Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]#[N:15])[CH2:9]1)(C)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]#[N:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@H]1CCC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 142.6 %

Procedure:
In a 25 mL round-bottomed flask, cis-(3-cyano-cyclohexyl)-carbamic acid tert-butyl ester (212 mg, 0.945 mmol) was combined with dichloromethane (3 ml) to give a colorless solution. Trifluoroacetic acid (0.9 mL, 11.7 mmol) was added to give a yellow solution which was stirred at room temperature for 1.5 h. The reaction mixture was then concentrated under reduced pressure. The residue was azeotroped with toluene to afford 321 mg of cis-3-aminocyclohexanecarbonitrile trifluoroacetate as a crude solid that was taken to the next step without purification. 1H NMR (300 MHz, DMSO-d6) δ: 7.96 (br. s., 3H), 2.93-3.14 (m, 1H), 2.87 (tt, J=12.2, 3.5 Hz, 1H), 2.22 (d, J=12.1 Hz, 1H), 1.96 (d, J=10.2 Hz, 1H), 1.87 (d, J=11.3 Hz, 1H), 1.68-1.81 (m, 1H), 1.49 (q, J=12.1 Hz, 1H), 1.18-1.41 (m, 3H).
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH2:4]([CH:6]([C:9]1[C:10]2[N:11]([C:16]([C:20]3[N:24]4[CH:25]=[CH:26][CH:27]=[C:28]([C:29](=[O:31])[CH3:30])[C:23]4=[N:22][C:21]=3[CH3:32])=[C:17]([CH3:19])[N:18]=2)[N:12]=[C:13]([CH3:15])[CH:14]=1)[CH2:7][CH3:8])[CH3:5]>C1COCC1>[CH2:4]([CH:6]([C:9]1[C:10]2[N:11]([C:16]([C:20]3[N:24]4[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([OH:31])([CH3:1])[CH3:30])[C:23]4=[N:22][C:21]=3[CH3:32])=[C:17]([CH3:19])[N:18]=2)[N:12]=[C:13]([CH3:15])[CH:14]=1)[CH2:7][CH3:8])[CH3:5]
Reactant: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C(C)=O)cccn34)c(C)nc12
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C(C)(C)O)cccn34)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A suspension of CeCl3 (0.37 g, 2.22 mmol) in THF (10 mL) is stirred at RT for 2 h. It is then cooled to 0° C., and treated with 3.0 M CH3MgBr (0.74 mL, 2.22 mmol). The mixture is stirred at 0° C. for 2 h. A solution of 1-{3-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-2-methyl-imidazo[1,2-a]pyridin-8-yl}-ethanone (0.57 g, 1.48 mmol) in THF (5 mL) is added to the mixture at 0° C. The reaction is stirred at 0° C. for 30 min and at RT for 2 h. It is finally quenched with sat. NH4Cl (10 mL), diluted with H2O (50 mL); extracted with EtOAc (3×100 mL). The combined organic layers is dried with Na2SO4, filtered and concentrated. Purification of the crude material by silica gel chromatography gives the title compound (0.36 g, 0.90 mmol, 61%). 1H NMR (CDCl3): δ 0.92 (t, J=7.5 Hz, 3H), 0.93 (t, J=7.5 Hz, 3H), 1.80 (s, 6H), 1.80-1.95 (m, 4H), 2.41 (s, 3H), 2.42 (s, 3H), 2.45 (s, 3H), 3.31-3.41 (m, 1H), 6.67-6.74 (m, 1H), 6.73 (s, 1H), 6.92 (bs, 1H), 7.09 (bs, 1H), 7.41 (d, J=5.6 Hz, 1H) ppm. ES-MS (m/z): calcd for C24H31N5O (M+H)+: 406.6. found: 406.3.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:14]C(=O)C)=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].N>Cl.O>[N+:1]([C:4]1[C:5]([NH2:14])=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCCC2
Agent: Cl
Agent: N
Solvent: O
Product: Nc1cc2c(cc1[N+](=O)[O-])CCCC2
Temperature: 100 °C
Reaction time: 6 h
Yield: 90.4 %

Procedure:
A suspension of nitroacetamide 167 (151 mg, 0.65 mmol) in 6 M HCl (30 mL) was stirred at 100° C. for 6 h. The suspension was cooled to 20° C., diluted with water (50 mL) and the pH adjusted to 8 with aqueous NH3 solution. The mixture was extracted with DCM (3×50 mL), the combined organic fraction dried, and the solvent evaporated to give amine 174 (113 mg, 100%) as an orange solid: 1H NMR δ 7.83 (s, 1H, H-4), 7.50 (s, 1H, H-1), 5.79 (s, 2H, NH2), 2.67-2.73 (m, 4H, 2×CH2), 1.78-1.83 (m, 4H, 2×CH2).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br.I.O>C(O)(=O)C>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(-c2ncc(-c3ccc(OC)cc3)s2)cc1
Agent: Br
Agent: I
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 22.8 %

Procedure:
In a 200 ml-round-bottomed flask, 8.20 g (21.6 mM) of 2-(4-octylphenyl)-5-(4-methoxyphenyl)thiazole, 80 ml of a solution of 25%-hydrogen bromide in acetic acid and 3 ml of 57%-hydroiodic acid were placed, followed by heat-stirring for 20 hours at 100° C. After the reaction, the reaction mixture was poured into 200 ml of water, followed by extraction with chloroform. The organic layer was washed with water and dried with anhydrous sodium sulfate, followed by distilling-off of the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=20/1) to obtain 1.80 g of 2-(4-octylphenyl)-5-(4-hydroxyphenyl)thiazole (Yield: 22.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:23][CH3:24])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][CH2:15]OS(C)(=O)=O)=[C:9]([CH3:21])[C:8]=2[CH:22]=1)[CH3:2].[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:1]([O:3][C:4]1[C:5]([O:23][CH3:24])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][CH2:15][N:34]3[CH2:35][CH2:36][CH:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:32][CH2:33]3)=[C:9]([CH3:21])[C:8]=2[CH:22]=1)[CH3:2]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CCOc1cc2c(C)c(CCOS(C)(=O)=O)c(=O)oc2cc1OC
Solvent: CCO
Product: CCOc1cc2c(C)c(CCN3CCC(c4ccccc4)CC3)c(=O)oc2cc1OC
Yield: 69 %

Procedure:
Process A; starting materials: 6-ethoxy-3-[2-(methanesulphonyloxy)ethyl]-7-methoxy-4-methyl-2H-1-benzopyran-2-one (Example 29) and 4-phenylpiperidine; yield 69%; m.p. 195°-196° C. (from ethanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[C:27]([O:30][CH2:31][CH2:32]Br)(=[O:29])[CH3:28]>CN(C=O)C>[CH2:31]([O:30][C:27]([CH2:28][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:29])[CH3:32]
Reactant: O=C(OCc1ccccc1)c1cc2cc(F)ccc2[nH]1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C(=O)OCc2ccccc2)cc2cc(F)ccc21
Reaction time: 5 h

Procedure:
Benzyl 5-fluoroindole-2-carboxylate (9.4 g) was dissolved in DMF (94 ml). Potassium carbonate (9.7 g) and bromoethyl acetate (4.0 ml) were added and the mixture was stirred for 5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from isopropyl alcohol to give 9.59 g of benzyl 1-ethoxycarbonylmethyl-5-fluoroindole-2-carboxylate.
Reaction SMILES: C([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C@H:21]([NH:35][C:36](=[O:48])[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[C:38]=2[Cl:47])[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH2:31][CH:32]3[CH2:34][CH2:33]3)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:10]1)C1C=CC=CC=1.C(O[C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C1)C1C=CC=CC=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C1CC=CCC=1>CCOCC.O.ClCCCl>[Cl:47][C:38]1[C:39]([C:43]([F:45])([F:44])[F:46])=[CH:40][CH:41]=[CH:42][C:37]=1[C:36]([NH:35][C@H:21]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH2:31][CH:32]2[CH2:33][CH2:34]2)(=[O:29])=[O:30])=[CH:24][CH:23]=1)[C@@H:11]1[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]1[C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])=[O:48]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1[C@H](NC(=O)c1cccc(C(F)(F)F)c1Cl)c1ccc(S(=O)(=O)CC2CC2)cc1
Agent: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOCC
Solvent: O
Solvent: C1=CCC=CC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1[C@H](NC(=O)c1cccc(C(F)(F)F)c1Cl)c1ccc(S(=O)(=O)CC2CC2)cc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 49.6 %

Procedure:
A mixture of tert-butyl (2S,4R)-4-(benzyloxy)-2-((R)-{[2-chloro-3-(trifluoromethyl)benzoyl]amino}{4-[(cyclopropylmethyl)sulfonyl]phenyl}methyl)-pyrrolidine-1-carboxylate (330 mg, 0.49 mmol) prepared from (2S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid using the method outlined for Examples 11-46, DDQ (0.78 g, 3.4 mmol), DCE (25 mL) and water (1.5 mL) was stirred at 60° C. for 10 hours. After cooling to rt, 1,4-cyclohexadiene (0.76 ml) was added. The mixture was stirred for 5 min. and diluted with ether (70 ml). The mixture was washed with sat. aq. NaHCO3. The organic extract was dried and concentrated. The residue purified by preparative TLC (DCM:MeOH 10%) to give the title product (150 mg, 50%). 1H NMR (CDCl3) δ (ppm) 9.77 (1H, d, J=5.9 Hz), 7.92 (2H, d, J=8.2 Hz), 7.76 (1H, d, J=7.5 Hz), 7.65 (1H, d, J=6.8 Hz), 7.54 (2H, t, J=8.0 Hz), 7.43 (1H, t, J=7.6 Hz), 5.12 (1H, d, J=6.4 Hz), 4.56 (1H, t, J=7.9 Hz), 3.92 (1H, br s), 3.40 (1H, d, J=12.2 Hz), 3.07-2.97 (2H, m), 2.52 (1H, dd, J=8.6 and 3.8 Hz), 2.32-2.22 (1H, m), 1.93-1.87 (1H, m), 1.49 (9H, s), 1.01 (1H, m), 0.57 (2H, m), 0.14 (2H, m).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@@H:12]([CH2:22][O:23][Si](C(C)(C)C)(C)C)[O:11][C@H:10]1[N:31]1[C:40]2[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=2[N:33]=[C:32]1[NH:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])=[CH:45][CH:44]=1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:63][C:64]([O:66][CH3:67])=[O:65]>CN(C)C=O>[CH3:67][O:66][C:64]([CH2:63][O:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[C:46]1[CH:45]=[CH:44][C:43]([CH2:42][NH:41][C:32]2[N:31]([C:40]3[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=3[N:33]=2)[C@@H:10]2[O:11][C@H:12]([CH2:22][OH:23])[C@@H:13]([OH:14])[C@H:9]2[OH:8])=[CH:48][CH:47]=1)=[O:65]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4ccccc4O)cc3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1-c1ccc(CNc2nc3c(N)ncnc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2′,3′,5′-tris-O-(tert-butyl-dimethylsilyl)-8-(2′-hydroxybiphenyl-4-ylmethylamino)-adenosine (0.313 g) in N,N-dimethylformamide (1.9 mL) was added potassium carbonate (0.080 g). Then methyl bromoacetate (0.048 mL) was added, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned between diethyl ether (35 mL) and water (10 mL). The organic layer was washed successively with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue (0.337 g) was dissolved in methanol (1.7 mL). Ammonium fluoride (0.379 g) was added, and the resulting mixture was stirred at 60° C. for 19 hours. The reaction mixture was cooled to room temperature. Dichloromethane (10 mL) was added, and the insoluble material was filtered out. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (0.053 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[N:11][N:10]([CH3:21])[C:9]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)c(Cl)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ncc(-c2ccnc(Cl)n2)c1-c1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
To the solution of 1 g (3.07 mMol) of 2-chloro-4-[3-(2,4-dichloro-phenyl)-1H-pyrazol-4-yl]-pyrimidine in 10 mL of DMF is added 0.467 g (3.38 mMol) of potassium carbonate at rt under an atmosphere of Argon. After stirring for 30 min, 1.15 mL (18.42 mMol) of methyl iodide is added. After completion of the reaction (28 h), the mixture is poured onto 100 mL of water, and extracted repeatedly with ethyl acetate. The combined organic layers are washed with NaHCO3, water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product is purified twice over silica gel, eluting with ethyl acetate/hexanes (1:1) and CH2Cl2/MeOH (99:1) to obtain the title compound as orange crystals; m.p. 122-125° C.; TLC (silica gel) Rf=0.19 (CH2Cl2/MeOH 99:1).
Reaction SMILES: [OH-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:35])=[C:18]([O:23][CH:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]([O:27]C)=[O:26])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:37])[CH3:36])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]>O1CCCC1.CO>[CH:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:16]3[C:17]([CH3:35])=[C:18]([O:23][CH:24]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:25]([OH:27])=[O:26])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:37])[CH3:36])=[CH:10][CH:11]=1)([CH3:5])[CH3:4]
Reactant: COC(=O)C(Oc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)C(C)(C)O2)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1OC(C(=O)O)c1ccccc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
An aqueous solution of 2 N sodium hydroxide (2.5 mL) was dropwise added to a solution of methyl α-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yloxy]phenylacetate (1.20 g, 2.54 mmol) in a mixture of tetrahydrofuran (24 mL) and methanol (6 mL), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, to which was added 2 N hydrochloric acid. Then, this was extracted twice with ethyl acetate. The organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized from hexane to obtain the title compound (0.31 g, yield 27%), which was a mixture of diastereomers (ratio: 8/1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.[F:22][C:23]([F:36])([F:35])[C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][C:32](O)=O)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:32]([CH2:31][CH2:30][C:26]5[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:35])[F:36])[CH:25]=5)=[N:21][N:20]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(-n2cnc3ccc(C(=O)NN)cc32)cc1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Product: CSc1ccc(-n2cnc3ccc(-c4nnc(CCc5cccc(C(F)(F)F)c5)o4)cc32)cc1
Yield: 70 %

Procedure:
In the same manner as in Example 14 and using 1-[4-(methylthio)phenyl]-1H-benzimidazole-6-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and using 3-[3-(trifluoromethyl)phenyl]propionic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 70%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][N:3](C)[C:4](C1N=CN(C2C=C(C3C=CC=CC=3)C=CC=2)C=1)=O.[F:24][C:25]1[C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N:37]3[CH:41]=[C:40]([C:42](Cl)=[O:43])[N:39]=[CH:38]3)[CH:32]=2)=[C:29]([O:45][CH3:46])[CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][N:3]([CH3:4])[C:42]([C:40]1[N:39]=[CH:38][N:37]([C:33]2[CH:32]=[C:31]([C:30]3[C:25]([F:24])=[CH:26][CH:27]=[CH:28][C:29]=3[O:45][CH3:46])[CH:36]=[CH:35][CH:34]=2)[CH:41]=1)=[O:43]
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)Cl)c2)c1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1

Procedure:
This compound is prepared analogously to 12a from 11g.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+].[CH2:14]([O:32][CH2:33][CH:34]1[O:36][CH2:35]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>O.C(O)(C)C>[ClH:1].[OH:36][CH:34]([CH2:33][O:32][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:35][NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCOCC(O)CNCCCC[C@H](N)C(=O)O
Yield: 23.6 %

Procedure:
L-lysine hydrochloride (18.3 g, 0.1 mols) and 2.0 g (0.2 mols) of sodium hydroxide were dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Then, 32.6 g (0.1 mols) of octadecylglycidyl ether were added dropwise thereto over a period of 30 minutes while being heat-refluxed and stirred. Further, the mixture was stirred under reflux for 3 hours. It was identified through TLC and gas chromatography that octadecylglycidyl ether disappeared. Thereafter, the resulting mixture was neutralized with 10.1 g (0.1 mols) of 36% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica-gel column chromatography (Kieselgel 60, eluent=mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 12.0 g of Nε-(2-hydroxy-3-octadecyloxypropyl)-L-lysine hydrochloride (yield 23.6%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])(=O)=O>CC(C)=O.CN(C=O)C.C(OCC)(=O)C.[NH4+].[Cl-]>[F:29][C:25]([F:30])([CH:26]([F:28])[F:27])[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCC(F)(F)C(F)F)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
Methyl 5-hydroxypyridine-2-carboxylate (0.903 g, 5.90 mmol) is suspended in acetone (7 mL) and DMF (7 mL). 325 Mesh potassium carbonate (2.44 g, 17.69 mmol) is added in one portion and stirred at room temperature for 1.5 hours under nitrogen. 2,2,3,3-Tetrafluoropropyl trifluoromethanesulfonate (2.02 g, 7.67 mmol) is added drop wise and the mixture is stirred for 2 hours. The reaction mixture is diluted with ethyl acetate and saturated NH4Cl and extracted with ethyl acetate (3 times). The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and the solvent removed in vacuo. The crude product is purified by silica gel flash chromatography, eluting with a gradient of 0-20% ethyl acetate in dichloromethane to give the title compound (1.047 g, 66%). ES/MS (m/e): 268.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][NH:24]1.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:20]([N:24]1[CH2:25][CH2:26][C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23]1)=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: c1ccc2c(c1)CCNC2
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyloxycarbonyl-L-tryptophan (3.00 g, 9.9 mmol) and 1,2,3,4-tetrahydroisoquinoline (1.31 g, 9.9 mmol) were suspended in THF (20 ml). At a temperature of 0° C., hydroxybenzotriazole (1.33 g, 9.9 mmol), diisopropylethylamine (1.27 g, 9.9 mmol), and EDC (N-3-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride, 1.89 g, 9.9 mmol) were added. The reaction mixture was stirred overnight at r.t. The solvent was evaporated, the residue was taken up in ethyl acetate, washed with water, and dried (Na2SO4). After evaporation of the solvent, the title compound, MS: m/e=420.5 (M+H+), (2.90 g, 70%) was obtained by chromatographic purification of the residue (silica gel, MeOH, CH2Cl2).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].[CH2:12](OS(OCC)(=O)=O)[CH3:13].C(N(CC)CC)C>ClCCl>[C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O:3][CH2:12][CH3:13])=[O:2]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: CCOS(=O)(=O)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a 3-neck 500 ml round-bottom flask equipped with a magnetic stirrer, reflux condenser and addition funnel was added 2-carboxybenzaldehyde (30.00 g, 0.200 moles), diethylsulfate (33.92 g, 0.220 moles) and 150 ml of dichloromethane under nitrogen. The mixture was heated to reflux and triethylamine (30.36 g, 0.300 moles) was added at such a rate to maintain a brisk reflux. After the addition was complete, the solution was heated at reflux for 1 hour and then allowed to cool to room temperature and stirred overnight. The mixture was then washed with water (1×50 ml), 1.0N hydrochloric and solution (1×50 ml), saturated sodium bicarbonate solution (1×50 ml), saturated sodium chloride solution (1×50 ml), dried over magnesium sulfate and concentrated in vacuo to give 21.0 g of the product as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10]C)=O.C(O)(=O)C.[O-:16][C:17]#[N:18].[K+].[OH-].[Na+].Cl>O>[CH3:7][C:6]1[C:2]2[NH:1][C:17](=[O:16])[NH:18][C:8](=[O:10])[C:3]=2[S:4][CH:5]=1
Reactant: N#C[O-]
Reactant: COC(=O)c1scc(C)c1N
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1csc2c(=O)[nH]c(=O)[nH]c12
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
Methyl 3-amino-4-methylthiophene-2-carboxylate IX (100 g, 0.584 mol) and acetic acid (750 mL, 13.1 mol) were stirred for 5 min to obtain a clear solution. A solution of potassium cyanate (56.8 g, 0.70 mol) in water (120 mL) was slowly added over 20 min, and the mixture was stirred for 1.5 h. Additional potassium cyanate (56.8 g, 0.70 mol) in water (120 mL) was slowly added over 20 min and the mixture was stirred for 2 h. Water (600 mL) was added and the mixture was cooled to 10° C. and stirred for 2 h. The solid was collected by filtration and washed with cold water (250 mL). The solid was then stirred for 12 h in a solution of sodium hydroxide (79.4 g, 1.99 mol) in water (1.4 L). The pH was adjusted to 6-7 by slow addition of aqueous concentrated hydrochloric acid solution (35 wt %, 110 mL) and was then stirred for 5 min. The resulting solid was collected by filtration, washed with water (2×250 mL) and dried under reduced pressure at 50° C. for 24 h to afford 7-methylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione VIII as an off-white solid (89.6 g, 84% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.68 (s, 1H), 2.20 (s, 3H); LCMS (ESI pos) m/z [M+H] 183.