Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([NH:13][CH2:14][CH2:15][OH:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N1C=CN=C1.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25].O>CC(N(C)C)=O>[Si:28]([O:16][CH2:15][CH2:14][NH:13][C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCNc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1c[nH]cn1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCNc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 89.1 %

Procedure:
A solution of the compound (0.38 g) obtained in step 1, imidazole (0.12 g) and tert-butyldimethylchlorosilane (0.26 g) in DMAc (5 mL) was stirred at room temperature for 14 hr, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 3→10% ethyl acetate/hexane) to give N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,5-bis(trifluoromethyl)aniline (0.48 g, 89%) as a colorless oil.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.C(=O)([O-])[O-].[Na+].[Na+]>CO>[O:6]=[C:1]1[CH2:5][CH2:4][CH:3]([N:11]2[C:7](=[O:17])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10]2=[O:12])[CH2:2]1
Reactant: O=C1C=CCC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCC(N2C(=O)c3ccccc3C2=O)C1
Reaction time: 22 h
Yield: 63.9 %

Procedure:
A slurry of methanol (88 mL), 2-cyclopenten-1-one (10.2 mL, 122 mmol), and phthalimide (17.9 g, 122 mmol) was stirred at ambient temperature and sodium carbonate (2M in water, 7.92 mL, 15.8 mmol) was added. After 22 hours, the thick white slurry was filtered and washed with MeOH (100 mL). Water (100 mL) was added to the wet cake, stirred for 1 hour, and filtered. The solid was washed with water (50 mL) and dried in a vacuum oven at 50° C. for 14 hours to provide the title compound (17.8 g, 78.0 mmol, 64% yield). MS (DCI) M/Z 247 [M+NH4]+.
Reaction SMILES: C([O:4][C:5]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C@H:9]1[CH2:11][O:10]1)C=C.[C:19]1(C)[CH:24]=C(C)C=C(C)[CH:20]=1>>[CH2:24]([C:15]1[C:5]2[O:4][CH:9]([CH2:11][OH:10])[CH2:8][O:7][C:6]=2[CH:12]=[CH:13][C:14]=1[N+:16]([O-:18])=[O:17])[CH:19]=[CH2:20]
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1OC[C@H]1CO1
Reactant: Cc1cc(C)cc(C)c1
Product: C=CCc1c([N+](=O)[O-])ccc2c1OC(CO)CO2

Procedure:
(R)-2-(2-Allyloxy-4-nitrophenoxymethyl)-oxirane (20 g, 80 mmoles) prepared as above was heated at 155° C. in mesitylene for 24 hours under nitrogen. Filtration of the black solid which formed gave 1.5 g of very polar material. Evaporation of the solvent in vacuum followed by column chromatography on silica gel with methylene chloride as eluent gave 10 g of recovered starting material and 7.5 g of the desired rearranged (S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol, which slowly crystallized on standing in vacuum (m.p. 67° C.). The yield based on recovered starting material is 75%.
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:23][CH2:24][O:25]C1C=CC(N)=CC=1>C(O)C>[ClH:1].[CH3:23][CH2:24][O:25][C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:4][CH:5]=1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: CCOc1ccc(N)cc1
Agent: Cl
Solvent: CCO
Product: CCOc1ccc(Nc2cc(C)nc3ccc4nc[nH]c4c23)cc1

Procedure:
A mixture of 33 g. (0.15 mole) of the compound of Example I, C. and 23 g. (0.15 mole) of p-phenetidine in 1800 ml. of ethanol was refluxed for 6 hr. The solvent was removed by evaporation in vacuo and the residue was slurried with ether. The crude solid was collected by filtration and was recrystallized from ethanol. The product was collected as yellow needles melting at 229°-230° in a yield of 19 g. (36%). Recrystallization from ethanol raised the melting point to 330°-331°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[H][H]>[Pd].C(O)(=O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1c(O)ccc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1c(O)ccc2c1CCCC2
Reaction time: 3 h

Procedure:
In 2.5 l. of glacial acetic acid is dissolved 417 g. of methyl 2-hydroxy-1-naphthoate, and with the addition of 150 g. of 5% palladium-on-carbon, reduction is carried out at a temperature of 60° to 80° C with hydrogen introduced at a pressure of 100kg./cm2. In 3 hours, approximately 2 moles of hydrogen is absorbed. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is then subjected to distillation under reduced pressure and the fraction boiling at 123° -125° C (0.6 mmHg) is recovered to obtain methyl 2-hydroxy-5,6,7,8-tetrahydro-1-naphthoate as a colorless oil. The oil solidifies on standing in the cold.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[S:8][CH2:7][C:6]2=1.[O:20](C(C)(C)C)[K].O=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[S:8](=[O:20])[CH2:7][C:6]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Reactant: CC(C)(C)O[K]
Agent: O=O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3c(c2c1)CS(=O)c1ccccc1-3

Procedure:
8-Methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (79 mg, 0.281 mmoL) in DMF (5 mL) was treated with KO-t-Bu (1.0 M in THF, 0.48 mL, 0.48 mmoL) under a flow of O2 for 6 hours. The reaction mixture was then partitioned between water and EtOAc. The EtOAc layer was washed with saturated NH4Cl, water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, CH2Cl2:MeOH 9:1 as eluent) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH2:27][CH2:28][C:29]([O:31]C)=[O:30])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:25][CH2:26]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)CC[C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC[C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1

Procedure:
Prepared from compound 240 of Example 1 by reaction with sodium hydroxide in a methanol/tetrahydrofuran mixture.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH2:19][CH2:20][CH2:21][CH3:22])=[C:10]([C:34]([N:36]2[C@H:45]([CH2:46][O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[CH:9]=1)=[O:7])(C)(C)C.N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C1COCC1>[CH2:19]([C:18]1[N:17]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:16]=[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][C:10]=1[C:34]([N:36]1[C@H:45]([CH2:46][O:47][Si:48]([C:51]([CH3:53])([CH3:52])[CH3:54])([CH3:49])[CH3:50])[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:35])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)c(C(=O)OCC)nn1-c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCCCc1c(-c2ccc(C(=O)O)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)c(C(=O)OCC)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.1 %

Procedure:
To a solution of ethyl 4-(4-(tert-butoxycarbonyl)-2-((S)-3-((tert-butyldimethylsilyloxy)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-butyl-1-phenyl-1H-pyrazole-3-carboxylate (335 mg, 0.445 mmol) in THF (5.0 mL) was added 2,6-lutidine (0.10 mL, 0.89 mmol) followed by TMS-OTf (0.121 mL, 0.668 mmol). After stirring at room temperature for 1 h, the reaction mixture was heated at 50° C. for 1 h. Additional equivalents of both 2,6-lutidine and TMS-OTf were added hourly until consumption of the starting material (6 additions). After cooling to room temperature, the reaction mixture was quenched with sat. aq. sodium bicarbonate solution. The mixture was extracted with EtOAc concentrated in vacuo. The residue was purified by flash chromatography (Isco 40 g column eluting with 0-80% EtOAc/hexanes) to give the title compound (115 mg, 37%). MS(ESI+) m/z 696.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[NH2:51][CH2:52][C:53]1[C:62](=[O:63])[C:61]2[C:56](=[CH:57][C:58]([Cl:64])=[CH:59][CH:60]=2)[N:55]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:54]=1[C:71]1[O:72][CH:73]=[CH:74][N:75]=1>CN(C=O)C>[Cl:64][C:58]1[CH:57]=[C:56]2[C:61]([C:62](=[O:63])[C:53]([CH2:52][NH:51][C:14]([C:11]3[CH:12]=[CH:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:9](=[O:17])[CH:10]=3)=[O:16])=[C:54]([C:71]3[O:72][CH:73]=[CH:74][N:75]=3)[N:55]2[C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)=[CH:60][CH:59]=1
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccn(Cc2ccccc2)c(=O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccn(Cc2ccccc2)c(=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a 10 mL round-bottomed flask, 1-benzyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (32.6 mg, 0.142 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (66.3 mg, 0.142 mmol) and N,N-diisopropylethylamine (73.5 mg, 0.099 mL, 0.569 mmol) were combined with DMF (2 mL). The reaction mixture was stirred at room temperature for 10 min. After this time, 3-aminomethyl-7-chloro-2-oxazol-2-yl-1-phenyl-1H-quinolin-4-one (intermediate A) was added (0.050 g, 0.142 mmol). The reaction mixture was stirred at room temperature for 3 hr. The product was purified using flash chromatography (40% ethyl acetate/hexane ramped to 100% ethyl acetate/hexanes). MS calcd. for C32H24ClN4O4 [(M+H)+] 563.1, obsd. 563.3.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][NH:8][S:9]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)(=[O:11])=[O:10])(=[O:6])[O:4][CH3:5].[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:1][O:2][P:3]([CH2:7][N:8]([S:9]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)(=[O:10])=[O:11])[CH3:21])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(CNS(=O)(=O)c1cc2ccccc2s1)OC
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COP(=O)(CN(C)S(=O)(=O)c1cc2ccccc2s1)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
A reaction mixture consisting of 290 mg (0.83 mmol) of [(2-benzothiophenesulfonylamino)-methyl]-phosphonic acid dimethyl ester, 380 mg (1.16 mmol) of anhydrous cesium carbonate, 0.11 mL (1.16 mmol) of methyl iodide and 5 mL of anhydrous DMF stirred for 16 hours at room temperature. After the reaction was complete, DMF was evaporated in vacuum, and the residue was suspended in 15 mL of water and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, filtered and evaporated, providing an oily residue which was chromatographed on a silica gel column, eluent EtOAc/hexane (7:3), then dichloromethane/MeOH (20:1), to yield the title compound as a yellowish oil (190 mg, 63%): 1H NMR: (300 MHz, CDCl3) δH 3.00 (s, CH3), 3.48 (d, J=11.5 Hz, 2 H), 3.83 (d, J=10.9 Hz, 6 H, 2CH3), 7.45–7.50 (m, 2 H, Ar—H), 7.83–7.89 (m, 3 H, Ar—H).
Reaction SMILES: [Cl:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][NH:5][C:6](=[O:33])[N:7]([C@H:9]([CH2:18][O:19][C:20](=[O:32])[NH:21][C:22]1[N:23]=[CH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[CH3:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][NH:5][C:6](=[O:33])[N:7]([C@H:9]([CH2:18][O:19][C:20](=[O:32])[NH:21][C:22]1[N:23]=[CH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:10][C:11]([OH:13])=[O:12])[CH3:8]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 180.9 %

Procedure:
To a mixture of (S)-tert-butyl 3-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-(isoquinolin-3-ylcarbamoyloxy)butanoate (0.8 g, 1.47 mmol) and DCM (10 mL) was added TFA (10 mL). The resulting solution was stirred at RT for 1 h. The mixture was concentrated, and the remaining residue was dried in vacuo to give (S)-3-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-(isoquinolin-3-ylcarbamoyloxy)butanoic acid (1.3 g), which was used without further purification. LRMS (M+H+) m/z 489.1.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[CH:8][CH:7]=1)=[O:5].Cl[C:18]([O:20][CH3:21])=[O:19].C(OCC)C>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[CH:8][CH:7]=1)=[O:5])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)Cl
Reactant: CN(C)CC(=O)c1ccc(OC(F)F)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)N(C)CC(=O)c1ccc(OC(F)F)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To 16.8 g (73 mmole) of 2-dimethylamino-4'-difluoromethoxyacetophenone in 100 ml of methylene chloride cooled to 0° C. was added 7.6 g (81 mmole) of methyl chloroformate. After the addition was complete the reaction mixture was allowed to warm to 20° C. and stirred overnight. Concentration in vacuo, partitioning between diethyl ether and 1M aqueous hydrochloric acid, washing with brine, drying over anhydrous magnesium sulfate, and reconcentration in vacuo gave a crude oil. Chromatography of this oil on silica gel using diethyl ether in hexanes gave 12 g of 2-(N-methyl-N-(methoxycarbonyl)amino)-4'-difluoromethoxyacetophenone an oil, bp 150°-190° C. at 0.7 torr.
Reaction SMILES: CCCC[Sn]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])(CCCC)CCCC.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32]O.O>C1C=CC=CC=1>[CH2:24]([Sn:15]([O:14][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Reactant: CN(C)CCCO
Solvent: O
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)OCCCN(C)C

Procedure:
3-Dimethylamino-1-Propyl Tributylstannyl Ether is prepared from 59.6 gm (0.1 mole) bis(tributyltin) oxide and 20.6 gm (0.2 mole) 3-dimethylamino-1-propanol in 200 ml benzene. This is stirred and heated to reflux in a system that contains a Dean-Starke tube. After 30 minutes refluxing water began to collect in the Dean-Starke tube and after refluxing for 22 hours a total of 1.9 ml of water (theory 1.8 ml) had collected. The benzene is stripped off on a rotating evaporator to provide 77.1 gm of straw colored liquid. This is fractionated at reduced pressure, with 53.0 gm water-white liquid (Percent yield - 67.6) being collected at 135°-139° C. at 0.7 mm. Infrared spectral analysis shows this to be the desired ether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:2]=1.C(N(CC)CC)C.[CH2:22]([O:24][C:25]([CH2:27][C:28](Cl)=[O:29])=[O:26])[CH3:23]>C(Cl)Cl>[CH2:22]([O:24][C:25](=[O:26])[CH2:27][C:28](=[O:29])[N:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH3:23]
Reactant: COC(=O)CCNCc1cccnc1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A mixture of methyl 3-(3-pyridylmethylamino)propionate (28.72 g), triethylamine (22 ml) and methylene chloride (240 ml) is cooled to 5°-10° C., and thereto is added dropwise a solution of ethoxycarbonylacetyl chloride (23.38 g) in methylene chloride (60 ml). The mixture is stirred at room temperature for one hour. The mixture is filtered to remove precipitates (triethylamine hydrochloride). The filtrate is washed with water, dried and then distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent, ethyl acetate) to give ethyl[N-(3-pyridylmethyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (35.22 g, 77.3%) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9](NC(=O)C)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl.C1C[O:21]CC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:21])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(=O)NC(=Cc1ccc(Cl)cc1)C(=O)O
Reactant: C1CCOC1
Agent: Cl
Product: O=C(O)C(=O)Cc1ccc(Cl)cc1
Yield: 77.3 %

Procedure:
4.55 g β-(4-chlorophenyl)-α-acetamidoacrylic acid, 91 mL of 1 mol·L−1 hydrochloric acid solution and 45 mL THF were added to a flask, and the mixture was heated for reflux for 10 h. After decolorization using active carbon and filtration, the filtrate was placed for crystallization, and an off-white crystalline powder was obtained in a yield of 77.3% by sucking filtration, washing and drying.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:11]([O-])([O-])[O:12][CH2:13][CH3:14].C(OC(=O)C)(=O)C>>[CH2:8]([O:7][C:5](=[O:6])[C:4](=[CH:11][O:12][CH2:13][CH3:14])[C:3]([CH2:2][Cl:1])=[O:10])[CH3:9]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)CCl)C(=O)OCC
Yield: 90.3 %

Procedure:
10 g (60.7 mM) of ethyl 4-chloroacetoacetate, 18 g (121 mM) of ethyl orthoformate and 25 g (245 mM) of acetic anhydride were stirred at 110° C. for 3 hours. Then, excessive ethyl orthoformate and acetic anhydride were distilled off under vacuum and the residue was recrystallized from hexane to obtain 12.1 g of a needle-like crystal with an yield of 90%.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[H-].[Na+].[CH3:17]I>CN(C=O)C>[CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][N:5]([CH3:17])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)CCNC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of tert-butyl 3,3-dimethylbutylcarbamate (1.72 g, 8.56 mmol) in dry DMF (20 mL) was portionwise added 60% NaH in mineral oil (685 mg, 17.12 mmol) under a N2 atmosphere. After 30 min, MeI (2.68 mL, 42.8 mmol) was added dropwise with ice cooling. The mixture was stirred at room temperature for 2 d, poured in ice-H2O and extracted with Et2O (30 mL). The organic layer was dried (Na2SO4) and concentrated to yield the desired product (1.43 g, 63%, 80% purity) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]([C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[CH:24]=[CH:25][CH:26]=1)([C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([F:20])[CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:38]1([N:43]=[C:44]=[O:45])[CH2:42][CH2:41][CH2:40][CH2:39]1.C1COCC1.[OH-].[Li+]>C(Cl)Cl>[CH:38]1([NH:43][C:44](=[O:45])[NH:1][C:2]([C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:24]=[CH:25][CH:26]=2)([C:10]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[C:12]([F:20])[CH:11]=2)[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CCOC(=O)CCCCCCc1cccc(C(N)(Cc2ccccc2)c2cc(F)cc(C(F)(F)F)c2)c1
Reactant: O=C=NC1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)CCCCCCc1cccc(C(Cc2ccccc2)(NC(=O)NC2CCCC2)c2cc(F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.7 %

Procedure:
To a solution of ethyl 7-(3-(1-amino-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoate (169 mg, 0.33 mmol) in anhydrous DCM (1 mL) was added cyclopentyl isocyanate (22 mg, 0.2 mmol). The reaction mixture was stirred at rt for 18 h. To the reaction mixture was added anhydrous THF (1 mL) and the mixture was stirred at room temperature for additional 1 h. The solvents were evaporated on a rotary evaporator and the residue was dissolved in methanol and purified by preparative HPLC (RT=11.3 min, Waters Sunfire C18 OBD, 19×100 mm eluting with 26-90% MeCN/H2O containing 0.1% TFA over 9 min and hold at 90% for 7 more minutes; 40 mL/min, monitoring at 220 nm). The resulting solid was dissolved in methanol (1 mL) followed by the addition of aqueous lithium hydroxide (1 N, 0.25 mL, 0.25 mmol). The reaction mixture was heated at 36° C. for 18 h. The crude product was purified by preparative HPLC (RT=10.7 min, Waters Sunfire C18 OBD, 19×100 mm eluting with 18-90% MeCN/H2O over 10 min and hold at 90% for 6 additional minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to yield 7-(3-(1-(3-cyclopentylureido)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoic acid (Example 234, 32 mg, 53% yield for 2 steps). LCMS: RT=4.33 min, Purity >95%, [M+H] 599.4 (Sunfire-S5-C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.36 ppm, 1H, s; 7.16-7.24 ppm, 4H, m; 7.10-7.13 ppm, 3H, m; 6.97 ppm, 1H, d, J=7.7 Hz; 6.94 ppm, 1H, s; 6.67 ppm, 2H, d, J=7.1 Hz; 5.58 ppm, 1H, brd, s; 3.87 ppm, 1H, d, J=12.6 Hz; 3.83 ppm, 1H, m; 3.65 ppm, 1H, d, J=12.7 Hz; 2.54, 2H, t, J=7.5 Hz; 2.29 ppm, 2H, t, J=7.4 Hz; 1.73-1.84 ppm, 2H, m; 1.50-1.60 ppm, 8H, m; 1.15-1.36 ppm, 6H, m.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][NH:13][C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[CH2:27][CH:28]1[CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][N:13]([CH2:27][CH:28]3[CH2:30][CH2:29]3)[C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2cc(=O)[nH]nc2-c2ccc(OC)c(F)c2)cc1F
Reactant: ClCC1CC1
Product: COc1ccc(-c2cc(=O)n(CC3CC3)nc2-c2ccc(OC)c(F)c2)cc1F

Procedure:
Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedures of Example 146 were repeated likewise, whereby the title compound was obtained quantitatively.