Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8].[CH3:11][C:12]([CH3:14])=O.O>Br.C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH:12]([CH3:14])[CH3:11])=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: CC(C)=O
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1c(C)[nH]c(C(C)C)c1C
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Anhydrous stannous bromide (5g) was stirred to solution in 20 ml of hydrogen bromide in acetic acid (30-32 %). 2,4-Dimethyl-3-acetyl-pyrrole (548 mg) was added and the mixture was warmed to dissolve this, then cooled to 30° C. Acetone(0.6 ml) was added and the solution was stirred at 35° C. for 21/2 hrs then poured into water at 10° C. The product was separated and washed with dilute hydrochloric acid then with water. It formed colourless micro-prisms (549 mg. 77%), m.p. 166°-167° C. or 173-174.5° C. after changing to cubes at about 136° C. For analysis it was recrystallized from aqueous ethanol as prismatic rods, m.p. 172° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:21])[CH:11]=[CH:12][C:13]1[CH:18]=[C:17](Br)[CH:16]=[C:15](Br)[CH:14]=1)[CH3:8].[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:7]([O:9][C:10](=[O:21])[CH:11]=[CH:12][C:13]1[CH:18]=[C:17]([C:29]#[C:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[C:15]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:14]=1)[CH3:8]
Reactant: CCOC(=O)C=Cc1cc(Br)cc(Br)c1
Reactant: C#Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=Cc1cc(C#Cc2ccccc2)cc(C#Cc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
A mixture of potassium carbonate (2.1 g, 15.2 mmol), tetra-N-butylammonium bromide (0.75 g, 2.4 mmol) and palladium(II) acetate (75 mg, 0.33 mmol) in dry DMF (8 ML), under nitrogen, was stirred for 10 min. 3-(3,5-Dibromophenyl)-acrylic acid ethyl ester (1.2 g, 3.6 mmol) was added and the mixture cooled on ice. Phenylacetylene (4.0 mL, 36.0 mmol) was added and the mixture stirred at room temperature for 7 days. The reaction mixture was added water and the product extracted with ethyl acetate (×3). The combined organic phases were dried and concentrated in vacuo to give crude 3-(3,5-bis-phenylethynyl-phenyl)-acrylic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([CH:8]=[O:9])[S:5][CH:4]=1)#[N:2].O1C[CH2:13][CH2:12][CH2:11]1.C([Mg]Cl)(C)C.C(OCC)(=O)C>CCOCC>[C:1]([C:3]1[CH:7]=[C:6]([CH:8]([OH:9])[CH:12]([CH3:13])[CH3:11])[S:5][CH:4]=1)#[N:2]
Reactant: C1CCOC1
Reactant: N#Cc1csc(C=O)c1
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)C(O)c1cc(C#N)cs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
3-Cyano-5-thiophenecarboaldehyde (2.00 g) was dissolved in anhydrous ether (100 ml) and anhydrous tetrahydrofuran (THF) (20 ml), and an ether solution (10.9 ml) of (2.0 M) isopropylmagnesium chloride was added thereto. After stirring at 0° C. for 2 hours, ethyl acetate was added thereto. The mixture was washed with an aqueous saturated ammonium chloride and further brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system), to give the title compound as a pale yellow oil (1.25 g, 47%).
Reaction SMILES: [ClH:1].C([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([N:18]=[C:19]([NH2:21])[NH2:20])[S:16][CH:17]=2)[CH:10]=[CH:11][CH:12]=1)(=O)C>C(O)C>[ClH:1].[ClH:1].[NH2:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([N:18]=[C:19]([NH2:21])[NH2:20])[S:16][CH:17]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)c1
Agent: Cl
Solvent: CCO
Product: NCc1cccc(-c2csc(N=C(N)N)n2)c1

Procedure:
Conc. hydrochloric acid (10 ml) was added slowly to a suspension of 4-(3-acetylaminomethylphenyl)-2-(diaminomethyleneamino)thiazole (2.8 g) in ethanol (100 ml). The mixture was refluxed for 18 hours. After cooling, the resulting precipitate was collected by filtration to afford 4-(3-aminomethylphenyl)-2-(diaminomethyleneamino)thiazole dihydrochloride (1.75 g).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2].[CH2:18](Br)[CH:19]=[CH2:20]>>[CH2:1]([C:3]1[N:4]([CH2:20][CH:19]=[CH2:18])[C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:13])[F:14])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2]
Reactant: C=CCBr
Reactant: CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: C=CCn1c(CC)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 149 from 2-ethyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and allyl bromide: 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=8.5 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 6.60 (s, 1H), 5.93 (ddt, J=17.7, 10.4, 4.3 Hz, 1H), 5.18 (app. d, J=10.3 Hz, 1H), 4.80-4.73 (m, 3H), 2.78 (q, J=7.4 Hz, 2H), 1.40 (t, J=7.4 Hz, 3H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[CH:26][CH:25]=1.O>CN(C=O)C>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]2[N:18]=[CH:19][N:20]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N:30]4[CH:34]=[N:33][CH:32]=[N:31]4)=[CH:28][CH:29]=3)[CH:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1c[nH]cn1
Reactant: BrCc1ccc(-n2cncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(Cc2ccc(-n3cncn3)cc2)cn1
Reaction time: 1 h

Procedure:
11 mg (0.23 mmol, 50%) of sodium hydride were added to a solution of 60 mg (0.23 mmol) of ethyl 3-(6-aminopyridin-3-yl)-2-(1H-imidazol-4-yl)propionate (example 1g) in 0.5 ml of DMF at RT, and stirred for 1 h. Then 55 mg (0.23 mmol) of 1-[4-(bromomethyl)phenyl]-1H-1,2,4-triazole were added, and the mixture was stirred at RT for 3 h. After this, 1 ml of water was added, the mixture was extracted with EA, and the organic phase was dried over Na2SO4, filtered and concentrated. Chromatography on silica gel afforded ethyl 3-(6-aminopyridin-3-yl)-2-[1-(4-[1,2,4]triazol-1-ylbenzyl)-1H-imidazol-4-yl]propionate. The product obtained in this way was taken up in 0.4 ml of 50% concentrated hydrochloric acid and treated in the microwave at 180° C. for 3 min. Freeze-drying after cooling of the reaction mixture afforded 5 mg of the title compound as bishydrochloride.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.Cl.N1CCCC(OC2C(SC)=C3C(=CC=2)NN=C3)CC1.[CH2:39]([S:41][C:42]1[C:50](O)=[CH:49][CH:48]=[C:47]2[C:43]=1[CH:44]=[N:45][NH:46]2)[CH3:40]>>[CH2:39]([S:41][C:42]1[C:50]([O:1][C@H:2]2[CH2:3][CH2:4][C@H:5]([N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[CH2:6][CH2:7]2)=[CH:49][CH:48]=[C:47]2[C:43]=1[CH:44]=[N:45][NH:46]2)[CH3:40]
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](O)CC1
Reactant: CCSc1c(O)ccc2[nH]ncc12
Agent: CSc1c(OC2CCCNCC2)ccc2[nH]ncc12
Agent: Cl
Product: CCSc1c(O[C@H]2CC[C@H](N3C(=O)c4ccccc4C3=O)CC2)ccc2[nH]ncc12

Procedure:
The title compound was synthesized by carrying out reaction according to the method described in Example 610, except for using the cis-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained in Example 323, (c) and the 4-(ethylthio)-1H-indazol-5-ol obtained in Example 628, as starting materials.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([OH:14])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[C:23]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([O:14][CH3:23])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: Cc1c(O)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol (52 mg, 0.17 mmol) in DMF (2 mL) was added Cs2CO3 (65 mg, 0.2 mmol) and the mixture was stirred at RT for 10 minutes. A solution of methyl iodide in DMF (0.2 mL, 0.2 mmol, 1 M) was added and the reaction solution was stirred at RT for 2 h. The reaction was quenched with EtOAc (5 mL) and H2O (5 mL). The organic layer was separated, dried with sodium sulfate and concentrated in vacuo to give the title compound (35 mg, 65%) as a yellow solid.
Reaction SMILES: C([O:5][C@H:6]1[CH2:10][N:9]([C:11](=[O:32])[CH2:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:8]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][C@@H:36]2[C:40]([OH:42])=O)=[O:34])[CH2:7]1)(C)(C)C.[NH2:43][CH2:44][CH:45]1[CH2:50][CH2:49][N:48](C(OC(C)(C)C)=O)[CH2:47][CH2:46]1>>[OH:5][C@H:6]1[CH2:10][N:9]([C:11](=[O:32])[CH2:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:8]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][C@@H:36]2[C:40]([NH:43][CH2:44][CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[O:42])=[O:34])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)O)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Product: O=C(NCC1CCNCC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by successively conducting procedures which were similar to Step 5 of Example 1 and Example 46, using (2R)-1-{(2S,4R)-4-(tert-butoxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxylic acid and 4-aminomethyl-1-(tert-butoxycarbonyl)piperidine. The compound was obtained as a colorless oily substance.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:15]=[CH:14][C:8]([CH2:9][P:10](Cl)(Cl)=[O:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:23][C:24]([CH3:29])([CH2:27][OH:28])[CH2:25][OH:26]>C(Cl)Cl.O.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:15]=[CH:14][C:8]([CH2:9][P:10]2(=[O:11])[O:28][CH2:27][C:24]([CH3:29])([CH3:23])[CH2:25][O:26]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(CP(=O)(Cl)Cl)cc1
Reactant: CC(C)(CO)CO
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC1(C)COP(=O)(Cc2ccc(S(C)(=O)=O)cc2)OC1
Temperature: 21 °C
Reaction time: 48 h

Procedure:
To a solution of (4-Methanesulfonyl-benzyl)-phosphonoyl chloride from Step 2 (100 mg, 0.35 mmol) in CH2Cl2 (5 mL) was added triethylamine (0.1 mL, 0.7 mmol) and 2,2-dimethyl-1,3-propanediol (48 mg, 0.47 mmol). The resulting reaction mixture was stirred 48 h at 21° C., then diluted with water and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by crystallization from CH2C2/hexane provided the 2-(4-methanesulfonyl-benzyl)-5,5-dimethyl-[1,3,2]dioxaphosphinane 2-oxide compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:28]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:35])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1C
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)c2cccnc2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a stirred solution of the [4-amino-2-(2-methylphenyl)benzoyl]methionine methyl ester (85 mg, 0.23 mmol) in CH2Cl2 (5 mL) was added nicotinic acid chloride hydrochloride (81 mg, 0.46 mmol) and saturated NaHCO3 (2 mL). The reaction was stirred at ambient temperature for 2 hours. The reaction was diluted with CH2Cl2 (10 mL), the layers were separated and the organic layer washed with saturated aqueous NaHCO3 (5 mL), dried (MgSO4) and concentrated in vacuo. Flash chromatography (CH2Cl2-methanol 50:1) and crystallization from ethyl acetate gave the desired compound (87 mg, 80%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 9.10 (dd, 1H, J=2.4, 1.0 Hz), 8.80 (dd, 1H, J=4.7, 1.7 Hz), 8.21 (ddd, 1H, J=7.8, 2.4, 1.7 Hz), 8.09-8.00 (m, 2H), 7.71-7.66 (m, 1H), 7.64-7.61 (m, 1H), 7.46 (ddd, 1H, J=7.8, 4.7, 1.0 Hz), 7.35-7.20 (m, 4H), 5.92 (bd, J=7.5 Hz), 4.67-4.57 (m, 1H), 3.66 (s, 3H), 2.23-2.01 (4 s and m, 8H), 2.00 (m, 1H), 1.65-1.52 (m, 1H). MS m/z 478 (M+1)+.
Reaction SMILES: Cl.Cl.C[O:4][C:5]1C=[CH:9][C:8](N2CCNCC2)=[CH:7][CH:6]=1.C(Cl)(=O)CC(C)C.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][C:33]=1[F:44])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)(=O)CCCC>>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:5](=[O:4])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:40][CH2:39]2)=[CH:34][C:33]=1[F:44])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(C)CC(=O)Cl
Agent: CCCCC(=O)Cl
Agent: Cl
Product: CCCCC(=O)N1CCN(c2ccc(OCc3ccccc3)c(F)c2)CC1

Procedure:
Production Example 3 was repeated except that 1-(4-methoxyphenyl)-piperazine dihydrochloride and isovaleryl chloride were replaced with 1-(4-benzyloxy-3-fluorophenyl)piperazine (286 mg) and valeryl chloride (131 μL), respectively, to provide crude 4-(4-benzyloxy-3-fluorophenyl)-1-valerylpiperazine (367 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]#[N:16])[CH:11]=2)[CH:6]=1)=[O:4].[N+:17]([O-])([O-:19])=[O:18].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]#[N:16])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1ccc2cc(C#N)ccc2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc([N+](=O)[O-])c2cc(C#N)ccc2c1

Procedure:
Nitration of 6-cyano-naphthalene-2-carboxylic acid methyl ester, prepared as described in U.S. Pat. No. 6,284,796, is carried out with KNO3 in sulfuric acid at 0° C. for 30 min. The reaction mixture is poured into ice and filtered, and the compound is washed with water and dried. The product, 6-cyano-4-nitro-naphthalene-2-carboxylic acid methyl ester is obtained and used without further purification.
Reaction SMILES: [NH2:1][C@@:2]([C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16])([CH3:8])[C:3]([F:7])([F:6])[CH2:4][OH:5].[Br:17][CH2:18][C:19](Cl)=[O:20]>>[Br:17][CH2:18][C:19]([NH:1][C@@:2]([C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16])([CH3:8])[C:3]([F:6])([F:7])[CH2:4][OH:5])=[O:20]
Reactant: O=C(Cl)CBr
Reactant: C[C@@](N)(c1cc(Br)ccc1F)C(F)(F)CO
Product: C[C@@](NC(=O)CBr)(c1cc(Br)ccc1F)C(F)(F)CO

Procedure:
Prepared in an analogous manner as described for intermediate A15A from (R)-3-amino-3-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-butan-1-ol (intermediate A14B) (2.96 g, 9.93 mmol) and bromoacetyl chloride (1.72 g, 914 μl, 10.9 mmol). Obtained was the title compound as an off-white solid. MS (ISP): m/z=418.0 [(M+H)+], 420.0 [(M+2+H)+] and 422.0 [(M+4+H)+].
Reaction SMILES: O1C=CC=C1.[NH:6]([C:16]([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].C(N)(N)=O.[CH2:37]([N:43]=[C:44]=[O:45])[C:38]1[O:42][CH:41]=[CH:40][CH:39]=1>>[CH:22]1[C:21]2[CH:20]([CH2:19][O:18][C:16]([NH:6][CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:44]([NH:43][CH2:37][C:38]3[O:42][CH:41]=[CH:40][CH:39]=3)=[O:45])[C:13]([OH:15])=[O:14])=[O:17])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C=NCc1ccco1
Agent: NC(N)=O
Solvent: c1ccoc1
Product: O=C(NCCCCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NCc1ccco1

Procedure:
After Boc deprotection of the Fmoc-Lys(Boc)-OH, Fmoc-Lys-OH was obtained (FIG. 23, (1)). The furan moiety was coupled to the ε-amine of Fmoc-Lys-OH by ureum formation with furfuryl isocyanate to obtain 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-(3-(furan-2-ylmethyl)ureido)hexanoic acid (FIG. 23, (2)), or by amide formation with pentafluorophenyl-furan-2-carboxylate (FIG. 23, (4)) to obtain 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-(furan-2-carboxamido)hexanoic acid (FIG. 23, (5)). The synthesis was finished with Fmoc deprotection, yielding the amphiphilic products (3) or (6) (FIG. 23) as a white powder. Hence, the furan amino acid of Formula (XId) or the furan amino acid of Formula (XIc) was obtained (FIG. 23, (3) or (6) respectively).
Reaction SMILES: C[Al](C)C.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1.[Si]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:52][C@H:51]([CH3:53])[O:50][C@H:49]([CH3:54])[CH2:48]2)=[C:34]([F:46])[C:35]2[O:39][N:38]=[C:37]([C:40](OCC)=[O:41])[C:36]=2[CH:45]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1(C)C=CC=CC=1.O>[CH3:54][C@@H:49]1[CH2:48][N:47]([C:33]2[C:32]([CH2:31][OH:30])=[CH:45][C:36]3[C:37]([C:40]([NH:12][CH2:11][C:8]4[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=4)=[O:41])=[N:38][O:39][C:35]=3[C:34]=2[F:46])[CH2:52][C@H:51]([CH3:53])[O:50]1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: NCc1ccncc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2c(CO)cc3c(C(=O)NCc4ccncc4)noc3c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
Trimethylaluminum (2M in Toluene, 2116 μl, 4.23 mmol) was slowly added (gas evolution) to a solution of pyridin-4-ylmethanamine (458 mg, 4.23 mmol) in toluene (10 ml) at room temperature and under a nitrogen atmosphere. The reaction was stirred for 2 hours at room temperature. Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204, 500 mg, 0.85 mmol) was added as a solution in 5 ml of toluene. The reaction was stirred at 45° C. for three days. The reaction was cooled to room temperature and then quenched drop wise with 3 ml of 1N HCl (vigorous gas evolution). The crude reaction was poured into a Biotage Isolute® HM-N tube (10 ml capacity) packed with a small amount of glass wool to prevent clogging. A Biotage sodium sulfate column (2.5 g) was attached to the bottom of the Isolute® tube. The reaction mixture was allowed to gravity elute through the tube and washed through with 2-3 column volumes of ethyl acetate. The eluent was concentrated. The residue was dissolved in THF (10 ml) and stirred at room temperature with acetic acid (0.097 ml, 1.70 mmol) and TBAF (1N in THF, 0.935 ml, 0.94 mmol) for 16 hours. The reactions were diluted with 1 ml of water and shaken vigorously. The sample was added to a Varian Chem Elute® CE 1003 tube with a Biotage sodium sulfate column (2.5 g) on the bottom of it. The sample was gravity eluted with 2-3 column volumes of ethyl acetate and concentrated. The residue purified by silica gel column chromatography. Fractions were combined and concentrated to give the title compound (241 mg, 0.552 mmol, 65%).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[N:21](COCC[Si](C)(C)C)[C:20]3[C:19](=[O:30])[N:18]([CH2:31][CH2:32][CH3:33])[C:17](Cl)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.C1CCCCC=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:31]([N:18]1[C:19](=[O:30])[C:20]2[NH:21][C:13]([C:11]3[CH:12]=[N:8][NH:9][CH:10]=3)=[N:14][C:15]=2[N:16]=[CH:17]1)[CH2:32][CH3:33]
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCCn1cnc2nc(-c3cn[nH]c3)[nH]c2c1=O
Yield: 36.7 %

Procedure:
A mixture of 8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.1 g, 0.201 mmol), Pd(OH)2 (20%) (0.2 g), in ethanol (4 ml) and cyclohexene were stirred under nitrogen balloon for 25 hrs. Reaction mixture was filtered through celite bed washed with methanol (20 ml). The filtrate was concentrated under vacuum and the crude product was purified by column chromatography using silica gel (100-200 mesh) and 5 to 6% methanol in DCM as an eluent to obtain 1-propyl-8-(1H-pyrazol-4-yl)-1,7-dihydro-purin-6-one (0.018 g, 24%) as white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:26]CC4C=CC(OC)=CC=4)[C:10]([F:25])=[C:11]([NH:15][CH2:16][CH2:17][NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:12]=3[F:14])[C:7](=[O:36])[CH:6]=[C:5]2[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:26][C:9]1[C:10]([F:25])=[C:11]([NH:15][CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:36])[CH:6]=[C:5]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(=O)c2c(NCc3ccc(OC)cc3)c(F)c(NCCNc3ccccn3)c(F)c2n1C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(=O)c2c(N)c(F)c(NCCNc3ccccn3)c(F)c2n1C1CC1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A solution of ethyl 1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-(4-methoxybenzylamino)-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-2-carboxylate (577 mg, 1.02 mmol) in CH2Cl2 (10 mL) was cooled to 0° C. and treated dropwise with trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for over night. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3, brine, and dried over anhyd Na2SO4 followed by the removal of CH2Cl2. The crude product was purified by column chromatography (Hexane:EtOAc 1:1) to yield ethyl 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-2-carboxylate (336 mg, 74%) as a orange amorphous solid.
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[Na+].Cl.[CH:16]#[CH:17]>CS(C)=O>[CH2:6]([O:5][CH2:4][C@@H:2]([OH:3])[CH2:1][C:16]#[CH:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#C
Reactant: c1ccc(COC[C@H]2CO2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CC[C@H](O)COCc1ccccc1
Temperature: 5 °C
Yield: 89 %

Procedure:
To a solution of 20.0 g (122 mmol) of (R)-O-benzylglycidol in dimethylsulfoxide (80 ml), 918.7 g (183 mmol) of a lithium acetylide-ethylenediamine complex (purity: 90%) was gradually added under stirring at a temperature of not higher than 5° C., and the mixture was stirred at the same temeprature for 40 minutes. To the reaction mixture, 150 ml of a saturated sodium chloride aqueous solution was added, and the mixture was acidified by an addition of concentrated hydrochloric acid. Then, the mixture was extracted with ethyl ether. The extract ether solution was washed with a 5% sodium bicarbonate aqueous solution and then with a saturated sodium chloride aqueous solution. The ether layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off from the ether layer. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 20.69 g (yield: 89%) of the above identified terminal acetylene compound. Boiling point: 95° C. (0.3 Torr).