Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][NH:9][CH2:8]1)=O.C(N(CC)C(C)C)(C)C.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CN(C)C=O>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:9]1[CH2:10][CH2:11][O:12][CH:7]([CH2:6][NH2:5])[CH2:8]1
Reactant: Fc1cccc(CBr)c1
Reactant: O=C(NCC1CNCCO1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NCC1CN(Cc2cccc(F)c2)CCO1
Temperature: 20 °C
Reaction time: 24 h
Yield: 47.3 %

Procedure:
A mixture of Intermediate 19 (0.300 g) and N,N-diisopropylethylamine (0.372 ml) in N,N-dimethylformamide (5 ml) was treated with 3-fluorobenzyl bromide (0.295 g). The solution was stirred at 20° C. under nitrogen for 24 h. The mixture was partitioned between dichloromethane (10 ml) and saturated aqueous potassium carbonate (10 ml). The phases were separated and the organic phase applied to an ion exchange cartridge (10 g Isolute SCX, prewashed with methanol). The SCX cartridge was eluted with methanol (40 ml) followed by 10% 0.880 ammonia in methanol (40 ml) and the appropriate fractions were concentrated in vacuo. The residue was dissolved in methanol (2 ml) and treated with aqueous 2N sodium hydroxide (2 ml). The solution was stirred at 20° C. for 24 h. The mixture was partitioned between dichloromethane (15 ml) and water (20 ml). The aqueous extract was washed with dichloromethane (15 ml) and the combined organic extracts concentrated to give the title compound as a colourless gum (0.150 g).
Reaction SMILES: C([S:9][CH2:10][CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH:15]1[C:26]([OH:28])=[O:27])=[O:13])(=O)C1C=CC=CC=1.C(SC(C)C(N1C2C(=CC=CC=2)CCC1C(O)=O)=O)(=O)C1C=CC=CC=1>>[SH:9][CH2:10][CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH:15]1[C:26]([OH:28])=[O:27])=[O:13]
Reactant: COc1ccc2c(c1)CCC(C(=O)O)N2C(=O)CCSC(=O)c1ccccc1
Agent: CC(SC(=O)c1ccccc1)C(=O)N1c2ccccc2CCC1C(=O)O
Product: COc1ccc2c(c1)CCC(C(=O)O)N2C(=O)CCS

Procedure:
By substituting (±) 1-(3-benzoylthio-1-oxopropyl)-1,2,3,4-tetrahydro-6-methoxy-2-quinolinecarboxylic acid for the (±) 1-(2-benzoylthio-1-oxopropyl)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid in the procedure of Example 21, (±)-1,2,3,4-tetrahydro-1-(3-mercapto-1-oxopropyl)-6-methoxy-2-quinolinecarboxylic acid was obtained as an oily residue. The dicyclohexylamine salt was prepared by the addition of dicyclohexylamine to a solution of the free acid in ether. The (±)-1,2,3,4-tetrahydro-1-(3-mercapto-1-oxopropyl)-6-methoxy-2-quinolinecarboxylic acid dicyclohexylamine salt thus obtained was recrystallized from acetonitrile; yield 0.9 g, m.p. 195°-197°.
Reaction SMILES: [CH2:1]([N:8]([CH2:43][CH:44](OCC)OCC)[C:9]([CH:11]([NH:24][C:25](=[O:42])[CH2:26][CH:27]([NH:31][C:32]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:28][CH:29]=[CH2:30])[CH2:12][C:13]1[CH:18]=[CH:17]C(OC(C)(C)C)=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:51]([OH:53])=O>>[CH2:35]([NH:34][C:32]([N:31]1[CH:27]([CH2:28][CH:29]=[CH2:30])[CH2:26][C:25](=[O:42])[N:24]2[CH:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:51]([OH:53])=[CH:17][CH:18]=3)[C:9](=[O:10])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:43][CH:44]12)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1ccccc1)CC(OCC)OCC)NC(=O)NCc1ccccc1
Reactant: O=CO
Product: C=CCC1CC(=O)N2C(Cc3ccc(O)cc3)C(=O)N(Cc3ccccc3)CC2N1C(=O)NCc1ccccc1
Yield: 38 %

Procedure:
A solution of crude 3-(3-Benzyl-ureido)-hex-5-enoic acid [1-[benzyl-(2,2-diethoxy-ethyl)-carbamoyl]-2-(4-tert-butoxy-phenyl)-ethyl]-amide (2.9 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and Hexane to give the 2-Allyl-8-benzyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic acid benzylamide (1.18 g, 3 step yield: 38%). 1H NMR (CDCl3, 300 MHz) δ 7.5˜7.26 (m, 5H), 7.25 (d, J=7.01, 2H), 6.85 (m, 5H), 6.55 (d, J=8.76, 2H), 5.7 (m, 1H), 5.3 (t, J=4.7, 1H), 5.05 (d, J=10.75, 1H), 5.0 (d, J=18.54, 1H), 4.87 (d, J=14.51, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H, OH), 3.5˜3.3 (m, 2H), 3.25˜3.1 (m, 2H), 2.6˜2.4 (m, 2H), 2.2 (t, J=7.2, 2H) MS ESI 539 (M+H), 561 (M+Na).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=[C:4]([N:18]2C(C)=CC=C2C)[CH:3]=1.Cl.NO.[OH-].[K+]>C(O)C.O>[NH2:18][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:5]=1
Reactant: Cc1cc(CCCCc2ccccc2)nc(-n2c(C)ccc2C)c1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)nc(CCCCc2ccccc2)c1

Procedure:
By analogy to Example 56, Step B, 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(4-phenylbutyl)pyridine was treated with 4,6 equivalents of hydroxylamine hydrochloride and 2.8 equivalents of potassium hydroxide in refluxing ethanol/water to yield 2-amino-4-methyl-6-(4-phenylbutyl)pyridine as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@H:4]([CH2:33][CH2:34][S:35][CH3:36])[NH:5][C:6](=[O:32])[CH2:7][N:8]([CH2:20][C@@H:21]([NH:26][CH2:27][C@@H:28]([NH2:31])[CH2:29][SH:30])[C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:9][C:10]1[CH:11]=N[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[C:38](C(O)=O)(F)(F)F>>[NH2:31][C@@H:28]([CH2:29][SH:30])[CH2:27][NH:26][C@@H:21]([C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:20][N:8]([CH2:9][C:10]1[C:19]2[C:16](=[CH:15][CH:14]=[CH:13][CH:18]=2)[CH:17]=[CH:38][CH:11]=1)[CH2:7][C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:37])[CH2:33][CH2:34][S:35][CH3:36])=[O:32]
Reactant: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cnc2ccccc2c1)NC[C@@H](N)CS
Reactant: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)O)Cc1cccc2ccccc12)NC[C@@H](N)CS

Procedure:
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-(3-quinolylmethyl)-glycyl methionine methyl ester Anal. calculated for C27H43N5O3S2. 3.85 CF3CO2H: C, 42.15; H, 4.78; N, 7.08; Found: C, 41.96; H, 5.01; N, 7.48.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.CCO>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(-c2nnnn2C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(-c2nnnn2C)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
10% Pd on carbon (7 mg, 0.268 mmol) was added to a solution of 5-(3-methoxy-4-nitrophenyl)-1-methyl-1H-tetrazole (Preparation 195, 63 mg, 0.268 mmol) in EtOAc (1.2 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. EtOH (0.5 mL) was added and the reaction mixture was stirred for 1.5 hours. The reaction was filtered and the filtrate concentrated in vacuo to afford the title product as a white solid (52 mg, 95%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]([CH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=O)=[O:14])[CH3:11].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:10]([O:12][C:13]([C:15]1[CH2:19][CH2:18][CH2:17][C:16]=1[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)=[O:14])[CH3:11]
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)C1CCCC1=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(NCc2ccc(F)cc2)CCC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4-Fluorobenzylamine (12.1 g, 97.5 mmol) was added to a solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (15.25 g, 97.6 mmol) in toluene (225 mL) at 23° C. Glacial acetic acid (6.15 mL, 107 mmol) was then added, producing a large amount of white solid. The reaction mixture was heated to 70° C. in an oil bath, whereupon most of the solids dissolved. After stirring for 2 h at 70° C., a Dean-Stark apparatus and reflux condenser were fitted to the reaction flask and approximately 40 mL of liquid (predominantly toluene) was removed by distillation over 45 min (oil bath temperature=145° C.). The mixture was allowed to cool to 23° C. and was used in the next step. A small aliquot of the crude reaction mixture was concentrated under reduced pressure to afford the desired product, 2-(4-fluoro-benzylamino)-cyclopent-1-enecarboxylic acid ethyl ester as an orange oil: 1H NMR (CDCl3) δ: 1.28 (3H, t, J=7.5), 1.79-1.86 (2H, m), 2.51-2.56 (4H, m), 4.15 (2H, q, J=6.9), 4.34-4.36 (2H, m), 6.98-7.03 (2H, m), 7.19-7.23 (2H, m), 7.73 (1H, bs).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH:4]=[C:5]1[CH2:14][CH2:13][C:8]2(OCC[O:9]2)[CH2:7][CH2:6]1.Cl.C(Cl)(Cl)Cl.O>O1CCCC1>[CH3:1][CH:2]([CH3:15])[CH2:3][CH:4]=[C:5]1[CH2:6][CH2:7][C:8](=[O:9])[CH2:13][CH2:14]1
Reactant: CC(C)CC=C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)CC=C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
In 50 ml of tetrahydrofuran is dissolved 10.0 g of 8-(3-methylbutylidene)-1,4-dioxaspiro[4.5]decane. After adding 50 ml of 6 mol/L hydrochloric acid, the mixture thus obtained is stirred at ambient temperature for one hour. Chloroform and water are added to the reaction mixture and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=98:2) to obtain 6.6 g of 4-(3-methylbutylidene)-1-cyclohexanone as a colorless oily product.
Reaction SMILES: [CH2:1]([O:6][CH:7]([CH3:12])[CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH3:5].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].O>N1C=CC=CC=1>[C:19]1([CH3:20])[CH:21]=[CH:22][C:16]([S:13]([O:11][CH2:10][CH2:9][CH2:8][CH:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH3:12])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCOC(C)CCCO
Solvent: O
Solvent: c1ccncc1
Product: CCCCCOC(C)CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
17 g of 4-pentyloxypentanol was dissolved in 60 ml of pyridine, and under stirring, 22.4 g of tosyl chloride was added at below 10° C. in 40 min. The mixture was raised to 25° C. and stirred for 3 hours. After the reaction, cold water was added, and the product was extracted with ether, followed by successive washing with 5% hydrochloric acid and water and drying with anhydrous MgSO4. The solvent was distilled off to obtain 31.9 g of 4-pentyloxypentyl p-toluenesulfonate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[I:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=1[OH:41]>>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[O:41][C:32]1[CH:33]=[CH:34][C:35]([C:37]([F:38])([F:39])[F:40])=[CH:36][C:31]=1[I:30])#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: Oc1ccc(C(F)(F)F)cc1I
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3I)c(C#N)c2)c(OC)c1

Procedure:
Prepared according to Method O (below) at room temperature using 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 68) and 2-iodo-4-(trifluoromethyl)phenol (Preparation 224). The title compound was isolated as a white solid.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])([O:3][CH3:4])=[O:2].S(Cl)(Cl)=O.[Br:16]N1C(=O)CCC1=O>>[Br:16][CH:8]([CH2:7][CH2:6][CH2:5][C:1]([O:3][CH3:4])=[O:2])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)CCCCC(=O)O
Reactant: O=C1CCC(=O)N1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCC(Br)C(=O)O

Procedure:
5-Carbomethoxypentanoic acid (12), wherein alk is methyl, was reacted with thionyl chloride and then N-bromosuccinimide (NBS) followed by base hydrolysis to give 2-bromo-5-carbomethoxypentanoic acid (13). Compound (13) was reacted with methyl-3-mercaptopropionate (m=1, R1 '=H and R2 '=OCH3) to yield 5-carbomethoxy-2-[(2-carbomethoxyethyl)thio]-pentanoic acid (14). Compound (14) reacted first with diborane and then with dimethylsulfoxide and trifluoroacetic anhydride to afford 5-carbomethoxy-2-[(2-carbomethoxyethyl)thio]-pentanal (15). Compound (15) was reacted under Wittig conditions with tridecyltriphenylphosphonium ylid to yield methyl-5-[(2-carbomethoxyethyl)thio]-6(Z)-nonadecenoate (16) which was saponified to afford a compound of the formula (IV) wherein m is 1, R1 is hydrogen, and R2 is hydroxyl.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]3=[N:10][C:9]=2[CH3:23])[CH:3]=1.[I-].[C:25]1([Zn+])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:18]([CH:17]([C:16]1[C:11]2[N:12]([C:8]([C:4]3[CH:3]=[C:2]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[S:6][C:5]=3[CH3:7])=[C:9]([CH3:23])[N:10]=2)[N:13]=[C:14]([CH3:22])[CH:15]=1)[CH2:20][CH3:21])[CH3:19]
Reactant: [Zn+]c1ccccc1
Reactant: CCC(CC)c1cc(C)nn2c(-c3cc(Br)sc3C)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [I-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3cc(-c4ccccc4)sc3C)c(C)nc12
Yield: 41 %

Procedure:
Using a procedure similar to Example 32, from 3-(5-bromo-2-methyl-thiophen-3-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.20 g, 0.51 mmol) and PdCl2(dppf) (0.019 g, 0.025 mmol) and 0.5 M solution of phenylzinc iodide in THF (2.0 mL, 1.02 mmol). The residue is purified by column chromatography (0-10% EtOAc/hexane gradient) and is chromatographed (50×250 C18 Symmetry column, 30-70% water: 0.1% TFA/ACN: 0.1% TFA gradient) furnish the title compound (0.081 g, 0.21 mmol, 41%). 1H NMR (CDCl3), δ 0.90 (t, J=7.5 Hz, 6H), 1.75-1.94 (m, 4H), 2.40 (s, 3H), 2.48 (s, 3H), 2.52 (s, 3H), 3.32-3.41 (m, 1H), 6.66 (s, 1H), 7.23-7.30 (m, 1H), 7.32 (s, 1H), 7.34-7.41 (m, 2H), 7.57-7.63 (m, 2H). LC/MS (m/z): calcd. for C24H27N3S (M+H)+: 390.2; found: 390.2.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[N:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[C:6]([CH3:13])[N:5]=1)[CH3:2].[CH2:16]([O:23][C:24]1[C:33]([CH3:34])=[CH:32][C:27]([C:28]([NH:30]O)=[NH:29])=[CH:26][C:25]=1[CH2:35][CH3:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.O1CCOCC1>[CH2:16]([O:23][C:24]1[C:33]([CH3:34])=[CH:32][C:27]([C:28]2[N:30]=[C:10]([C:8]3[CH:7]=[C:6]([CH3:13])[N:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH2:14][CH3:15])[N:9]=3)[O:12][N:29]=2)=[CH:26][C:25]=1[CH2:35][CH3:36])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCN(CC)c1nc(C)cc(C(=O)O)n1
Reactant: CCc1cc(C(=N)NO)cc(C)c1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OCc1ccccc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
To a solution of 2-diethylamino-6-methyl-pyrimidine-4-carboxylic acid (5.56 g, 27.0 mmol mmol) and 4-benzyloxy-3-ethyl-N-hydroxy-5-methyl-benzamidine (7.69 g, 27 mmol) in DMF (80 mL), EDC (6.74 g, 35.2 mmol) and HOBt (4.75 g, 35.2 mmol) are added at 0° C. Stirring is continued at rt for 2 h and the reaction mixture is then diluted with EtOAc and washed with sat. aq. NaHCO3. The aq. phase is extracted with EtOAc and the combined org. extracts are dried over MgSO4, filtered and evaporated to give a brown oil. The oil is dissolved in dioxane (30 mL) and the solution is heated to 85° C. for 18 h. The reaction mixture is evaporated and purified by CC (eluting with Heptane/EA 9:1) to afford {4-[3-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyrimidin-2-yl}-diethyl-amine as a yellow oil (4.3 g, 35%); LC-MS: tR=1.35; [M+H]+=458.48.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][O:2]1.Br[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[C:13]2[NH:20][C:21]([NH:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)=[O:22]>>[CH2:1]1[CH:5]2[CH2:6][N:7]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[C:13]4[NH:20][C:21]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)=[O:22])[CH2:8][CH:4]2[CH2:3][O:2]1
Reactant: O=C(Nc1cnccn1)Nc1ccnc2ccc(Br)cc12
Reactant: C1NCC2COCC12
Product: O=C(Nc1cnccn1)Nc1ccnc2ccc(N3CC4COCC4C3)cc12

Procedure:
The compound was prepared by the method described for Example 1 using hexahydro-furo[3,4-c]pyrrole and 1-(6-bromoquinolin-4-yl)-3-(pyrazin-2-yl)urea as starting compounds.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:15]=1)[CH3:10].O>ClCCl>[Br:1][C:13]1[S:12][C:11]([CH2:9][CH3:10])=[N:15][C:14]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1
Reactant: CCc1nc(-c2ccc(F)cc2)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: CCc1nc(-c2ccc(F)cc2)c(Br)s1
Reaction time: 2 h

Procedure:
At room temperature, 1.72 g (9.64 mmol) of N-bromosuccinimide are added a little at a time to a solution of 2.00 g (9.64 mmol) of 2-ethyl-4-(4-fluorophenyl)-1,3-thiazole in 40 ml of dichloromethane. After 2 h, 50 ml of water are added to the reaction mixture, and the organic phase is separated off, washed with saturated NHCO3 solution, dried over MgSO4 and concentrated under reduced pressure. This gives 2.47 g (85%) of the desired product; 1H-NMR(DMSO-d6) δ: 7.92 (m, 2H), 7.32 (m, 2H), 3.02 (q, 2H), 1.31 (t, 3H).
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH2:8]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH:21]=[O:22])=[CH:16][CH:15]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(Cl)(Cl)Cl.CCCCCC.C(OCC)(=O)C>C(O)(=O)C>[CH2:8]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:21]=2[OH:22])=[CH:16][CH:15]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCc1ccc(C(=O)C=O)cc1
Reactant: CNN=CC(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCCCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 6.4 %

Procedure:
2-Oxopropanal methylhydrazone (16.1 mmol, 1.62 g) and (4-n-hexylphenyl)(oxo)acetaldehyde (16 mmol, 4.57 g) synthesized in Reference Synthetic Example 14 were dissolved in acetic acid (35 mL) and stirred at 100° C. for 6 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1), then by silica gel thin layer chromatography (chloroform) and by silica gel thin layer chromatography (n-hexane/ethyl acetate=7/2) to give the desired product as a brown solid (308 mg, yield 6%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[CH:32]([OH:59])[CH:33]([NH:36][C:37](=[O:58])[C@@H:38]([CH:48]([F:57])[C:49]([N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)=[O:50])[CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:34][CH3:35].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[C:32]([CH:33]([NH:36][C:37](=[O:58])[C@@H:38]([CH:48]([F:57])[C:49]([N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)=[O:50])[CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:34][CH3:35])=[O:59]
Reactant: CCC(NC(=O)[C@H](CCCc1ccccc1)C(F)C(=O)N1CCOCC1)C(O)c1nc2ccccc2o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCC(NC(=O)[C@H](CCCc1ccccc1)C(F)C(=O)N1CCOCC1)C(=O)c1nc2ccccc2o1
Reaction time: 3 h

Procedure:
Dess-Martin Periodinane (15 wt % in DCM, 0.15 mmol, 424 mg) was added to a solution of (S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid[1-(benzoxazol-2-yl-hydroxy-methyl)-propyl]-amide (0.074 mmol) in dry methylene chloride and stirred for three hours. The reaction was quenched with Na2S2O3 (0.37 mmol, 56 mg) in aqueous NaHCO3, the organic layer was separated, the aqueous extracted once more with methylene chloride, the organic extracts were dried over Na2SO4 and concentrated under reduced pressure. Column chromatography on silica eluting with a mixture of ethyl acetate and methylene chloride gave the title compound as a white solide (30 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2N(C(=O)C(C)C)C(C3C=CC(Cl)=CC=3)C(C3C=CC(Cl)=CC=3)[N:17]=2)=[CH:9][CH:8]=1)[CH3:2].OC1C=CC(C#N)=CC=1.BrCC(OCC)=O>>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:37])=[CH:8][CH:9]=1)#[N:17]
Reactant: CCOC(=O)COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)C(C)C)cc1
Agent: CCOC(=O)CBr
Agent: N#Cc1ccc(O)cc1
Product: CCOC(=O)COc1ccc(C#N)cc1

Procedure:
{4-[4,5-Bis-(4-chloro-phenyl)-1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl]-phenoxy}-acetic acid ethyl ester. HR-MS (ES, m/z) calculated for C29H29N2O4Cl2[(M+H)+]539.1499, observed 539.1506. The starting ethyl (4-cyano-phenoxy)-acetate was prepared from 4-hydroxy-benzonitrile and ethyl bromoacetate as described in Kirkiacharian, S.; Goma, J. R. et al. Ann. Pharm. Fr. 1989, 47, 16-23.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:5]=2[CH:6]=1.C(O)C.C([O-])=O.[NH4+]>[Pd].C1COCC1>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:5]=2[CH:6]=1
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2o1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2cc(N)ccc2o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 35° C. mixture of 50 g of 2-methyl-5-nitrobenzofuran, ethanol (250 mL), THF (250 mL) and wet 10% Pd/C (4 g) was added ammonium formate (53.4 g, 0.85 mol) over 50 min. After an additional 4 h, the reaction was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was taken up in methyl t-butyl ether. This mixture was filtered, concentrated and dried to provide 2-methyl-5-benzofuranamine which was converted to its hydrochloride salt or its oxalate salt. The oxalate was prepared as follows: To a solution of 2-methyl-5-benzofuranamine in TBME (415 mL) was added a solution of oxalic acid (25.4 g) in methanol (80 mL) dropwise. The precipitate was stirred for 2 h, collected, washed with methanol/TBME and dried to provide 2-methyl-5-benzofuranamine oxalate.