Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[C:2]([O:7][CH2:8][CH3:9])(=[O:6])[C:3]([O-:5])=O.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1OC.[N+]([C:27]1C=CC=CC=1)([O-])=O>>[CH3:27][C:16]1[CH:17]=[C:18]([F:21])[C:19]([C:3](=[O:5])[C:2]([O:7][CH2:8][CH3:9])=[O:6])=[CH:20][C:15]=1[Cl:14]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CCOC(=O)C(=O)[O-]
Reactant: COc1cc(F)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)C(=O)c1cc(Cl)c(C)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under ice-cooling, monoethyl oxalate monochloride (10.5 g) is added dropwise to a solution of aluminum chloride (10.5 g) in nitrobenzene (30 ml). To the solution is added dropwise 2-chloro-5-fluoroanisole (84 g). After 30 minutes, the mixture is poured into ice-water and extracted with ether. The extract is washed with dilute hydrochloric acid and dilute aqueous sodium bicarbonate, dried and evaporated to remove the solvent. Recrystallization from a mixture of ether and n-hexane gives ethyl 4-methyl-3-chloro-6-fluorophenylglyoxalate (mp. 84°-85° C.). A mixture of the glyoxalate (5.21 g), ethylene glycol (28 ml), potassium hydroxide (4.5 g) and hydrazine monohydrate (2.85 ml) is heated at 155°-158° C. for 1.5 hours and then at 220° C. for 2 hours and poured into water. The mixture is washed with ether, acidified with hydrochloric acid and extracted with ether. The extract is evaporated. The obtained residue is recrystallized from dichloromethane to give 3-chloro-4-hydroxy-6-fluorophenylacetic acid (mp. 137°-138° C.). A part of the acid (0.615 g) is suspended in dichloromethane (15 m) and esterified with diphenyldiazomethane to give crystals of the corresponding diphenylmethyl ester (mp. 121°-122° C.).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[N:23]=[C:22]([C:24]([O:26]CC)=O)[O:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:32][CH2:31]1.C[Al](C)C>ClCCCl>[NH3:4].[CH:1]1([N:4]([CH2:18][C:19]2[N:23]=[C:22]([C:24]([N:40]3[CH2:39][CH2:38][N:37]([CH2:36][CH:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)[CH2:42][CH2:41]3)=[O:26])[O:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: CCOC(=O)c1nc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)no1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2noc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)n2)C2CC2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using ethyl 3-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,2,4-oxadiazole-5-carboxylate (30 mg, 0.07 mmol), 1-[(1-methylpiperidin-4-yl)methyl]piperazine (31 mg, 0.14 mmol) and trimethylaluminium (2 M in toluene, 0.07 mL) in DCE (5 mL). A portion of the crude product was purified using prep method C, then FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: C([OH:5])(C)(C)C.O.CC[C@H]1[C@H]2C[C@H]([C@H](OC3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]([O:41][C@H:42]([C:53]4C=CN=[C:59]5[C:54]=4[CH:55]=[C:56]([O:63]C)[CH:57]=[CH:58]5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[CH2:34]([O:41][C:42]1[CH:53]=[C:54]([C@H:55]([OH:5])[CH2:56][OH:63])[CH:59]=[CH:58][CH:57]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: OC[C@@H](O)c1cccc(OCc2ccccc2)c1
Reaction time: 3.5 h

Procedure:
At 0° C. were combined t-butyl alcohol (150 mL), water (150 mL), and AD-mix-α (42 g). Example 1 (6.4 g, 30 mmol) was added and stirred for 3.5 hours. The reaction was refrigerated overnight (15.5 hours), stirred for 8 hours, refrigerated for another 16 hours, and stirred for a further 1 hour. Sodium sulphite (45 g, 36 mmol) was added and the reaction stirred for 2 hours at room temperature. The mixture was poured into ethyl acetate (300 mL) and the aqueous extracted with ethyl acetate (3×150 mL). The organics were dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (ethyl acetate:heptane 9:1) gave the product as a yellow oil, 30 mmol, 100%.
Reaction SMILES: C(C1N(CC2C=CC(C3C=CC=CC=3C3NN=NN=3)=CC=2)C(C(O)=O)=C(Cl)N=1)CCC.[CH2:32]([C:36]1[N:37]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[C:58]3[N:62]([C:63]([C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=4)([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)[C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)[N:61]=[N:60][N:59]=3)=[CH:48][CH:47]=2)[C:38]([C:42]([OH:44])=[O:43])=[C:39]([Cl:41])[N:40]=1)[CH2:33][CH2:34][CH3:35].C1O[C@@H]2[C@H](O[N+]([O-])=O)CO[C@@H]2[C@H]1O.O[CH2:96][P:97](=[O:104])([O:101][CH2:102][CH3:103])[O:98][CH2:99][CH3:100]>>[CH2:32]([C:36]1[N:37]([CH2:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[C:58]3[N:62]([C:63]([C:70]4[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=4)([C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=4)[C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=4)[N:61]=[N:60][N:59]=3)=[CH:50][CH:51]=2)[C:38]([C:42]([O:44][CH2:96][P:97]([O:101][CH2:102][CH3:103])([O:98][CH2:99][CH3:100])=[O:104])=[O:43])=[C:39]([Cl:41])[N:40]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCOP(=O)(CO)OCC
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: O=[N+]([O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Product: CCCCc1nc(Cl)c(C(=O)OCP(=O)(OCC)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
The title compound was prepared by following example 7, except that the reagent 2-butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid was replaced by 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid, and isosorbide-5-mononitrate was replaced by diethyl (hydroxymethyl)phosphonate. 1H NMR (500 MHz, CDCl3) δ 7.94 (d, J=7.4 Hz, 1H), 7.52 (td, J=7.1, 1.3 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.39-7.34 (m, 4H), 7.28 (t, J=7.8 Hz, 6H), 7.13 (d, J=8.3 Hz, 2H), 6.95 (d, J=8.1 Hz, 6H), 6.80 (d, J=8.1 Hz, 2H), 5.47 (s, 2H), 4.49 (d, J=8.4 Hz, 2H), 4.24-4.16 (m, 4H), 2.53 (t, J=7.8 Hz, 2H), 1.67 (quintet, J=7.7 Hz, 2H), 1.33 (t, J=7.0 Hz, 6H), 1.30 (sextet, J=7.4 Hz, 2H), 0.88 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:11])[CH2:4][CH2:5][CH2:6][C:7]([CH3:10])([OH:9])[CH3:8].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[OH:9][C:7]([CH3:10])([CH3:8])[CH2:6][CH2:5][CH2:4][CH:3]([NH:2][S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19])[CH3:11]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(N)CCCC(C)(C)O
Agent: Cl
Product: CC(CCCC(C)(C)O)NS(=O)(=O)c1ccccc1

Procedure:
In this case, 6-amino-2-methyl-2-heptanol hydrochloride (381.6 g, i.e. 2.1 mol) is neutralized and reacted with 353 g of benzenesulphonyl chloride (2 mol) according to Example 1(a).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:13]([CH2:15][CH3:16])[CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:17][CH:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19]1>>[CH2:23]([N:20]1[CH2:21][CH2:22][CH:18]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([N:13]([CH2:15][CH3:16])[CH3:14])=[CH:4][C:5]=2[O:11][CH3:12])[CH2:19]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: CCN(C)c1cc(OC)c(C(=O)O)cc1Cl
Product: CCN(C)c1cc(OC)c(C(=O)NC2CCN(Cc3ccccc3)C2)cc1Cl

Procedure:
Following the procedure set forth in general method A supra using 1.22 g. of 5-chloro-4-(N-ethyl-N-methylamino)-2-methoxybenzoic acid and 0.97 g. of 3-amino-1-benzyl-pyrrolidine, 1.31 g. of N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-(N-ethyl-N-methylamino)-2-methoxybenzamide was obtained.
Reaction SMILES: [CH2:1]([C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O.C(OC(=O)C)(=O)C>>[CH2:10]1[C:11](=[O:13])[O:16][C:14](=[O:15])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCCCCCCCCC(=O)O1
Yield: 61.2 %

Procedure:
A starting mixture of 23 gms (0.1 mole) of 1,10-decanedicarboxylic acid and 18 gms (0.1 mole) of acetic anhydride was refluxed for 18 hours and then concentrated in vacuo to remove acetic acid and excess acetic anhydride. The residue was dissolved in 300 ml methylene chloride, filtered, washed with ice-cold 5% sodium bicarbonate solution, water, and saturated sodium chloride. After the final separation of the layers, the organic solution was dried over MgSO4, filtered, and evaporated in vacuo to give 20 gms crude product. This was purified by dissolving it in 100 ml boiling methylene chloride, filtering hot, diluting with 200 ml hexanes, and refrigerating. This resulted in 13 gms pure title product m.p. 85°-9°.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][C:16]=2[F:24])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl.ClCC1N=C(NC2C=CC(OCC)=CC=2F)C2C(=CC=CC=2)[N:29]=1.CI.[H-].[Na+]>C1COCC1>[NH2:29][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][C:16]=2[F:24])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOc1ccc(N(C)c2nc(CCl)nc3ccccc23)c(F)c1
Reactant: CCOc1ccc(Nc2nc(CCl)nc3ccccc23)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOc1ccc(N(C)c2nc(CN)nc3ccccc23)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2-Chloromethyl-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-methyl-amine: To (2-chloromethyl-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-amine hydrochloride (531 mg, 1.5 mmol) dissolved in THF at 0° C. was added methyl iodide (1.89 mL, 30.3 mmol) and sodium hydride (363 mg, 15.1 mmol). The reaction was stirred at room temperature for 4 h then warmed to room temperature for 1 h. The reaction was quenched with H2O and diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine, dried (MgSO4), concentrated and purified by gradient MPLC (0-100%, EtOAc/hexanes, SiO2) to give 341 mg of the title compound. 1H NMR (CDCl3) δ 7.83 (d, 1H), 7.59 (t, 1H), 7.31-7.04 (m, 3H), 6.75-6.69 (m, 2H), 4.74 (s, 2H), 4.02 (q, 2H), 3.58 (s, 3H), 1.45 (t, 3H); LC-MS (ESI+; 365 ([M+H]+)).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClCCl.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl>C(N(CC)CC)C>[CH2:21]([O:20][C:18]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:19])[CH3:22]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)n1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.6 %

Procedure:
An argon filled RB flask containing carbazole (0.500 g, 2.99 mmol) at 0° C. was treated with dichloromethane (12.5 mL) and triethylamine (2.5 mL), followed by slow addition of ethyl chloroformate (0.59 mL, 5.98 mmol). The mixture was stirred at ambient temperature for 16 h, poured into 25 mL of 2N HCl, and extracted with chloroform. The organic portion was washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4) and concentrated. The crude product was treated with methanol (4 mL) and filtered. The filtrate was concentrated to give carbazole-9-carboxylic acid ethyl ester (169 mg). Carbazole-9-carboxylic acid ethyl ester (95 mg, 0.39 mmol) was converted to hydroxamic acid by procedure A. Purification by HPLC gave the title compound (19 mg). 1H NMR (400 MHz, CD3CN): δ 9.43 (br, 1H), 8.08 (d, 2H, J=7.7 Hz), 7.50 (d, 2H, J=8.1 Hz), 7.43 (t, 2H, J=7.1 Hz), 7.22 (t, 2H, J=7.1 Hz). 13C NMR APT (100 MHz, CD3OD): δ 125.8 (down), 120.3 (down), 119.4 (down), 110.6 (down). ESI-MS (m/z): [M+Na]+ 249.6. Analytical HPLC: Purity=99%, tR=8.51 min, Method A.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:26]3[CH:31]=[CH:30][C:29]([C:32]#[C:33][CH2:34][N:35]4[CH2:40]COC[CH2:36]4)=[CH:28][CH:27]=3)=[CH:11]/[CH2:12][O:13][C:14]3[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:16]([CH3:25])[CH:15]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:41]N(CC#C)C.C(NC(C)C)(C)C>O1CCCC1.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>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:26]3[CH:31]=[CH:30][C:29]([C:32]#[C:33][CH2:34][N:35]([CH3:36])[CH3:40])=[CH:28][CH:27]=3)=[CH:11]/[CH2:12][O:13][C:14]3[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([O:22][CH3:41])=[O:21])=[C:16]([CH3:25])[CH:15]=3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C3CC3)cc2)ccc1OCC(=O)O
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2ccc(C3CC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a degassed solution of the ester (486 mg, 0.877 mmol; prepared as described in example 38), 1-(N,N-dimethylamino)prop-2-yne (150 mg, 1.80 mmol) and diisopropyl amine (0.589 mL, 4.24 mmol) in anhydrous tetrahydrofuran (12 mL), bis(triphenylphosphine)palladium(II) dichloride (47 mg, 0.067 mmol) and copper(I) iodide (14.0 mg, 0.074 mmol) were added. The reaction mixture was stirred at ambient temperature for 6 h under nitrogen. The solvents were evaporated in vacuo and the residue was purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 100:0-95:5) yielding methyl (Z)-[4-[3-(4-cyclopropylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: CC([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18]CCC2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)(C)C(O)=O.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](CCO)=[CH:38][CH:37]=1.C([O:47][C:48](=[O:60])[C:49]([CH3:59])([CH3:58])[CH2:50]SC1SC(N)=NC=1)C>>[CH3:34][O:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:18][CH2:17][N:16]([C@H:27]2[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:50][C:49]([CH3:59])([CH3:58])[C:48]([OH:60])=[O:47])=[CH:9][N:10]=2)=[CH:40][CH:41]=1
Reactant: COc1ccc(CCO)cc1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Product: COc1ccc(CCN(C(=O)Nc2ncc(SCC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl) -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 2-(4-methoxy-phenyl)-ethanol and 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester.
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:10][CH:9]=1.[CH3:20][C:21]([CH3:23])=O>>[C:5]([C:21]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:12][CH:13]=1)([CH3:23])[CH3:20])#[N:6]
Reactant: CC(C)=O
Reactant: NC(=O)CCCc1ccc(N)cc1
Reactant: C[Si](C)(C)C#N
Product: CC(C)(C#N)Nc1ccc(CCCC(N)=O)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
TMSCN (0.3 mL, 2.36 mmol) was added to a mixture of the compound 33 (140 mg, 0.79 mmol), acetone (0.35 mL, 1.56 mmol) and 12 (10 mg, 0.08 mmol). The reaction mixture was stirred at 40° C. for 1 h. The reaction was concentrated in vacuo. The residue was diluted with aqNa2SO3, and extracted with ethyl acetate. The combined organic layers were washed with aqNa2SO3 and brine, dried over Na2SO4 and concentrated to dryness to give compound 34 (80 mg) as a light yellow oil. The crude product was used directly for the next step without purification. 1H NMR (400 MHz, CDCl3) δ7.08 (d, 2H, J=8.5 Hz), 6.88 (d, 2H, J=8.5 Hz), 5.29 (br s, 1H), 2.61 (t, 2H, J=7.4 Hz), 2.20 (t, 2H, J=7.4 Hz), 1.87-1.97 (m, 2H), 1.68 (s, 6H).
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:27])=[CH:29][CH:30]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1sc(C2CCCCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: CCc1sc(C2CCCCC2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 74.4 %

Procedure:
An operation similar to that in Example 69 (9) was performed using 4-{[cyclohexyl(5-cyclohexyl-2-ethylthiophen-3-yl)methyl]amino}benzoic acid (233 mg) synthesized in Example 79 (3) and ethyl 3-(methylamino)propanoate (86.0 mg) to give the title compound (208 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][CH2:25][C:26]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)=[O:27]>O1CCCC1>[Cl:24][CH2:25][C:26]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:8][CH2:9]2)=[O:34])=[CH:31][CH:30]=1)=[O:27]
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1ccc(C(=O)N2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
2.18 g of 4-chlorobenzylpiperazine are dissolved in 40 ml of absolute tetrahydrofuran. With stirring, 1.73 g of Hunig base and 2.64 g of 4-chloroacetylaminobenzoic acid chloride are added thereto in succession. The internal temperature rises to approximately 38°. After 30 minutes, the solution is concentrated by evaporation. The oily residue is digested with water, yielding 1-[4-(N-chloroacetylamino)benzoyl]-4-(4-chlorobenzyl)piperazine having a melting point of 205°-207°.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C:11]1[CH:12]=[N:13][C:14]([NH:17][CH:18]2[CH:23]3[CH:19]2[CH2:20][N:21]([S:24]([C:27]2[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=2)(=[O:26])=[O:25])[CH2:22]3)=[N:15][CH:16]=1)=[O:10].C(O)(C(F)(F)F)=O>CO.C(Cl)Cl>[OH:7][NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([NH:17][CH:18]2[CH:23]3[CH:19]2[CH2:20][N:21]([S:24]([C:27]2[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=2)(=[O:26])=[O:25])[CH2:22]3)=[N:13][CH:12]=1)=[O:10]
Reactant: O=C(NOC1CCCCO1)c1cnc(NC2C3CN(S(=O)(=O)c4ccc5ccccc5c4)CC32)nc1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NO)c1cnc(NC2C3CN(S(=O)(=O)c4ccc5ccccc5c4)CC32)nc1
Reaction time: 8 h
Yield: 28.1 %

Procedure:
To a solution of N-(tetrahydro-2H-pyran-2-yloxy) 2-{[3-(2-napthylsulphonyl)-3-azabicyclo[3.1.0]hex-6-yl]amino}pyrimidine-5-carboxamide (110 mg, 0.21 mmol) in MeOH (15 ml) and DCM (15 ml), was added TFA (1.5 ml) at r.t. The mixture was stirred for 8 h before removal of solvent in vacuo. Excess TFA was removed by re-dissolving in DCM (5 ml×2) and concentration to dryness under reduced pressure. Purification by preparative HPLC gave the title compound as a white solid (25.1 mg, 21%). LCMS purity 100%, m/z 426 [M+H]+, 1H NMR (400 MHz, d6-DMSO) δ: 1.15 (2H, s), 2.55 (1H, s), 3.20 (2H, d), 3.65 (2H, d), 7.65 (2H, m), 7.75 (1H, d), 7.90 (1H, m), 8.15-8.30 (3H, m), 8.50 (1H, s), 8.65 (2H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:24][C:25]([O:27]CC)=O)O[N:9]([CH3:11])[C:8]([CH2:12][C:13]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:7]1)=[O:5])[CH3:2].C[O:31]C(C1N=C(CC2(C3C=CC=CC=3)CCCC2)NC(=O)C=1O)=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:12][C:13]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:15][CH2:16][CH2:17]2)[N:9]([CH3:11])[C:25](=[O:27])[C:24]=1[OH:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)CC1(C(=O)OCC)N=C(CC2(c3ccccc3)CCCC2)N(C)O1
Reactant: COC(=O)c1nc(CC2(c3ccccc3)CCCC2)[nH]c(=O)c1O
Product: CCOC(=O)c1nc(CC2(c3ccccc3)CCCC2)n(C)c(=O)c1O

Procedure:
5-Hydroxy-1-methyl-6-oxo-2-(1-phenyl-cyclopentylmethyl)-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester was synthesized as a brown solid (35 mg, 20%) from 200 mg of 5-ethoxycarbonylmethyl-2-methyl-3-(1-phenyl-cyclopentylmethyl)-2,5-dihydro-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester following the procedure described for 5-hydroxy-6-oxo-2-(1-phenyl-cyclopentylmethyl)-1,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (Example 6). LCMS: m/z=357.0 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:13][C:14]1[CH:25]=[CH:24][C:17]2[CH2:18][CH2:19][CH2:20][C:21](=O)[CH2:22][C:16]=2[CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[ClH:13].[Cl:13][C:14]1[CH:25]=[CH:24][C:17]2[CH2:18][CH2:19][CH2:20][CH:21]([NH:1][CH2:2][C@H:3]([OH:12])[CH2:4][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:22][C:16]=2[CH:15]=1
Reactant: O=C1CCCc2ccc(Cl)cc2C1
Reactant: NC[C@H](O)COc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cl
Product: O[C@@H](CNC1CCCc2ccc(Cl)cc2C1)COc1ccccc1
Reaction time: 6.5 h
Yield: 88.3 %

Procedure:
Under nitrogen, to a solution of (2S)-1-amino-3-phenoxy-2-propanol (280 mg) in 1,2-dichloroethane (10 ml) were added 3-chloro-5,7,8,9-tetrahydrobenzocyclohepten-6-one (300 mg), sodium triacetoxyborohydride (820 mg) and acetic acid (0.26 ml) at room temperature, and the mixture was stirred at the same temperature for 6.5 hours. The resulting mixture was poured into aqueous 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1 to 10:1) and followed by treatment with 4N hydrogen chloride in ethyl acetate to give (2S)-1-(3-chloro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanol hydrochloride (260 mg).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=O.CO[C:15]1[C:16]([NH2:21])=C[CH:18]=[CH:19][CH:20]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C(C)=CC=CC=1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]1[O:4][C:5]2[CH:18]=[CH:19][CH:20]=[CH:15][C:16]=2[N:21]=1
Reactant: COc1ccccc1N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1C
Product: Nc1ccccc1-c1nc2ccccc2o1
Reaction time: 8 h
Yield: 23 %

Procedure:
Isatoic anhydride (0.2 m), o-anisidine (0.22 m), and xylene (200 ml) were placed in a 3-neck, 300 ml round bottom flask fitted with thermometer, condenser, and magnetic stirrer. The reaction mixture was heated to reflux and allowed to stir at reflux overnight. Gas evolution appeared to be vigorous. Added a Dean-Stark trap and attempted to collect water. No water was evident after eight hours. Reaction mixture was cooled and allowed to stand overnight. Toluenesulfonic acid (1.5 g) was added and reaction mixture heated to reflux. Water was azeotroped from the reaction mixture. The xylene was stripped from the reaction mixture under aspirator vacuum. The residue was leached with benzene (500 ml). The benzene extract was then washed with 2% caustic until no further color was extracted. The benzene solution was filtered and evaporated to dryness. The residue was dissolved in boiling ethanol and allowed to stand in the refrigerator. The reddish crystals were filtered out and dried. Obtained 10 grams (23% yield); m.pt.=104°-107° C. Structure was confirmed by infra red (IR) and nuclear magnetic resonance (NMR) analysis.