Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:33][CH2:32][CH2:31][C@@:3]1([CH3:34])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:27]([CH3:30])[CH2:28][CH3:29])[C@H:16]([O:25][CH3:26])[CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[CH2:33][CH2:32][CH2:31][C@@:3]1([CH3:34])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:27]([CH3:30])[CH2:28][CH3:29])[C@H:16]([O:25][CH3:26])[CH2:17][C:18]([OH:20])=[O:19])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Yield: 152 %

Procedure:
According to the general procedure B, from #202 (5.2 g, 10.77 mmol, 1 eq.), dichloromethane (45 mL), and trifluoroacetic acid (20 mL) was synthesized the crude desired material, to obtain #203 (7 g, quantitative yield) which was used in the next step without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[C:16]([F:20])=[C:17]([F:19])[F:18]>C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Zn]>[F:20][C:16]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:16]([F:20])=[C:17]([F:19])[F:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)=[C:17]([F:19])[F:18]
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: FC(F)=C(F)I
Agent: [Pd]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)=C(F)c1ccc(-c2ccc(C(F)=C(F)F)cc2)cc1
Reaction time: 24 h

Procedure:
After 24 hours, a GC/MS of the mixture allows identification of all the reaction components. After 72 hours, the reaction seems to stop proceeding while excess diiodobiphenyl remains: another batch of iodotrifluoroethylene (25.0 g, 0.12 mole) is reacted with zinc in THF and added to the reaction mixture along with 1.0 g of palladium tetrakis(triphenylphosphine) catalyst. The reaction is allowed to stir an additional 12 hours, then is removed and evaporated to dryness under high vacuum on a rotary evaporator. Residue from evaporation is added to a 3 fold volumetric excess of water. A heavy precipitate is formed which is filtered and air dried on a vacuum funnel. The precipitate is dissolved in THF and filtered. Resulting filtrate is coated on silica gel by adding the silica gel to the THF solution and evaporating to dryness. This silica gel is then eluted on a short silica gel column using hexane as eluent to remove the colored material from the product. A fine white crystalline material remains after evaporation of the hexane. This crystalline material is then chromatographed again carefully on an alumina column using hexane as an eluent. The first band to elute from the column is the desired monomer product CF2 =CF--Ph--Ph--CF=CF2. A total of 44.2 g of product is recovered (58.7% yield).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30]([O:32]CC3C=CC=CC=3)=[O:31])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[C:22]([CH2:28][CH3:29])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[NH:3]1.[H][H]>[Pd].CO>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30]([OH:32])=[O:31])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[C:22]([CH2:28][CH3:29])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: CCc1ccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)OCc2ccccc2)cc1CC
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC

Procedure:
A mixture of 350 mg (0.60 mmol) (R)-1-benzyloxycarbonyl-2-(3,4-diethyl-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 30 mL MeOH was hydrogenated in the presence of 50 mg Pd/C (5%) at RT and 3 bar hydrogen pressure until the calculated volume of hydrogen had been taken up. The catalyst was filtered off, the solvent was eliminated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:39])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([C:29](=[O:38])[C:30]#[C:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2I)[CH:15]=1>>[CH3:11][O:12][C:13](=[O:39])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)/[C:30](=[C:31](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)/[C:29]2=[O:38])[CH:15]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC2CCCCC2)c2ccccc2I)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccc(Cl)cc3)C3CCCCC3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 84 starting from 4-chlorophenylboronic acid (commercially available) and 3-{[(3-cyclohexyl-propynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.02 (s, 1H), 7.93 (d, 1H), 7.47-7.51 (m, 13H), 7.39 (t, 1H), 7.10 (d, 2H), 7.01 (t, 1H), 6.59-6.63 (m, 2H), 5.71 (d, 2H), 5.02 (s, 2H), 4.62 (t, 1H), 3.91 (s, 3H), 1.44-1.76 (m, 6H), 1.01-1.18 (m, 4H).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][N:43]([CH2:46][CH3:47])[CH2:42][CH2:41]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>[C].[Pd].CO>[CH2:46]([N:43]1[CH2:42][CH2:41][N:40]([CH2:39][CH2:38][O:37][C:34]2[CH:35]=[CH:36][C:9]([OH:8])=[C:10]([CH:33]=2)[C:11]([NH:13][C:14]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][C:15]=2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])[CH2:45][CH2:44]1)[CH3:47]
Reactant: CCN1CCN(CCOc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CCN1CCN(CCOc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a methanol (20 mL) solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(2-(4-ethylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate, 10% palladium-carbon (1.7 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. To the reaction mixture, 10% palladium-carbon (0.70 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure to obtain tert-butyl 2-(5-(2-(4-ethylpiperazin-1-yl)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[C:15](=[O:16])[O:14][C:12](=[O:13])[C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]([CH3:23])([CH2:21][NH2:22])[CH2:19][OH:20].O>C1(C)C=CC=CC=1>[OH:20][CH2:19][C:18]([CH3:23])([CH3:17])[CH2:21][N:22]=[C:12]([C:8]1[CH2:9][CH2:10][CH2:11][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=2[C:7]=1[C:15]([OH:14])=[O:16])[OH:13]
Reactant: CC(C)(CN)CO
Reactant: O=C1OC(=O)C2=C1CCCc1ccccc12
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(CO)CN=C(O)C1=C(C(=O)O)c2ccccc2CCC1
Temperature: 25 °C

Procedure:
21.4 g (0.1 mol) of 6,7-dihydro-5H-benzocycloheptene-8,9-dicarboxylic acid anhydride and 10.3 g (0.1 mol) of 2,2-dimethyl-3-aminopropanol are dissolved in 60 ml of toluene and the solution is refluxed for 1 hour, the water formed being separated off by means of a water separator downstream of the reaction vessel. After cooling to room temperature, the crystals which have precipitated out are filtered off. This yields 28.9 g (96.6% of theory) of N-(3'-hydroxy-2',2'-dimethylpropyl)-6,7-dihydro-5H-benzocycloheptene-8,9-dicarboxylic acid imide.
Reaction SMILES: [C:1]12([C:11]3[C:12](=O)[C:13]4[C:21](=[CH:22][CH:23]=3)[C:20]3[C:15](=[CH:16][C:17]([C:24]56[CH2:33][CH:28]7[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]7)[CH2:25]5)[CH2:31]6)=[CH:18][CH:19]=3)[CH:14]=4)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:35]([OH:43])(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[C:24]12([C:17]3[CH:18]=[CH:19][C:20]4[C:21]5[C:13](=[CH:12][C:11]([C:1]67[CH2:10][CH:5]8[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]8)[CH2:2]6)[CH2:8]7)=[CH:23][CH:22]=5)[C:14]([C:37]5[C:36]([C:35]([OH:43])=[O:42])=[CH:41][CH:40]=[CH:39][CH:38]=5)([C:41]5[C:36]([C:35]([OH:43])=[O:42])=[CH:37][CH:38]=[CH:39][CH:40]=5)[C:15]=4[CH:16]=3)[CH2:31][CH:30]3[CH2:32][CH:26]([CH2:27][CH:28]([CH2:29]3)[CH2:33]1)[CH2:25]2
Reactant: O=C1C2=Cc3cc(C45CC6CC(CC(C6)C4)C5)ccc3C2=CC=C1C12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: O=C(O)c1ccccc1C1(c2ccccc2C(=O)O)c2cc(C34CC5CC(CC(C5)C3)C4)ccc2-c2ccc(C34CC5CC(CC(C5)C3)C4)cc21
Temperature: 150 °C
Reaction time: 12 h
Yield: 80.9 %

Procedure:
In a 500 mL recovery flask, 44.9 g of 2,7-di(1-adamantyl)-fluorenone obtained in the same manner as in Synthesis example 7 (100 mmol), 36.6 g of benzoic acid (300 mmol), 203 mL of Eaton's reagent (7.7 wt % methanesulfonic acid solution of diphosphorus pentoxide) and a stirrer were charged and agitated at 150° C. for 12 hours under a nitrogen atmosphere. After reaction solution reached room temperature, mL of ion-exchange water was added slowly. An aqueous layer was separated and removed therefrom. Then, solvent was removed from the reaction solution under reduced pressure. Solid thus obtained was purified by column chromatography, thus obtaining 54.7 g of 2,7-di(1-adamantyl)-fluorene-9,9-bisbenzoic acid (81 mmol; yield: 81%).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:34])[C:12]1[CH:17]=[C:16]([O:18]CC2C=CC=CC=2)[CH:15]=[C:14]([O:26]CC2C=CC=CC=2)[CH:13]=1.[H][H]>C(O)(C)C.O.[C].[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:34])[C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([OH:26])[CH:13]=1
Reactant: COc1ccc(CCNCC(O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(CCNCC(O)c2cc(O)cc(O)c2)cc1OC
Yield: 63.7 %

Procedure:
1.4 g of α-(3,4-dimethoxyphenethylaminomethyl)-3,5-dibenzyloxybenzylalcohol hydrochloride are suspended in a mixture of 32 ml of isopropanol and 8 ml of water. 0.42 g of 10 % palladium-carbon is added to the solution. Then, the mixture is subjected to catalytic hydrogenation in a hydrogen atmosphere at room temperature for 1 hour under atmospheric pressure. After the reaction is completed, the mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure, and the residue thus obtained is recrystallized from a mixture of methanol and ether. 0.6 g of α-(3,4-dimethoxyphenethylaminomethyl)-3,5-dihydroxybenzylalcohol hydrochloride is obtained. Yield: 63.5 % M.p. 193° - 194°C
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[CH:33][NH:32][C:31]3=[O:35])=[CH:26][CH:25]=2)[CH:23]=[CH:22][N:21]=[CH:20]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:32]1[CH:33]=[CH:34][N:30]([C:27]2[CH:28]=[CH:29][C:24]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)=[CH:25][CH:26]=2)[C:31]1=[O:35])[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ccn1-c1ccc(-n2ccnc2)cc1
Product: C[C@@H](n1ccn(-c2ccc(-n3ccnc3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(1H-1-imidazolyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-imidazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 23).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([O:16][C:17]([C:19]12[CH2:26][CH2:25][C:22]([NH:27][CH2:28][C:29]([N:31]3[CH2:35][C@@H:34]([F:36])[CH2:33][C@H:32]3[C:37]([NH2:39])=O)=[O:30])([CH2:23][CH2:24]1)[CH2:21][CH2:20]2)=[O:18])[CH3:15].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:14]([O:16][C:17]([C:19]12[CH2:26][CH2:25][C:22]([NH:27][CH2:28][C:29]([N:31]3[CH2:35][C@@H:34]([F:36])[CH2:33][C@H:32]3[C:37]#[N:39])=[O:30])([CH2:23][CH2:24]1)[CH2:21][CH2:20]2)=[O:18])[CH3:15]
Reactant: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C(N)=O)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Trifluoroacetic anhydride (80 μL) was added to a solution of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ac etyl]-4-fluoropyrrolidine-2-carboxamide (100 mg) in tetrahydrofuran (1 mL). The mixture was stirred at room temperature for 2 hours and then at 40° C. for 1.5 hours. Subsequently, additional trifluoroacetic anhydride (40 μL) was added and the mixture was further stirred for 30 minutes. A saturated aqueous sodium bicarbonate solution (5 mL) was then added and the reaction mixture was extracted with ethyl acetate (2×10 mL). The ethyl acetate extracts were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on an aminated silica gel column (eluant=ethyl acetate:methanol=30:1) to give (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ac etyl]-4-fluoropyrrolidine-2-carbonitrile as a colorless solid (63.7 mg, 67% yield). This compound was identical to the compound obtained in Example 7.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][CH:6]([CH:12]=[C:13]=[CH2:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(O)C>[CH3:5]/[C:6](=[CH:12]\[CH:13]=[CH2:14])/[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C=C=CC(C)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C=C/C=C(\C)C(=O)OCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium ethoxide solution (21% in ethanol, 33.3 ml, cat.) was added to a solution of ethyl 2-methylpenta-3,4-dienoate (Bedoukian, 125.0 g, 890 mmol) in anhydrous ethanol (350 ml) and stirred at ambient temperature for 12 hours. The solution was concentrated in vacuo and the residue partitioned between ether and saturated NH4Cl solution. The aqueous phase was re-extracted twice with ether, then the combined organic phase washed with NH4Cl and then brine, dried over Na2SO4, filtered and the solvents removed in vacuo to yield the crude ester, 125.8 g as an orange oil which was used directly in the next step without further purification.
Reaction SMILES: C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.[CH2:15]([O:22][CH2:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]([O:30][C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][CH:35]=[CH:34]3)[CH:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([O:22][CH2:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]([O:30][C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][CH2:35][CH2:34]3)[CH:25]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(COCc2cc(Oc3ccc4[nH]ccc4c3)ncn2)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COCc2cc(Oc3ccc4c(c3)CCN4)ncn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylsilane (4 mL, 24.7 mmol) and TFA (6 mL) are added to 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-1H-indole (0.22 g, 0.682 mmol) in 6 mL of acetonitrile and stirred at rt overnight. The reaction is concentrated to an oil that is dissolved in EtOAc and washed with a saturated aqueous sodium bicarbonate. The organic layer is removed, dried, and concentrated to an to obtain crude 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-2,3-dihydro-1H-indole. MS (ESI) m/z 334.2 (M+1).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH:16]([C:33]([O:35][CH2:36][CH:37]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[C@H:17]([C:30](O)=[O:31])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:21][CH:20]=1.[NH2:50][C@H:51]([C:73]([NH:75][C@H:76]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[CH2:77][C:78](=[O:80])[NH2:79])=[O:74])[CH2:52][S:53][C:54]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:16]([C:33]([O:35][CH2:36][CH:37]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[C@H:17]([C:30]([NH:50][C@H:51]([C:73]([NH:75][C@H:76]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[CH2:77][C:78](=[O:80])[NH2:79])=[O:74])[CH2:52][S:53][C:54]([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:31])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:23][CH:24]=1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.63 g of DCC are added to a stirred solution of 3.4 g of Fmoc-Tyr(tBu)-OH, 3.95 g (7.4 mmol) of H-Cys(Trt)-Asn-OtBu (Liebigs Ann. Chem. 1979, 242) and 1 g of HOBT in 50 ml of dimethylformamide at 0° C., and the mixture is left to stir at 0° C. for 1 h and to stand at room temperature overnight. The next day, the precipitate is filtered off with suction and the filtrate is concentrated. The residue is triturated with ethyl acetate. Yield 2.83 g. A further 3.63 g can be isolated from the mother liquor. Total yield: 6.46 g (89%).
Reaction SMILES: [CH:1]1([CH2:8][C:9]2[NH:13][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[N:11][C:10]=2[C:24](O)=[O:25])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][O:28][C:29]([O:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:37]=[C:38]([CH2:40][O:41][C:42]([O:44][CH3:45])=[O:43])[CH:39]=1)[NH2:36])=[O:30]>>[CH3:45][O:44][C:42]([O:41][CH2:40][C:38]1[CH:37]=[C:35]([NH:36][C:24]([C:10]2[N:11]=[C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)[NH:13][C:9]=2[CH2:8][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:25])[CH:34]=[C:33]([CH2:32][O:31][C:29]([O:28][CH3:27])=[O:30])[CH:39]=1)=[O:43]
Reactant: O=C(O)c1nc(-c2ccc3ccccc3c2)[nH]c1CC1CCCCCC1
Reactant: COC(=O)OCc1cc(N)cc(COC(=O)OC)c1
Product: COC(=O)OCc1cc(COC(=O)OC)cc(NC(=O)c2nc(-c3ccc4ccccc4c3)[nH]c2CC2CCCCCC2)c1
Yield: 41.7 %

Procedure:
5-Cycloheptylmethyl-2-naphthalen-2-yl-1H-imidazole-4-carboxylic acid (Example 20, step c) (605 mg, 1.75 mmol) was reacted with 3,5-bis-methoxycarbonyloxymethyl-aniline (492 mg, 1.75 mmol) according to the procedure of Example 20, step d to afford the product as a white solid (438 mg, 42%). 1H NMR (300 MHz, CDCl3) 9.42 (1H, br s), 9.35 (1H, s), 8.27 (1H, s), 8.06-7.89 (4H, m), 7.79 (2H, s), 7.56 (2H, m), 7.14 (1H, s), 5.18 (4H, s), 3.83 (6H, s), 3.12 (2H, d), 2.00-1.29 (13H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:22]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCCCSc1cccc2nccn12
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCCSc1cccc2nccn12)c1ccccc1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a solution of 5-[3-(hydroxy)propylthio]imidazo[1,2-a]pyridine (1.00 g, 4.80 moles) and triethylamine (0.80 ml, 5.74 moles) in methylene chloride (25 ml) was added benzoyl chloride (1.10 ml, 11.6 moles) with stirring at room temperature and the mixture was further stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous 1N sodium hydroxide solution and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent: hexane/acetone (1:1)] to obtain 1.32 g of the desired product (88.1%, white solid).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]2=[N:4][C:3]=1[C:14]([O:16]CC)=O.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:14]([C:3]2[N:4]=[C:5]3[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:6]3[C:7](=[O:8])[C:2]=2[OH:1])=[O:16])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N2C
Reactant: NCc1ccc(F)cc1
Product: CN1C(=O)Cn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Yield: 61.1 %

Procedure:
Reaction of intermediate 13, ethyl 6-hydroxy-1-methyl-2,5-dioxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (0.050 g, 0.197 mmol) with 4-fluorobenzylamine (0.11 g, 0.87 mmol) as described in the preparation of example 1 gave 0.040 g (60% yield) of the title amide as white crystals. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.15 (3H, s, NCH3), 4.49 (2H, s, CH2), 4.5 (2H, d, J=6.5 Hz, CH2), 7.18 (2H, m, aromatics), 7.38 (2H, m, aromatics), 9.49 (1H, broad t, NH), 12.28 (1H, s, OH). MS (ESI+) m/z 333 [M+H+].
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]1[CH2:11][NH:10][C:9](=O)[CH2:8][O:7]1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1>>[CH:23]1([C:2]2[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=2[O:4][C@@H:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:6]2[O:7][CH2:8][CH2:9][NH:10][CH2:11]2)[CH2:25][CH2:24]1
Reactant: O=C1COC(C(Oc2ccccc2Br)c2ccccc2)CN1
Reactant: OB(O)C1CC1
Product: c1ccc([C@H](Oc2ccccc2C2CC2)[C@@H]2CNCCO2)cc1

Procedure:
(S)-2-[(S)-(2-Cyclopropyl-phenoxy)-phenyl-methyl]-morpholine was synthesized from 6-[(2-Bromo-phenoxy)-phenyl-methyl]-morpholin-3-one and cyclopropyl boronic acid according to general procedures A and B and was isolated as a viscous colorless oil. 1H NMR (CDCl3): δ 7.40-7.24 (m, 5H), 6.91 (m, 1H), 6.80 (m, 2H), 6.66 (d, 1H), 5.15 (d, 1H), 3.94 (m, 2H), 3.65 (dt, 1H), 2.85-2.59 (m, 4H), 2.32 (m, 1H), 0.99-0.89 (m, 2H), 0.74-0.59 (m, 2H); MS (ES) 310.1 [C20H23NO2+H]+; HPLC purity (98.6%); Analysis: Calc'd for C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C, 76.61; H, 7.58; N, 4.37.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH2:20][CH3:21])=[C:9]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:8]2=[O:17]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C(Cc1ccc(F)cc1)c1cc(Br)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(Br)cc2c(=O)c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
Intermediate 6 (3.0 g, 9.70 mmoles) was taken in a RB flask and to this triethylamine (30 ml) and propionic anhydride (3.94 g, 30.37 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (1.60 g, 47% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.33(d, J=2.4Hz, 1H), 7.76(dd, J=8.8,2.4 Hz, 1H), 7.38(d, J=8.8Hz, 1H), 7.24(dd, J=5.5,2.0Hz, 2H), 7.16 (dt, J=11.4,2.8 Hz, 2H), 2.61(q, J=7.6Hz, 2H), 1.27(t, J=7.5Hz, 3H).