Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12.CCN(CC)CC.[CH:18]([N:21]1[C:25]([C:26]2[N:35]=[C:34]3[N:28]([CH2:29][CH2:30][O:31][C:32]4[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][C:33]=43)[CH:27]=2)=[N:24][CH:23]=[N:22]1)([CH3:20])[CH3:19]>C(Cl)Cl>[CH2:1]1[N:6]([S:40]([C:37]2[CH:38]=[CH:39][C:32]3[O:31][CH2:30][CH2:29][N:28]4[CH:27]=[C:26]([C:25]5[N:21]([CH:18]([CH3:19])[CH3:20])[N:22]=[CH:23][N:24]=5)[N:35]=[C:34]4[C:33]=3[CH:36]=2)(=[O:42])=[O:41])[CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Reactant: C1CCN2CCNCC2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCN4CCCCC4C3)ccc1OCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of octahydropyrido[1,2-a]pyrazine (50 mg, 0.38 mmol) and NEt3 (83 μL, 0.59 mmol) in DCM (15 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (93 mg, 0.12 mmol) in DCM (5 mL) and the resulting mixture warmed to RT after 10 min then stirred for 1 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-8% MeOH in EtOAc) then freeze-dried from MeCN/H2O affording 132 (36 mg, 62%) as a white solid. LCMS: RT 2.90 min [M+H]+ 498.3. 1H NMR (DMSO, 400 MHz): δ 8.78 (1H, d, J=2.41 Hz), 8.01 (1H, s), 7.94 (1H, s), 7.63 (1H, dd, J=8.63, 2.42 Hz), 7.28 (1H, d, J=8.62 Hz), 5.73-5.72 (1H, m), 4.63-4.59 (4H, m), 3.53 (1H, d, J=11.02 Hz), 3.43 (1H, d, J=9.07 Hz), 2.70-2.68 (2H, m), 2.33-2.32 (1H, m), 2.19-2.11 (1H, m), 1.93-1.92 (3H, m), 1.62 (1H, d, J=12.59 Hz), 1.57-1.52 (2H, m), 1.49 (6H, t, J=6.30 Hz), 1.38-1.16 (2H, m), 1.01-0.87 (1H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[O:23]C2CCCCO2)[C:10]([NH:12][C:13]([NH:15][CH3:16])=[O:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[OH:23])[C:10]([NH:12][C:13]([NH:15][CH3:16])=[O:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC(=O)NC(=O)C(CC1CCCC1OC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CNC(=O)NC(=O)C(CC1CCCC1O)c1ccc(Cl)c(Cl)c1
Temperature: 55 °C
Yield: 84.6 %

Procedure:
A solution of 1-{2-(3,4-dichloro-phenyl)-3-[2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionyl}-3-methyl-urea (45 mg, 0.10 mmol) in ethanol (1.01 mL) was treated with pyridinium p-toluenesulfonate (2.5 mg, 0.01 mmol). The reaction mixture was heated to 55° C. for 5 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 100% ethyl acetate) afforded the 1-[2-(3,4-dichloro-phenyl)-3-(2-hydroxy-cyclopentyl)-propionyl]-3-methyl-urea (30.4 mg, 83.4%) as a white solid: mp 62-64° C.; FAB-HRMS m/e calcd for C16H20Cl2N2O3 (M+H)+ 359.0929. found 359.0929.
Reaction SMILES: [N:1]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].CCN(C(C)C)C(C)C.Cl.[Cl:27][C:28]1[CH:39]=[CH:38][C:31]2[NH:32][C:33]([C@@H:35]([NH2:37])[CH3:36])=[N:34][C:30]=2[CH:29]=1>CN(C=O)C>[Cl:27][C:28]1[CH:39]=[CH:38][C:31]2[NH:32][C:33]([C@@H:35]([NH:37][C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][C:2]4=[O:7])=[CH:16][CH:15]=3)[CH3:36])=[N:34][C:30]=2[CH:29]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(N2CCOCC2=O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc(N2CCOCC2=O)cc1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
254 mg (1.15 mmol) 4-(morpholin-3-on-4-yl)-benzoic acid (prepared by synthesis sequence analogously to Example 30a, 2d and 21a) are placed in 5 ml DMF and 428 mg (1.0 mmol) PfTU and 514 μl (3.0 mmol) DIPEA are added. After stirring at ambient temperature for 10 minutes 232 mg (1.0 mmol) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine-hydrochloride are added and the mixture is stirred for 16 hours at ambient temperature. Then the reaction mixture is filtered through basic aluminium oxide and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/methanol 100:0->90:10), the corresponding fractions are evaporated down i. vac., the residue is dissolved in acetonitrile/water and lyophilised.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[H-].[Na+].C1(C)C=CC(S([O:21][CH2:22][C@@H:23]([CH2:26][CH3:27])[CH2:24]O)(=O)=O)=CC=1>CN(C)C=O>[CH2:26]([C@H:23]([CH2:24][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:22][OH:21])[CH3:27]
Reactant: CC[C@@H](CO)COS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccccc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](CO)CSc1ccccc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
0.47 ml (0.0038 mol) of 2-methoxythiophenol, in solution in 5 ml of dimethylformamide, is added dropwise to a round-bottomed flask, kept under an inert atmosphere, comprising 0.19 g (0.0047 mol) of sodium hydride in suspension in 10 ml of dimethylformamide cooled to 0° C. The mixture is reheated to ambient temperature and stirred for 1 hour, then 0.99 g (0.0038 mol) of 2-(S)-ethyl-3-hydroxypropyl p-toluene-sulfonate (XIXd-1), in solution in 10 ml of dimethyl-formamide, is added. After stirring at ambient temperature for 2 hours, the dimethylformamide is evaporated under high vacuum and the residue is taken up in dichloromethane. The organic phase is washed with water and with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol=98:2). 0.87 g (0.0038 mol) of the title compound (XXd-1) is recovered in the form of an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([N:16]1[CH2:22][CH2:21][CH:20]([C@H:23]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:24])[CH:19]([OH:34])[CH:18]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:17]1=[O:42])[CH3:15])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:48](Cl)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49].O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([N:16]1[CH2:22][CH2:21][CH:20]([C@H:23]([CH2:25][O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:24])[CH:19]([O:34][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH:18]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:17]1=[O:42])[CH3:15])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)N1CCC([C@@H](C)COCc2ccccc2)C(O)C(Cc2ccccc2)C1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)N1CCC([C@@H](C)COCc2ccccc2)C(O[Si](C)(C)C(C)(C)C)C(Cc2ccccc2)C1=O

Procedure:
A single isomer of the alcohol (62) is dissolved in DMF and treated with imidazole (2 equivalents) and t-butyldimethylsilyl chloride (1.05 equivalents) at room temperature overnight. The reaction mixture is poured into water and extracted with ethyl acetate. The combined organic extracts are dried over MgSO4 and evaporated at reduced pressure. The residue is purified by flash chromatography to give (63).
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])([O-:3])=[O:2].[CH3:11][OH:12]>>[CH3:11][O:12][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:4][N+:1]([O-:3])=[O:2]
Reactant: CO
Reactant: O=C1CCCCC1[N+](=O)[O-]
Product: COC(=O)CCCCC[N+](=O)[O-]
Yield: 89 %

Procedure:
2-Nitrocyclohexanone (6.77 g; 47.3 mmol) was dissolved in dried MeOH (150 mL) and a two fold excess by weight of Amberlyst® A21 (13.5 g) was added. The mixture was refluxed under nitrogen for 1.5 h then filtered and evaporated to give 6-nitrohexanoic acid methyl ester (7.72 g; 42 mmol). Yield: 89%.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CC1C=CC(S([N:24]=[C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]2[CH:34]([CH3:44])[C:35](=O)[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])(=O)=O)=CC=1>ClCCl>[CH3:44][C:34]1[N:26]2[CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[CH:29]=[CH:30][C:25]2=[N:24][C:35]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)CCC(=O)C(C)n1cc([N+](=O)[O-])ccc1=NS(=O)(=O)c1ccc(C)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCc1nc2ccc([N+](=O)[O-])cn2c1C
Temperature: 40 °C
Reaction time: 6 h
Yield: 83.7 %

Procedure:
Trifluoroacetic anhydride (3 mL) was added to a dichloromethane solution (6 mL) of ethyl 5-[2-{[(4-methylphenyl)sulfonyl]imino}-5-nitropyridin-1(2H)-yl]-4-oxohexanoate (635 mg) obtained in Production Example 47-4, at room temperature. The reaction liquid was heated up to 40° C., stirred for 6 hours, and then concentrated under reduced pressure. Aqueous saturated sodium hydrogencarbonate solution was added to the residue, and extracted with ethyl acetate. The organic layer was dried with sodium sulfate, concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (ethyl acetate/chloroform/hexane=1/1/1) to obtain the entitled compound (328 mg).
Reaction SMILES: [OH-].[K+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:13][CH2:14][CH2:15][CH2:16][C:17]([N:20]=[N:21][C:22]([CH3:25])([CH3:24])[CH3:23])(Cl)[CH3:18])(=O)C>CO>[C:22]([N:21]=[N:20][C:17]([O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([CH3:18])[CH2:16][CH2:15][CH2:14][OH:13])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(=O)OCCCC(C)(Cl)N=NC(C)(C)C
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)N=NC(C)(CCCO)Oc1ccccc1
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
To a solution of 1.72 grams (0.026 moles) of 85% KOH in 20 mls. of methanol in a 100 ml. 3-necked round bottom flask equipped with a magnetic stirrer and thermometer was added 2.44 grams (0.026 moles) of phenol. The reaction was stirred for 15 minutes at 15° C and then 6.25 grams (0.025 moles) of the chloro compound prepared in step B was added dropwise over 20 minutes. The reaction was stirred an additional 30 minutes at room temperature. A sample was withdrawn and checked by infrared analysis which indicated the acetate was partially saponified to the alcohol. An additional 1.5 grams of KOH was added to the reaction mixture and the reaction stirred another 15 minutes. Infrared analysis indicated the saponification was complete so the reaction mixture was diluted with 200 mls. water and extracted with pentane. The pentane solution was washed with saturated NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated to leave 5.2 grams (80% yield) of the desired alcohol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]([NH2:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:8][C:4]1[S:5][C:6]([CH3:7])=[C:2]2[C:3]=1[C:9](=[O:11])[N:19]1[CH:18]=[C:17]([C:20]([NH2:22])=[O:21])[CH:16]=[CH:15][C:14]1=[N:1]2
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: COC(=O)c1c(C)sc(C)c1N
Solvent: c1ccncc1
Product: Cc1sc(C)c2c(=O)n3cc(C(N)=O)ccc3nc12
Temperature: 180 °C
Yield: 3.2 %

Procedure:
A mixture of 5 g (0.0226 mol) of 4-amino-2,5-dimethyl-3-thiophenecarboxylic acid, methyl ester and 3.5 g (0.0226 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) is heated in an oil bath at 180° C. for thirty minutes. The mixture is cooled, dissolved in hot pyridine, cooled, the precipitate collected and dissolved in hot methanol, activated charcoal (Darco-G60, Matheson, Coleman and Bell) is added and the hot suspension is filtered through Supercell Hyflo® (Johns-Manville). The filtrate is cooled to give 0.2 g of 1,3-dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide with methanol (1:0.125); mp 272°-275° C. after recrystallization from methanol.
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(OCC)(=O)C>[CH2:6]([NH:5][C:3](=[O:4])[C@H:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:13][O:14][CH:15]([F:16])[F:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H](COC(F)F)C(=O)NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N[C@H](COC(F)F)C(=O)NCc1ccccc1
Reaction time: 0.25 h
Yield: 22.3 %

Procedure:
A solution of (2R)-2-amino-N-benzyl-3-(difluoromethoxy)propanamide (113 mg, 0.46 mmol) in ethyl acetate was cooled in an ice bath. To the cooled solution was added triethylamine (139 mg, 1.38 mmol) followed by methanesulfonylchloride (63 mg, 0.55 mmol). The reaction mixture was stirred for 15 minutes and then quenched with water, extracted with ethyl acetate and washed with brine. The organic layer was dried, concentrated and triturated with diethyl ether to give the product (33 mg, 22%) as a white solid. 1H NMR (300 MHz, CDCl3): (ppm) 7.31 (m, 5H), 6.73 (br, 1H), 6.24 (t, 1H), 5.21 (d, 1H), 4.48 (d, 2H), 4.21 (m, 3H), 3.01 (s, 3H)
Reaction SMILES: C1C2C(COC([NH:18][C:19]([CH3:71])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:33]([O:65][CH3:66])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:63][CH3:64])[C@@H:43]([CH3:62])[C:44]([NH:46][C@@H:47]([CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>ClCCl>[CH3:20][C:19]([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:33]([O:65][CH3:66])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@H:42]([O:63][CH3:64])[C@@H:43]([CH3:62])[C:44]([NH:46][C@@H:47]([CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])([CH3:71])[NH2:18]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: CCNCC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a stirring mixture of #122 (600 mg, 0.611 mmol, 1.00 eq.) in 15 mL of dichloromethane, diethylamine (5 mL, 50 mmol, 80 eq.) was added. The reaction was allowed to stir at room temperature for 3 hours. Reaction was concentrated in vacuo and mixture was purified by Silica Chromatography (Gradient: 0%-40% methanol in dichloromethane) producing #123 (0.46 g, 99%) as a solid. LC-MS (Protocol Q1): m/z 760.3 [M+H+] retention time=0.83 minutes. 1H NMR (400 MHz, CD3OD), δ 7.14-7.30 (m), 4.70-4.78 (m), 4.56-4.64 (m), 4.05-4.19 (m), 3.87 (dd), 3.79-3.84 (m), 3.72-3.77 (m), 3.62-3.70 (m), 3.46-3.56 (m), 3.37-3.45 (m), 3.33-3.36 (m), 3.16-3.24 (m), 3.09-3.11 (m), 2.98-3.05 (m), 2.95 (d), 2.91 (d), 2.87 (d), 2.83 (d),2.73-2.79 (m), 2.40-2.51 (m), 2.29-2.39 (m), 2.16-2.28 (m), 2.04-2.15 (m), 2.01 (s), 1.73-1.96 (m), 1.50-1.68 (m), 1.47-1.49 (m), 1.46 (s), 1.43 (s), 1.38 (s), 1.35 (d), 1.23-1.32 (m), 1.17-1.22 (m), 1.15 (d), 1.04-1.11 (m), 0.94-1.03 (m), 0.82-0.91 (m).
Reaction SMILES: Cl.C([O:4][C:5](=[O:8])[CH2:6][NH2:7])C.[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C1C=CC=CC=1>[C:9]1([NH:15][C:16]([NH:7][CH2:6][C:5]([OH:4])=[O:8])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(O)CNC(=O)Nc1ccccc1
Reaction time: 5 h

Procedure:
7.0 g of glycine ethyl ester hydrochloride was suspended in 100 ml of benzene, and 10 ml of phenylisocyanate and 8 ml of triethylamine were added thereto. The mixture was stirred for 5 hours and benzene was distilled away. Ethyl acetate was added to the residue, washed with water and brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled away and 100 ml of 1N aqueous solution of sodium hydroxide was added to the resulting residue. The solution was stirred at 50° C. for 2 hours. Insoluble substance was filtered off and the filtrate was acidified with concentrated hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from methanol/water to give 6.8 g of phenylcarbamoylglycine.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[CH:4]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:5]1[CH:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[N:8]=[CH:7][N:6]=1
Reactant: Oc1cc(C(F)(F)F)ncn1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Cl)ncn1

Procedure:
6-Trifluoromethyl-pyrimidin-4-ol ([1546-78-7], 5 g) was refluxed in phosphorus oxychloride (17 mL) for 2 hours. The reaction mixture was carefully concentrated in vacuo and the residue was distilled (Kugelrohr) under reduced pressure (bp=30-55° C. @ 10 mbar) to yield the title compound ([37552-81-1], 1.4 g). MS (EI): 182.0 (M).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[C:5]([NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCCCCCNC(=O)Nc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCNC(=O)Nc1ncccc1N
Yield: 99.7 %

Procedure:
To a suspension of 1-(3-nitro-2-pyridyl)-3-heptylurea (1.00 g) in ethanol (10 ml) was added a catalytic amount of 10% palladium/carbon to perform catalytic reduction under 1-2.5 atms at room temperature for 5 hrs. After filtering the catalyst and distilling off the solvent, the crystallization of the residue from hexane afforded 1-(3-amino-2-pyridyl)-3-heptylurea (0.89 g, 99%).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:27][C:28]1[O:32][C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:30][C:29]=1[CH2:38][CH2:39]OS(C1C=CC(C)=CC=1)(=O)=O>>[C:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:39][CH2:38][C:29]2[N:30]=[C:31]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:28]=2[CH3:27])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:26])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C(C)(C)C)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2cccc(C(C)(C)C)c2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(3-tert-butyl-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester by the procedure of Example 24. 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, 1H, J=3.91 Hz, 1.17 Hz), 7.37 (dd, 1H, J=5.09 Hz, 1.17 Hz), 7.19-7.16 (m, 3H), 7.08-7.06 (m, 2H), 6.89 (t, 1H, J=2.35 Hz), 6.82 (d, 2H, J=8.60 Hz), 6.71 (dd, 1H, J=8.60 Hz, 2.74 Hz), 4.19 (t, 2H, J=6.26 Hz), 3.25 (d, 1H, J=14.08 Hz), 3.15 (d, 1H, J=14.08 Hz), 2.96 (t, 2H, J=6.26 Hz), 2.35 (s, 3H), 1.43 (s, 3H), 1.26 (s, 9H). HRMS (ES+) m/z exact mass calcd for C30H34NO5S 520.2157, found 520.2182.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:10]2[C:11]3[C:12](=[O:18])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:21]1([Mg]Br)[CH2:23][CH2:22]1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:10]2[C:11]3[C:12]([CH:21]4[CH2:23][CH2:22]4)([OH:18])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Br[Mg]C1CC1
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(=O)CC3
Solvent: CCOCC
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)(C1CC1)CC3
Temperature: 25 °C

Procedure:
Into a stirred 100 ml flask containing Intermediate 3 (200 mg, 0.732 mmol) dissolved in diethyl ether (20 ml), cyclopropylmagnesium bromide (0.5M in THF, 7.32 ml, 3.66 mmol) was added at reflux. The reaction mixture was stirred at reflux for 1 hour. The reaction mixture was allowed to cool to room temperature and was quenched by addition of 10% aq. NH4Cl (50 ml). The aqueous mixture was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the sub-titled compound which was used without further purification. MS: ESI (positive): 298, (M-OH).
Reaction SMILES: O[CH:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[C:12]2[CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:7][CH:6]=1)[CH:3]=[CH2:4].CO[C:30]([O:35]C)([N:32]([CH3:34])[CH3:33])[CH3:31]>C1(C)C=CC=CC=1>[CH3:34][N:32]([CH3:33])[C:30]([CH2:31][CH2:4][CH:3]=[CH:2][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[C:12]2[CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:7][CH:6]=1)=[O:35]
Reactant: COC(C)(OC)N(C)C
Reactant: C=CC(O)c1ccc2cccc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cc2cccc3ccc(C=CCCC(=O)N(C)C)cc23)c(OC)c1
Yield: 90 %

Procedure:
A mixture of methyl 4-[7-(1-hydroxyallyl)naphth-1-ylmethyl]-3-methoxybenzoate (2.4 g), N,N-dimethylacetamide dimethyl acetal (1.62 ml) and toluene (50 ml) was refluxed for 12 hours. Evaporation and flash chromatgraphy, eluting with a gradient of 1) 3:3:2 petroleum ether:methylene chloride:ethyl acetate, 2) 1:1:1 petroleum ether:methylene chloride:ethyl acetate, and 3) 6:6:7 petroleum ether:methylene chloride:ethyl acetate, afforded methyl 4-[7-[4-(dimethylcarbamoyl)but-1-enyl]naphth-1-ylmethyl]-3-methoxybenzoate (90%) as a light yellow syrup; MS(CI), m/e=432(M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])=[CH:4][CH:3]=1.O(C)[Na].[CH3:22][C:23]([CH3:34])([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]I)[C:24]([O:26][CH3:27])=[O:25]>CN(C=O)C>[O:18]=[C:9]1[C:10]2[C:11](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:13])[N:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:23]([CH3:22])([CH3:34])[C:24]([O:26][CH3:27])=[O:25])=[CH:7][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(O)cc1
Reactant: COC(=O)C(C)(C)CCCCCI
Agent: CO[Na]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCCCCOc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C

Procedure:
N-[p-Hydroxyphenyl]phthalimide (5.0 g) described in Example 1 was dissolved in 100 ml of DMF and 1.13 g of NaOCH3 was added. The solution was stirred at room temperature for one-half hour, then 6.25 g of methyl 2,2-dimethyl-7-iodoheptanoate was added dropwise. The mixture was stirred at room temperature overnight and then heated at reflux for two hours and concentrated on rotary evaporator. H2O (100 ml) was added and a solid was obtained. The product was extracted with EtOAc leaving the insoluble starting material behind. Concentration of the ethyl acetate solution followed by recrystallization of the resulting solid from isopropyl ether gave the purified product; mp 82°-3° C.