Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CN([CH:23]=[O:24])C.Cl>C1COCC1>[CH2:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH:23]=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCCc1ccsc1Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccsc1C=O
Temperature: 0 °C
Yield: 54.6 %

Procedure:
Magnesium (0.63 g; 25.8 mmol) and anhydrous THF (25 ml) were put into a flask, and 2-bromo-3-dodecylthiophene (7.78 g; 23.5 mmol) was added dropwise thereto. After starting Grignard reaction, the solution was refluxed until magnesium was almost removed. The purified DMF (3.65 g; ˜4 ml; 50 mmol) was slowly added dropwise to the reaction solution. The reaction solution was refluxed for one day, and cooled to 0° C., and 5% HCl (100 ml) was added thereto to terminate the reaction. An organic material layer was extracted from ethyl ether, and the obtained organic material layer was washed sequentially with NaHCO3, a saturated NaCl solution, and water. The residual moisture was removed over anhydrous magnesium sulfate. After removing the solvent, the residue was column separated using silica gel (ethyl acetate/hexane=1/9) to obtain 3-dodecylthiophene-2-carboaldehyde (3.6 g; 55%).
Reaction SMILES: [CH2:1]([CH:5]([C:14]#[N:15])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[CH2:2][CH2:3][CH3:4].[CH2:16]=[O:17].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1>N1C=CC=CC=1>[C:14]([C:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:16][OH:17])#[N:15]
Reactant: C=O
Reactant: CCCCC(C#N)c1ccc(Cl)cc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCCC(C#N)(CO)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice cold stirred solution of α-n-butyl-2,4 -dichlorobenzyl cyanide (5g., 0.02 mole) in 20 ml. of pyridine containing a suspension of paraformaldehyde (2.4g., 0.08 mole is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 16 hours. The reaction mixture poured into 300 ml. of water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 5.6g. of a thick oil, which is identified by nmr.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=O.[C:18](N1C=CN=C1)([N:20]1C=CN=C1)=O.C(N(CC)CC)C.Cl.CN>CN(C=O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:15]([NH:20][CH3:18])=[O:17]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(-n2ncc(C(=O)O)c2Cl)cc1
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccc(OC)cc2)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.5 %

Procedure:
To a solution of 1.2 g of 5-chloro-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid in 150 ml DMF was added 1.1 g of carbonyldiimidazole and the mixture was allowed to stir at room temperature for 20 minutes. One gram of triethylamine and 0.6 g of methylamine hydrochloride were next added to the reaction mixture and the solution was stirred at room temperature for 20 hours. The mixture was poured into ice water and extracted with ethyl acetate. The organic phase was separated and washed with water, dried, and concentrated under vacuum to dryness. The residue was recrystallized from toluene/hexane to afford 650 mg of 5-chloro-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-4-carboxamide. Yield 71%. mp=144°-146° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH2:17][CH2:18][CH:19]=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])=[O:34])[CH:27]=[CH:26]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH2:17][CH2:18][CH2:19][N:39]3[CH2:38][CH2:37][N:36]([S:33]([C:28]4[CH:27]=[CH:26][C:25]5[C:30](=[CH:31][CH:32]=[C:23]([Cl:22])[CH:24]=5)[CH:29]=4)(=[O:35])=[O:34])[CH2:41][CH2:40]3)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(CCC=O)cc2C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCc2sc(CCCN3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1

Procedure:
In a similar manner to Referential Example 47 except for the use of 3-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propanal, 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([N:9]=[CH:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[N:3]=1.[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1)[CH3:19]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([C:19]#[C:18][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][CH:21]=2)=[CH:6][N:5]=[C:4]([N:9]=[CH:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[N:3]=1
Reactant: CC(C)N(C=Nc1ncc(I)c(Cl)n1)C(C)C
Reactant: C#Cc1ccc(CC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCc1ccc(C#Cc2cnc(N=CN(C(C)C)C(C)C)nc2Cl)cc1
Yield: 63.7 %

Procedure:
A mixture of 6.3 g of 4-chloro-2-diisopropylaminomethyleneamino-5-iodopyrimidine, 33 mL of triethylamine, 2.43 g of 4-ethyl-1-ethynylbenzene, 0.304 g of dichlorobis(triphenyl)phosphine palladium II and 0.21 g copper iodide was magnetically stirred at reflux temperature for 1.5 hrs. The mixture was filtered and the filtrate evaporated in vacuo. Both the precipitate and the evaporated filtrate were dissolved in dichloromethane and washed with water, dried over sodium sulfate, filtered and evaporated. The residues were dissolved in 1:1 dichloromethane-hexanes and separately purified by column chromatography. After initial elution with 1:1 dichloromethane-hexanes, the product was obtained by elution with dichloromethane and 50% ethyl acetate-dichloromethane. Evaporation of the eluates gave 4.04 g of 4-chloro-2-diisopropylaminomethyleneamino-5-(4-ethylphenylethynyl)pyrimidine as a thick amber syrup.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)(=[O:24])=[O:23]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: CCOC(=O)c1sc(N)nc1C
Product: CCOC(=O)c1sc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)nc1C

Procedure:
This compound was prepared from ethyl 2-amino-4-methylthiazole-5-carboxylate and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described for EXAMPLE 30. Yield 254 mg, 62%: 1H NMR (DMSO) δ 7.64 (d, 1H), 7.53 (d, 1H), 4.22 (q, 2H), 2.67 (s, 3H), 2.41 (s, 3H), 1.25 (t, 3H); MS-ES (neg) In/z 407.1.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])[N:8]=1.[CH3:14][N:15]1[CH:17](SC)[CH:16]1[N+:20]([O-:22])=[O:21]>O>[CH3:14][NH:15][C:17]([NH:13][CH2:12][CH2:11][S:10][CH2:9][C:7]1[N:8]=[C:4]([CH2:3][NH:2][CH3:1])[S:5][CH:6]=1)=[CH:16][N+:20]([O-:22])=[O:21]
Reactant: CSC1C([N+](=O)[O-])N1C
Reactant: CNCc1nc(CSCCN)cs1
Solvent: O
Product: CNCc1nc(CSCCNC(=C[N+](=O)[O-])NC)cs1

Procedure:
Following the above procedure, 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine and N-methyl-1-methylthio-2-nitroethyleneamine were reacted in water solution. The reaction was worked up and the product isolated by the above procedure to yield N-methyl-N'-2-(2-methylaminomethyl-4-thiazolylmethylthio)ethyl 2-nitro-1,1-ethenediamine melting at 105°-107° C. after recrystallization from acetonitrile followed by recrystallization from ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[CH:3]=1.Br[CH:13]([CH:16]=O)[CH:14]=[O:15].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[S:10][C:13]([CH:14]=[O:15])=[CH:16][N:11]=2)[CH:3]=1
Reactant: Cc1ccnc(NC(N)=S)c1
Reactant: O=CC(Br)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccnc(Nc2ncc(C=O)s2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
A mixture of (4-methylpyridin-2-yl)-thiourea (334 mg, 2 mmol), 2-bromomalonaldehyde (302 mg, 2 mmol) and sodium acetate (250 mg, 3.0 mmol) in acetic acid (5 mL) was stirred at 100° C. for 3 h. The mixture was cooled to RT and diluted with water and the precipitate formed was collected, washed with water and dried to afford 2-(4-methylpyridin-2-ylamino)-thiazole-5-carbaldehyde (350 mg, 80%). MS m/z 220 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:26][C:27](=[N:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:42]=1)OC1C=CC=CC=1)#[N:25]>>[C:24]([NH:26][C:27]([NH:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:21])=[N:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]2[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]2)[CH:42]=1)#[N:25]
Reactant: N#CNC(=NCCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: CN(CCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCCNC(=NCCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.50 g (1.6 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[4-[3-(piperidinomethyl)phenoxy]butyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=629 ([M+H]+, 18), 229 (98), 109 (100); IR (KBr): 2164 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from isopropanol/ether; m.p.: 102°-105° C. (isopropanol/ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[N:33]=[C:32]([NH2:34])[C:31]([N+:35]([O-])=O)=[CH:30][CH:29]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.S1C=CC=C1.N.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[N:33]=[C:32]([NH2:34])[C:31]([NH2:35])=[CH:30][CH:29]=3)[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Nc1nc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: c1ccsc1
Solvent: CO
Product: Nc1ccc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)nc1N
Yield: 94 %

Procedure:
A mixture of 10 parts of N6 -[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-3-nitro-2,6-pyridinediamine, 3 parts of a solution of thiophene in methanol 4% and 400 parts of methanol, saurated with ammonia, was hydrogenated at normal pressure and at room temperature with 4 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 9 parts (94%) of N6 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-ethyl]-2,3,6-pyridinetriamine as a residue (intermediate 154).
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6](=[O:22])[N:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:8]=1)(=O)[NH2:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C:4]1[NH:5][C:6](=[O:22])[N:7]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:13][CH2:14]2)[CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(N)=O)[nH]c2=O)CC1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C#N)[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
tert-Butyl 4-(4-carbamoyl-2-oxo-2,3-dihydroimidazol-1-yl)piperidine-1-carboxylate (175 mg, 0.564 mmol) was suspended in pyridine (3.0 mL). Phosphorus oxychloride (53 μL, 0.569 mmol) was added to the mixture drop-wise. Mixture stirred at ambient temperature for 30 minutes. Reaction was quenched with the drop-wise addition of water. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Material was washed successively with 1N hydrochloric acid brine and the aqueous phases were discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as white solid in 29% yield. MS (M−H)−=291.1.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:13][C:14]1[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=1>CO>[CH:1]1([NH:4][CH2:13][C:14]2[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CC(=O)c1cccc(CBr)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)c1cccc(CNC2CC2)c1
Yield: 34.9 %

Procedure:
Cyclopropylamine (5.71 g; 10.0 mmol) and triethylamine (1.01 g; 10.0 mmol) were dissolved in methanol (50 ml). While the mixture was stirred in an ice bath, 3′-bromomethylacetophenone (2.13 g; 10.0 mmol) in methanol (10 ml) was added dropwise. The mixture was removed from the ice bath, and stirred for 18 hours at room temperature. The solvent was evaporated under reduced pressure, and the residue was taken up in 2N hydrochloric acid (100 ml), followed by extraction with diethyl ether (100 ml). The aqueous layer was alkalinized with aqueous sodium hydroxide solution, and the mixture was extracted with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1→0:1), to thereby yield 0.66 g of the target compound as yellow oily matter (yield: 34.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C:19]3[N:20]=[CH:21][N:22]([C:24]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=3)([OH:18])[CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[CH:3]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[OH:18][C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:43](=[O:45])[CH3:44])[CH:7]=[CH:6][N:5]=2)=[CH:13][CH:12]=1)([C:19]1[N:20]=[CH:21][N:22]([C:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:23]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C(O)(c1ccc(-c2cc(N)ccn2)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccnc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 1-[4-(4-amino-2-pyridyl)phenyl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.40 g), acetic anhydride (0.46 ml), triethylamine (0.71 ml) and p-dimethylaminopyridine (20 mg) was stirred in THF (20 ml) at 60° C. for 16 h. The solvent was evaporated and ethyl acetate and water were added to the residue for partitioning. The organic layer was washed with aqueous sodium hydrogen carbonate and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was dissolved in a mixture of acetonitrile (10 ml)—water (10 ml) and tetrabutylammonium bromide (13 mg) was added. The mixture was stirred at room temperature for 10 h. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer was combined, and the mixture was dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chomatography (eluent; hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate gave the title compound (630 mg) as colorless powder crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31].O.[OH-].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[N:15]([C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:31])[C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)cc2F)NC(OC)=N1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)cc2F)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
To a well stirred solution of 5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl)pyrimidine (22.5 g, 59.3 mmol) and 4-(N,N-dimethylamino)pyridine (9.3 g, 75.8 mmol) in CH2Cl2 (200 mL) was added powdered 4-nitrophenyl chloroformate (15.3 g, 75.8 mmol) at 0° C. The reaction mixture was stirred for 12 h at room temperature and then water (50 mL) was added. The pH of the aqueous layer was adjusted to 10-11 by the addition of 6 N sodium hydroxide. The dichloromethane layer was separated and dried (Na2SO4). Solvent was evaporated in vacuo and the residue was purified by column chromatography (SiO2, dichloromethane/hexane, 20%-50%) to yield the product as a viscous oil (32.0 g, 98%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)[NH:9][CH:8]([C:4]2[CH:3]=[C:2]([NH:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27])[CH:7]=[CH:6][CH:5]=2)[CH2:17]1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(C(F)(F)F)cc21
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1cccc(C2CC(C)(C)c3cc(C(F)(F)F)ccc3N2)c1)C(=O)O
Temperature: 25 °C
Yield: 21.1 %

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (384.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (85.6 mg, 21.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 407.1.
Reaction SMILES: [CH2:1]([S:7][S:8][CH2:9][C@H:10]([NH2:14])[C:11]([OH:13])=[O:12])[C@H:2]([NH2:6])[C:3]([OH:5])=[O:4].[CH3:15][C:16]([S:21][CH3:22])([CH3:20])[C:17](Cl)=[O:18]>[OH-].[Na+]>[CH3:15][C:16]([S:21][CH3:22])([CH3:20])[C:17]([NH:6][C@H:2]([C:3]([OH:5])=[O:4])[CH2:1][S:7][S:8][CH2:9][C@H:10]([NH:14][C:17](=[O:18])[C:16]([S:21][CH3:22])([CH3:20])[CH3:15])[C:11]([OH:13])=[O:12])=[O:18]
Reactant: CSC(C)(C)C(=O)Cl
Reactant: N[C@@H](CSSC[C@H](N)C(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CSC(C)(C)C(=O)N[C@@H](CSSC[C@H](NC(=O)C(C)(C)SC)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.6 %

Procedure:
To a stirred solution of 3.1 g (13 mM) of L-cystine in 105 ml of 0.5 N sodium hydroxide, 4.0 g (26 mM) of 2-methyl-2-(methylthio)propanoyl chloride is added dropwise at 5°-10° C. After the addition the reaction mixture is stirred for 45 minutes at the same temperature and for additional 20 minutes at the room temperature. The reaction mixture is washed with ether, acidified with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water and dried. Ehtyl acetate is distillated off and the residue is purified by silica gel column chromatography to give 5.1 g (83%) of the titled compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1.[OH:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1>O1CCCC1>[CH3:39][N:36]1[CH2:37][CH2:38][CH:33]([O:32][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[CH2:34][CH2:35]1.[CH3:39][N:36]1[CH2:37][CH2:38][CH:33]([O:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[CH2:34][CH2:35]1
Reactant: Oc1cccnc1
Reactant: CN1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.4 %

Procedure:
Under a nitrogen atmosphere, a solution of diethyl azodicarboxylate (6.80 g. 39.0 mmol) in tetrahydrofuran (THF) (25 mL) was added drop-wise at ambient temperature to a stirring solution of triphenylphosphine (10.23 g, 390 mmol) in THF (100 mL). The resulting solution was allowed to stir at ambient temperature for 30 min. 4-Hydroxy-1-methylpiperidine (3.05 g, 26.5 mmol) and 3-hydroxypyridine (3.71 g, 39.0 mmol) were added, and the reaction mixture was stirred at ambient temperature for 18 h. The solution was concentrated by rotary evaporation, and the resulting residue was dissolved in CHCl3 (100 mL). The suspension was cooled in an ice-water bath, and a solution of 1 M HCl (75 mL) was added with stirring. The aqueous phase was separated. The organic phase was extracted with water (3×75 mL). The combined aqueous extracts were cooled in an ice-water bath, basified with 1 M NaOH solution (125 mL) to pH˜11 and extracted with CHCl3 (6×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation. The crude product was dissolved in CHCl3 (75 mL), and the CHCl3 solution was extracted with 1 M NaOH solution (4×25 mL) to remove residual 3-hydroxypyridine. The CHCl3 phase was separated, and the combined NaOH layers were back extracted with CHCl3 (3×50 mL). All CHCl3 extracts were combined, dried (Na2SO4), filtered, and concentrated by rotary evaporation. The resulting oil was purified by vacuum distillation using a test-tube distillation apparatus, collecting the fraction with bp 83-93° C. at 0.10-0.075 mm Hg. Further purification by a second vacuum distillation yielded 120 mg (2.4%) of a colorless oil, bp 72-75° C. at 0.75 mm Hg. The compound exhibits a Ki of 4897 nM.