl 2-hydroxy-3-((S)-1-(triisopropylsilyloxy)propan-2-yloxy)propanoate (Intermediate AU5) (2 g, 5.98 mmol) in toluene (6 mL) was added and the reaction was allowed to warm to room temperature and then refluxed for 6 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq.) and then diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The combined organics were washed with brine (20 mL), then dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to afford the product (1.390 g, 56.5%). 1H NMR (400 MHz, CDCl3) δ 1.04-1.17 (24H, m), 2.54 (3H, s), 3.62-3.67 (3H, m), 3.81-3.85 (1H, m), 4.05-4.09 (1H, m), 4.22 (1H, d), 4.34 (1H, q), 8.13 (1H, d), 9.12 (1H, s), 9.44 (1H, d); m/z (ES+) (M+H)+412.34; HPLC tR=3.82 min.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:17][C@H:18]([C:29]([OH:31])=[O:30])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>CS(C)=O>[C:29]([C@@H:18]([NH:17][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)([OH:31])=[O:30]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with L-tryptophan in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:15][C:16]([OH:18])=O)[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].C1(B(O)O)C=CC=CC=1.[CH3:28][CH:29]([CH3:45])[CH2:30][C@H:31]([NH2:44])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:15][C:16]([NH:44][C@H:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[N:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)[CH2:30][CH:29]([CH3:45])[CH3:28])=[O:18])[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: CC(C)C[C@H](N)c1ccccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Agent: OB(O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)cc1OCC
Temperature: 27.5 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
In a round bottom flask fitted with a dean stark condenser, 3-Ethoxy-4-ethoxycarbonyl phenyl acetic acid (10.26 g, 0.0426 mol) was dissolved in toluene (100 ml) followed by slow addition of phenylboronic acid (0.494 g, 0.0040 mol) and (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (10 g, 0.0406 mol). The reaction mixture was refluxed for 16-18 hours. The resulting mass was cooled at 25-30° C. followed by filtration. The toluene layer was washed with water and 1% sodium bicarbonate solution followed by complete distillation of toluene. Hexane (50 ml) was added to the resulting residue after complete removal of toluene in order to precipitate the solid, with stirring for 1 hour. The resulting solid was filtered and washed with hexane (10 ml). The wet material was further dried at 50-55° C. under vacuum for 4-6 hours to produce Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzoate (Yield=89.6%; HPLC Purity: 99.66%).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11](C(=O)C(F)(F)F)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.O.C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C1CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(c1ccc(Br)cc1)C1CCNCC1
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a solution of 1-[4-(4-bromo-benzoyl)-piperidin-1-yl]-2,2,2-trifluoroethanone (11.6 g, 31.9 mmol) (Palani A.; et al., J. Med. Chem., 2001, 44, 3339-3342) in MeOH (60 mL) and H2O (15 mL) at room temperature was added K2CO3 (10.0 g, 72.5 mmol) and the mixture was stirred for 16 hours to give (4-bromophenyl)-piperidin-4-yl-methanone as a pale yellow solid (7.81 g, 96%) following work-up and purification.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([C:26]([F:29])([F:28])[F:27])[N:15]([CH2:30][CH2:31][OH:32])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:33]([O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][N:15]([CH2:30][CH2:31][OH:32])[C:16]=1[C:26]([F:27])([F:29])[F:28])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: OCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccccc2O)c1C(F)(F)F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccccc2OCc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.5 %

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-trifluoromethyl-1H-pyrazole (111 mg) in N,N-dimethylformamide (0.5 mL) were added benzyl bromide (49 mg) and potassium carbonate (43 mg), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1–5/1) to give the title compound (108 mg).
Reaction SMILES: [CH3:1][CH2:2][CH:3](P(OCC)(OCC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:17]([O-])([O-])=O.[K+].[K+].C=O.O>CCOCC>[CH2:17]=[C:3]([CH2:2][CH3:1])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: C=C(CC)C(=O)OCC
Temperature: 80 °C
Yield: 86.2 %

Procedure:
A mixture of 5.0 g (0.019 mol) of triethyl 2-phosphonobutyrate, 5.5 g (0.039 mol) of K2CO3, 6.2 g (0.076 mol) of 37% aqueous formaldehyde solution, and 15 mL of water was heated to about 80° C. for about 45 min. After cooling to RT, 75 mL of ether was added and the organic layer was separated, washed with brine (1×20 mL), dried (MgSO4), and filtered. The ether was carefully removed by distillation, leaving behind 2.1 g (87%) of the title compound as a clear oil which was used directly without further purification. 1H NMR (CDCl3): δ 1.01 (3H, t, J=7), 1.24 (3H, t, J=7), 2.26 (2H, q, J=7), 4.14 (2H, q, J=7), 5.45 (1H, s), 6.06 (1H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=[O:4].[Li][CH2:19]CCC.CI>O1CCCC1>[CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[C:7]=1[CH3:19])=[O:4]
Reactant: CC(C)(C)C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(NC(=O)C(C)(C)C)cccc1C(F)(F)F
Temperature: 5 °C
Yield: 80 %

Procedure:
A solution of 2,2-dimethyl-3'-trifluoromethyl-propionanilide (6.1 g, 25 mmol) in 100 ml dry tetrahydrofuran was cooled to 0° C. under nitrogen atmosphere and a solution of n-BuLi (1.6M in hexane, 50 ml, 75 mmol) was added dropwise in such a rate that the internal temperature did not rise above 10° C. (about 20 min.) and it was stirred at that temperature for 10 more minutes during which time a grayish turbidity appeared. The cooling bath was removed and the reaction mixture was stirred at room temperature for 2.5 hours. It was cooled to about 5° C. again and a solution of methyl iodide (4.258 g, 30 mmol) in tetrahydrofuran (10 ml.) was slowly transferred via a canula. It was stirred at room temperature for 4 hours and then quenched with water. The solution was concentrated in vacuo and then diluted with water and acidified with dilute HCl. It was then extracted with ether, and the ethereal extracts were washed with water followed by brine. The ether extract was dried with MgSO4 and concentrated to give a light yellow creamy solid (6.2 g., 95%). This was purified by crystallization from dichloromethane and petroleum ether mixture to afford colorless needles of 2,2,2'-trimethyl-3'-trifluoromethyl-propionanilide (80-85%, m.p. 122.5° C.).
Reaction SMILES: [N+](C1C=CC2C(=CC=CC=2)C=1[N+]([O-])=O)([O-])=O.[N+:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[N+:30]([O-])=O)[CH:23]=[CH:22][CH:21]=1)([O-])=O.[N+](C1C2C(=CC=CC=2)C=CC=1)([O-])=O.[H][H]>C1(C)C=CC=CC=1.[Pt]>[NH2:17][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[NH2:30])[CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1cccc2cccc([N+](=O)[O-])c12
Reactant: [H][H]
Agent: [Pt]
Agent: O=[N+]([O-])c1ccc2ccccc2c1[N+](=O)[O-]
Agent: O=[N+]([O-])c1cccc2ccccc12
Solvent: Cc1ccccc1
Product: Nc1cccc2cccc(N)c12
Reaction time: 10 h
Yield: 86 %

Procedure:
88 g of dinitro naphthalene with a content of 89.8% by weight of 1,8-dinitro naphthalene, 7.8% by weight of 1,5- and 1,3-dinitro naphthalene, less than 0.1% by weight each of 1,3,8- , 1,4,5- , 1,3,5-trinitronaphthalene, 1,7- , 1,6- and 1,4-dinitro naphthalene, α-nitro-naphthalene as well as less than 0.4% by weight of other unknown impurities, were hydrogenated, in a 0.7 liter stirrer autoclave, in 300 ml of toluene in the presence of 4 g of 1% by weight catalyst of platinum on activated charcoal, at a temperature of 50° C. and a constant hydrogen pressure of 10 bars. Hydrogenation was completed after 10 hours, the reaction solution was filtered off from the catalyst and fractionally distilled in vacuo. 49 g of 1,8-diamino naphthalene of 98-99% purity were obtained in the boiling range 140°-142° C. at a pressure of 0.2 mm Hg; this corresponds to a yield of 86% of the theory.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17]CC)=[O:16])[CH:13]=2)[N:8]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]=1[CH3:27])[CH3:2].[OH-].[Na+].Cl>CCO>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=2)[N:8]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:7]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccccc2)c2ccc(C(=O)OCC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)Cc1c(C)n(Cc2ccccc2)c2ccc(C(=O)O)cc12
Reaction time: 18.5 h
Yield: 7.5 %

Procedure:
A solution of 1.6 g (4.2 mmol) of 5-ethoxycarbonyl-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid ethyl ester and 4.2 mL of 1N NaOH in 75 mL of EtOH was stirred 2.25 hours, 10 mL of 1N NaOH added, and stirred an additional 18.5 hours. The reaction mixture was acidified with 1N HCl, extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was heated in 150 mL of EtOH for 4.5 hours, and left at room temperature for 96 hours. After concentrating at reduced pressure, the residue was chromatographed on silica (25% ether/hexane→50% ether/hexane) to give 110 mg (7.5% yield) of 5-carboxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1.Cl[C:24]1[CH:31]=[N:30][CH:29]=[C:28]([Cl:32])[C:25]=1[C:26]#[N:27].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[C:3]([O:22][C:24]2[CH:31]=[N:30][CH:29]=[C:28]([Cl:32])[C:25]=2[C:26]#[N:27])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: N#Cc1c(Cl)cncc1Cl
Reactant: Oc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: N#Cc1c(Cl)cncc1Oc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Yield: 7.3 %

Procedure:
A mixture of 5-bromo-2-(4-phenethylthiazol-2-ylamino)pyridin-4-ol (0.060 g, 0.16 mmol), 3,5-dichloroisonicotinonitrile (0.030 g, 0.18 mmol) and Cs2CO3 (0.057 g, 0.18 mmol) was stirred in DMSO (2 mL) at 100° C. overnight. The solution was cooled, quenched with water, extracted with EtOAc, dried, and concentrated. The crude material was purified by flash chromatography gave the desired product (0.006 g, 7% yield) as a white solid. 1H NMR (CDCl3) δ 8.55 (s, 1H), 8.50 (s, 1H), 8.27 (s, 1H), 7.12-7.26 (m, 5H), 6.87 (s, 1H), 6.37 (s, 1H), 2.89 (bs, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][S:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][CH2:15][NH:16]C(OC(C)(C)C)=O)[C:10]([C:24](=[O:33])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:9][N:8]=1)[CH3:2]>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][S:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][CH2:15][NH2:16])[C:10]([C:24](=[O:33])[NH:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCNC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCN)n1
Reaction time: 2 h
Yield: 112.7 %

Procedure:
[4-(2-tert-Butoxycarbonylaminoethylamino)-5-(4-fluorophenylcarbamoyl)pyrimidin-2-ylsulfanyl]acetic acid ethyl ester (113 mg, 0.23 mmol) was dissolved in a trifluoroacetic acid/dichloromethane solution (50%, 4 mL) and the resulting solution was stirred under N2 for 2 h. The solvent was removed by rotary evaporation, and trituration with diethyl ether was attempted. The resulting gummy solid was dissolved in water and lyophilized to yield the titled product (102 mg, 88% as trifluoroacetic acid salt) as a hygroscopic and flocculent white solid. 1H NMR: (d6-DMSO) δ 10.28 (s, 1H), 8.64 (m, 1H), 8.60 (s, 1H), 7.65 (in, 2H), 7.18 (t, 2H), 4.09 (q, 2H), 3.98 (s, 2H), 3.62 (m, 2H), 2.98 (m, 2H), 1.17 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([OH:29])=O)[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[NH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([NH:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[O:29])[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:31][CH:32]=1
Reactant: O=C(O)CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Reactant: NCCc1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21)NCCc1ccncc1
Reaction time: 8 h

Procedure:
20 mg (0.042 mmol) of [4-(4-chlorobenzoyl)-2-oxo-2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-yl]acetic acid trifluoroacetate was dissolved in 2 ml of dichloromethane. 7 mg (0.055 mmol) of 4-aminoethylpyridine, 11 mg (0.055 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.018 ml (0.126 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].[Br:6][CH2:7][CH2:8][CH2:9]Br.[H-].[Na+]>C1COCC1>[Br:6][CH2:7][CH2:8][CH2:9][O:3][CH2:2][C:1]([OH:5])=[O:4]
Reactant: O=C(O)CO
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)COCCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
To a stirred solution of glycolic acid (2.03 g, 26 mmol) and 1,3-dibromopropane (6.41 g, 32 mmol) in THF (50 ml) was added sodium hydride (1.56 g, 65 mmol). This was stirred at room temperature for 16 h. The reaction mixture was quenched with dilute HCl (1.0 M, 100 ml) and then extracted into chloroform (3×50 ml). This was then washed with brine, dried, filtered and evaporated to dryness in vacuo. The residue was purified by chromatography (SiO2, CHCl3 /MeOH) to yield the title compound (2.91 g, 57%).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])=[CH:5][CH:4]=1.[N:14]([O-])=O.[Na+]>O>[ClH:1].[NH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])=[CH:7][CH:8]=1)[NH2:14]
Reactant: CC(C(N)=O)c1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C(N)=O)c1ccc(NN)cc1
Reaction time: 0.25 h

Procedure:
Concentrated hydrochloric acid (4 ml) was added slowly, with cooling and stirring to 4-aminophenyl propionamide (0.80 g), maintaining the temperature below 5° C. To this slurry was added a solution of sodium nitrite (0.37 g) in water (2 ml), dropwise over 15 min, followed by stirring for a further 15 min. The turbid solution thus formed was added portionwise to a cooled, stirred solution of stannous chloride (2.19 g) in conclusion. HCl (4 ml), and the resulting mixture was stirred for 1 h. After filtering, the solution was reduced in volume until an inorganic precipitate formed. This was filtered off, and the filtrate was evaporated to dryness. The residual gum was crystallized from acetic acid to give crude 4-hydrazinophenyl propionamide hydrochloride (1.05 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.[CH3:30][C:31]([CH3:36])=[CH:32][C:33](Cl)=[O:34]>CN(C)C(=O)C>[CH3:26][N:25]1[C:21]([C:19]([NH:18][C:16]2[CH:17]=[C:12]([O:11][C:8]3[CH:9]=[CH:10][C:5]4[N:6]([CH:29]=[C:3]([NH:2][C:33](=[O:34])[CH:32]=[C:31]([CH3:36])[CH3:30])[N:4]=4)[N:7]=3)[CH:13]=[CH:14][C:15]=2[CH3:28])=[O:20])=[CH:22][C:23]([CH3:27])=[N:24]1
Reactant: CC(C)=CC(=O)Cl
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)=CC(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Yield: 68 %

Procedure:
In the same manner as in Example 264 and using N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol), 3-methylbut-2-enoylchloride (81 μL, 0.73 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (150 mg, 68%) was obtained as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)[C:21](=[O:30])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:21](=[O:30])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CON(C)C(=O)COc1ccccc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)COc2ccccc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methyl-2-phenoxyacetamide. The product is used in crude form in the following reaction.
Reaction SMILES: C([O:5][C:6](=[O:53])[CH2:7][CH2:8][S:9][CH2:10][CH:11]([O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:12][O:13][C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:46]1([CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][C:34]([O:33][CH:11]([CH2:12][O:13][C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:10][S:9][CH2:8][CH2:7][C:6]([OH:53])=[O:5])=[O:52])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)CCSCC(COC(=O)CCCCCCCCCCCc1ccccc1)OC(=O)CCCCCCCCCCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSCC(COC(=O)CCCCCCCCCCCc1ccccc1)OC(=O)CCCCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of 6,7-bis(12-phenyldodecanoyloxy)-4-thiaheptanoic acid t-butyl ester as obtained in Reference Example 33 (1.22 g) in dichloromethane (2 ml)-trifluoroacetic acid (6 ml) was stirred at room temperature for 2 hours, after which the solvent was distilled off under reduced pressure, to yield the title compound (1.12 g, yield 99%) as a colorless oily substance.