Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:29]=1[N:37]=[C:38]=[O:39])([CH3:27])[CH3:26]>>[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:35])[CH3:36])[C:29]=1[NH:37][C:38](=[O:39])[N:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)([CH3:26])[CH3:27]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCc1ccc(NCc2cccc(OC)c2)cc1
Product: CCCCCCCCc1ccc(N(Cc2cccc(OC)c2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 18.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (3-methoxyphenylmethyl)(4-octylphenyl)amine (1.5 g) and 2,6-diisopropylphenyl isocyanate (1.12 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-(3-methoxyphenylmethyl)-N-(4-octylphenyl)urea (0.46 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O.[Si:48]([O:65][CH:66](O)[C:67]#[C:68][CH3:69])([C:61]([CH3:64])([CH3:63])[CH3:62])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C1(C)C=CC=CC=1.O1CCCC1>[Si:48]([O:65][CH2:66][C:67]#[C:68][CH2:69][N:4]1[C:3](=[O:8])[C:2]([CH3:1])([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[NH:6][C:5]1=[O:7])([C:61]([CH3:62])([CH3:63])[CH3:64])([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CC#CC(O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(C2(C)NC(=O)N(CC#CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2=O)cc1
Yield: 54.7 %

Procedure:
5-Methyl-5-[4-(1-methylethoxy)phenyl]imidazolidine-2,4-dione (248 mg), triphenylphosphine (655 mg) and a solution of ethyl azodicarboxylate in toluene (2.2 mol/L, 1.00 mL) were added to a mixed solution of t-butyl-diphenylsilyloxy-2-butyn-1-ol (326 mg, 1.00 mmol) in tetrahydrofuran (10 mL) at room temperature. After completion of the reaction, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 303 mg of the title compound (yield: 55%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]3)[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[OH:22][CH:23]([CH3:26])[CH2:24][NH2:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[OH:22][CH:23]([CH3:26])[CH2:24][NH:25][C:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:10]2[NH:11][CH:12]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[N:9]=2)[CH2:18][CH2:17]1)=[O:21]
Reactant: O=C(O)[C@H]1CC[C@H](c2nc(-c3cccc(Br)c3)c[nH]2)CC1
Reactant: CC(O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)CNC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(Br)c3)c[nH]2)CC1

Procedure:
The solution of trans-4-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-cyclohexyl-carboxylic acid (1.22 mmol), 2-hydroxy-propylamine(3.65 mmol) and BOP (1.22 mmol) in DMF (6 mL) was stirred overnight at room temperature. The mixture was diluted with water, extracted with EtOAc, washed with saturated NaHCO3, dried over Na2SO4, and concentrated under vacuum. The residue was purified with flash chromatography (90:10:1 CH2Cl2/MeOH/NH4OH) to give trans-4-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-cyclohexane-carboxylic acid (2-hydroxy-propyl) amide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([N+:12]([O-])=O)=[C:4]([CH3:15])[N:3]=1.C(O)C.[H][H].Cl>[Pd].C.C(O)(C)C>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[C:5]([NH2:12])=[C:4]([CH3:15])[N:3]=1
Reactant: Cc1nc(N)c([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: Cc1nc(N)c(N)c(C)c1N

Procedure:
A 500 ml Parr Bottle was charged with 2-amino-4,6-dimethyl-3,5-dinitropyridine (21.2 g, 0.10 mole), 250 ml absolute ethanol, and 20 g 5% Pd/charcoal catalyst. The mixture was subjected to hydrogenation at ambient temperature with an initial hydrogen pressure of 60 psig. When no further uptake of hydrogen was observed, the mixture was filtered free of catalyst under a nitrogen atmosphere, and concentrated under vacuum to a volume of about 100 ml. The product concentrate was treated, under nitrogen at ice temperature, with a cold solution of hydrogen chloride (0.5 mole) in 85 ml anhydrous isopropyl alcohol. The trihydrochloride salt of 2,3,5-triamino-4,6-dimethylpyridine was obtained after vigorous stirring, filtering under nitrogen, and vacuum drying under high vacuum over P2O5 at 80°-90° C.
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.C(O)(=O)C.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: CC(=O)O
Product: c1ccc(COc2ncnc3nc[nH]c23)cc1
Temperature: 100 °C
Reaction time: 120 h
Yield: 28 %

Procedure:
Sodium (2.5 g, 109 mmol) was added to distilled benzyl alcohol (45 ml) under nitrogen. 6-Chloropurine (1.0 g, 6.47 mmol) was dissolved in distilled benzyl alcohol (73 ml) and the above solution (27 ml, 64.7 mmol) was added. The reaction was stirred at 100° C. under nitrogen for 5 days. After cooling to room temperature and neutralisation using glacial acetic acid, the solvent was removed in vacuo. Water (70 ml) was added and the product was extracted into ethyl acetate (3×30 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed. After further drying in vacuo, the product was recrystallised from acetone to yield the title compound as a white crystalline solid (0.39 g, 28%), m.p. 173-175° C.; (Found: C, 63.14; H, 4.29; N, 24.80. Calc. for C12H10N4O: C, 63.71; H, 4.46; N, 24.76%); δH (200 MHz, d6-DMSO) 8.480 (1H, s, C(2)H or C(8)H), 8.307 (1H, s, C(2)H or C(8)H), 7.522-7.301 (5H, m, Ph), 5.592 (2H, s, OCH2); m/z 226 (M+, 36%), 197 (8), 120 (35), 91 (Bn+, 100%), 81 (9), 65 (24), 57 (23), 43 (16), 32 (8).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH:6]([C:8]1[C:9](=[O:21])[N:10]([CH3:20])[C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)[NH2:7].C(N(CC)CC)C>O1CCOCC1>[CH3:20][N:10]1[C:11]2[C:16](=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)[N:17]=[C:8]([NH:6][NH:7][C:1](=[O:4])[CH2:2][CH3:3])[C:9]1=[O:21]
Reactant: CCC(=O)Cl
Reactant: COc1ccc2c(c1)nc(NN)c(=O)n2C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCC(=O)NNc1nc2cc(OC)ccc2n(C)c1=O

Procedure:
Propionyl chloride (2.63 g., 28.4 mmol) is added dropwise to a solution of 3-hydrazino-1-methyl-6-methoxy-1H-quinoxalin-2-one (4.5 g., 23.7 mmol) and triethylamine (2.87 g., 28.4 mmol) in 250 ml. of dioxane and stirred at room temperature for four days. The dioxane is then removed under vacuum and the residue washed with water, filtered, and dried at 80° C. under high vacuum. The material is then recrystallized from ethanol, filtered and dried at 80° under high vacuum overnight to yield purified product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([NH:28][CH2:29][CH2:30][NH:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)(=[O:27])=[O:26].[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(N(CC)CC)C>ClCCl.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])=[O:13])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([NH:28][CH2:29][CH2:30][N:31]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)[S:41]([CH3:40])(=[O:43])=[O:42])(=[O:26])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(S(=O)(=O)NCCNc2ccc(OC)cc2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)(=O)NCCN(c2ccc(OC)cc2)S(C)(=O)=O)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The material from Example 96, Step C was combined with methanesulfonyl chloride (1.1 equivalents) and triethylamine (3 equivalents) in dichloromethane, and stirred for for one hour at room temperature. The reaction was diluted with EtOAc, washed with sat NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo to obtain the titled compound. ESI+ MS: 714 [M+H]+.
Reaction SMILES: O.[OH-].[Li+:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:17])[C:13]([O:15]C)=[O:14])=[N:9][CH:10]=1>O1CCCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:17])[C:13]([O-:15])=[O:14])=[N:9][CH:10]=1.[Li+:3]
Reactant: COC(=O)C(=O)Nc1ccc(Cl)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.6 %

Procedure:
Methyl chlorooxoacetate (78.7 ml) was added dropwise to a suspension of 2-amino-5-chloropyridine (100 g) and sodium hydrogencarbonate (78.4 g) in tetrahydrofuran (2000 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was added to a mixture of diethyl ether (2000 ml), ammonium chloride (62.4 g) and water (1000 ml), liquid separation was performed. The resultant water layer was extracted with methylene chloride. Organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate (162 g). Water (450 ml) and lithium hydroxide (18.2 g) were added to a solution of this ester (160 g) in tetrahydrofuran (1800 ml). After the mixture was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure, and hexane (3000 ml) was added to the resultant residue to stir the mixture for 3 hours. Solids were collected by filtration and dried. Acetonitrile (1000 ml) was added to the solids (190 g), and the mixture was stirred for 1 hour. Solids formed were collected by filtration, washed with diethyl ether (500 ml) and then dried to obtain the title compound (158 g).
Reaction SMILES: [Si](OCC(OCC1C=CC=CC=1)=O)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH2][O:35][C:36](C1C=CC=CC=1)(C1C=CC=CC=1)[C:37]1[C:42]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([NH:49][C:50]3[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=3)[N:44]=2)=[CH:41][N:40]=[C:39]([NH2:56])[N:38]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[NH2:56][C:39]1[N:38]=[C:37]([CH2:36][OH:35])[C:42]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([NH:49][C:50]3[CH:51]=[CH:52][N:53]=[CH:54][CH:55]=3)[N:44]=2)=[CH:41][N:40]=1
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1nc(N)ncc1-c1ccnc(Nc2ccncc2)n1
Agent: CC(C)(C)[Si](OCC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Nc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CO)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
This compound was synthesized in an analogous manner to 21 utilizing benzyl 2-(tert-butyldiphenylsilyloxy)acetate in step one, and further TBDPS deprotection as the last step. To 4′-(tert-Butyl-diphenyl-silanyloxymethyl)-N2-pyridin-4-yl-[4,5]bipyrimidinyl-2,2′-diamine (150 mg, 0.281 mmol), TBAF (1N in THF) (562 μl, 0.562 mmol) was added. The reaction was stirred rt for 1 hour. Additional TBAF (1N in THF) (281 μl, 0.281 mmol) was added, and the reaction mixture was stirred for an additional 2 hours. The reaction was quenched by slow addition of saturated ammonium chloride and the volatiles were evaporated. The residue was then partitioned between water and EtOAc. The organic layer was washed with brine, dried with sodium sulfate, and concentrated. The crude product was purified by reverse-phase HPLC [100% aqueous phase to 60% organic phase over 15 minutes] to obtain the desired product as a slightly pale yellow solid (50 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6) ppm 4.66 (d, J=2.53 Hz, 2 H) 5.04 (br. s., 1 H) 7.18 (s, 2 H) 7.30 (d, J=5.05 Hz, 1 H) 7.77 (d, J=6.06 Hz, 2 H) 8.36 (d, J=6.06 Hz, 2 H) 8.57 (d, J=5.56 Hz, 1 H) 8.63 (s, 1 H) 10.03 (s, 1 H). HRMS (ES+) for C14H13N7O.H+ [MH+]: calcd. 296.1260. found 296.1263. UV-LC: 100/100% UV purity at 214/254 nm; tR=2.87 minutes over 7.75 minutes
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](O)[CH:3]=1.[Cl:12]CCCl.[Cl-].[P+]=O>CN(C=O)C>[Cl:12][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: Cc1cc(O)ncc1[N+](=O)[O-]
Reactant: ClCCCl
Agent: O=[P+]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A 100 ml three-necked round-bottomed flask equipped with a magnetic bar, a thermometer, a dropping funnel and a reflux condenser is charged with 4-methyl-5-nitro-pyridin-2-ol (5.0 g), and 1,2-dichloroethane (30 ml). Phosphorous oxide chloride (3.6 ml) is added dropwise. Into this mixture DMF (2.5 ml) is added dropwise at ambient temperature. The reaction mixture is heated at 70° C. under stirring for 0.5 hours. After cooling the mixture to ambient temperature, it is concentrated in vacuo at 50° C., to obtain a brown oily gum. Purification of this gum by flash chromatography over silica gel with hexane/ethyl acetate 7:3 (v:v) gives 4.91 g of the compound as a light yellow solid (MP: 35-38° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:20]4[S:21][C:22]([Cl:25])=[CH:23][CH:24]=4)O)[CH:16]=3)[N:11]([CH3:26])[C:10](=[O:27])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:30])=O>C(Cl)Cl>[Cl:30][CH:18]([C:20]1[S:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:26])[C:10](=[O:27])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(O)c3ccc(Cl)s3)ccc21
Solvent: ClCCl
Product: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(Cl)c3ccc(Cl)s3)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(3-chloro-phenyl)-6-[(5-chloro-thiophen-2-yl)-hydroxy-methyl]-1-methyl-1H-quinolin-2-one 49 mg, 0.12 mmol) in CH2Cl2 (0.5 ml) was added thionyl chloride dropwise. The reaction mixture was stirred at room temperature for four hours. Thionyl chloride was removed under reduced pressure. The crude chloride was taken up in toluene and concentrated under vacuum to give a yellow solid which was used without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[S:17][C:18]([C@H:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[Cl:34])[N:22]5[CH2:26][CH2:25][CH2:24][C@H:23]5[OH:27])=[CH:19][N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1>CC#N>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[S:17][C:18]([C@@H:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[Cl:34])[N:22]5[CH2:26][CH2:25][CH2:24][C@H:23]5[OH:27])=[CH:19][N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Nc1ncc([C@H](c2ccccc2Cl)N2CCC[C@H]2O)s1)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CC#N
Product: O=C(Nc1ncc([C@@H](c2ccccc2Cl)N2CCC[C@H]2O)s1)C1(c2ccc3c(c2)OCO3)CC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((R)-(2-chlorophenyl)((R)-hydroxypyrrolidin-1-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((R)-(2-chlorophenyl)((R)-3-dimethyl-t-butylsilylhydroxypyrrolidin-1-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide using the same protocol described for 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-hydroxypyrrolidin-1-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide. 1H-NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.79 (dd, J=7.8, 1.6 Hz, 1H), 7.45-7.39 (m, 3H), 7.30-7.26 (m, 1H), 6.97 (s, 1H), 6.87 (d, J=0.9 Hz, 2H), 6.02 (s, 2H), 4.99 (s, 1H), 4.73 (d, J=4.3 Hz, 1H), 4.24-4.18 (m, 1H), 2.72 (dd, J=9.9, 6.1 Hz, 1H), 2.62 (q, J=7.8 Hz, 1H), 2.37-2.32 (m, 1H), 2.22 (dd, J=9.9, 3.2 Hz, 1H), 2.04-1.96 (m, 1H), 1.64-1.57 (m, 1H), 1.44 (q, J=3.8 Hz, 2H), 1.13 (t, J=3.8 Hz, 2H). HPLC ret. time 2.56 min, 10-99% CH3CN, 5 min run; ESI-MS 498.3 m/z (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:36]=[CH:35][C:26]3[C@H:27]([CH2:30][C:31]([O:33]C)=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:16]=1.[OH-].[Na+]>CO>[CH3:14][C:4]1[CH:5]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:36]=[CH:35][C:26]3[C@H:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:16]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCOC5)cc4C)c3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(O[C@H]2CCOC2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Yield: 98.3 %

Procedure:
Methyl 2-((S)-6-((2′,6′-Dimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 1d (220 mg, 0.45 mmol) was dissolved in 15 mL of methanol, followed by addition of 3 M aqueous sodium hydroxide solution (1.5 mL, 4.50 mmol). The reaction mixture was reacted for 3 hours. The mixture was concentrated under reduced pressure, mixed with 10 mL of water, and 1M hydrochloric acid was added dropwise to adjust the pH to 2. The resulting solution was extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 2-((S)-6-((2′,6′-dimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 1 (210 mg, yield 100%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[NH2:27][CH:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:27][CH:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(Cl)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
1.00 g of 4-chlorobenzoic acid and 1.45 g of dicyclohexylcarbodiimide (DCC) were solved in 30 ml of tetrahydrofuran, and the resulting solution was stirred at the room temperature for 2 hours. Subsequently, 1.35 g of diethyl aminomalonate hydrochloride and 0.65 g of triethylamine were added to 20 ml of tetrahydrofuran, and after stirring for about 20 minutes, the previously prepared solution was added to the this resulting solution. The mixed solution was then stirred at the room temperature for 2 hours to complete the reaction. After filtration of the solution and concentration of the filtrate, the concentrated filtrate was diluted with 50 ml of chloroform, washed with 20 ml of water twice and subjected to dry filtration to yield 1.72 g (86%) of diethyl 4-chlorobenzamidomalonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2cc(C(F)(F)F)ccn2)CC1
Yield: 31.9 %

Procedure:
Using the procedure from Example 1A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-4-(trifluoromethyl)pyridine (99 μl, 0.76 mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (49 mg), an off-white solid, in 32% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH:21]3[CH2:24][CH:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:22]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O:34]CC)=[O:33].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:31])[NH:20][CH:21]3[CH2:22][CH:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:24]3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CC(c5ccccc5)C4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NC1CC(c2ccccc2)C1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(3-phenylcyclobutylcarbamoyl)phenoxy)chroman-4-carboxylate (0.086 g, 0.17 mmol) in 3:1 THF/ethanol (4 ml) was added 1M sodium hydroxide (0.36 ml, 0.36 mmol), and the reaction was stirred overnight. The reaction was concentrated, taken up in water, acidified with 1M hydrochloric acid, and extracted twice with EtOAc. The combined organic layers were washed with saturated sodium chloride, dried over Na2SO4, filtered, and concentrated to yield 67 mg of the title compound (82% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7](=[CH2:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[H][H]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: C=C(C(=O)O)c1ccc(OC)cc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Product: COc1ccc([C@@H](C)C(=O)O)cc1
Yield: 88.8 %

Procedure:
In a 100 ml autoclave, the inside atmosphere of which had previously been replaced with argon, were placed 0.36 g (2 mmoles) of p-methoxyatropic acid and 20 ml of methanol. Then, 7.5 mg (0.009 mmole) of Ru((+)-BINAP)-(O2CCH3)2 prepared according to the same manner as in Referential Example 3 except using (+)-BINAP in place of (-)-BINAP was added to the mixture to perform hydrogenation for 12 hours at a hydrogen pressure of 100 kg/cm2 and at a reaction temperature of 19° C. Thereafter, the solvent was distilled off to provide 0.32 g of (2R)-(-)-2-(p-methoxyphenyl)propionic acid. The yield was 89%.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OC=CC1CC(=O)N1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCCC1CC(=O)N1
Yield: 97.9 %

Procedure:
A solution of 4-(2-acetoxyvinyl)-2-azetidinone (10.0 g, 0.065 mole) in 200 ml ethyl acetate containing 100 mg of 10% Pd/C is hydrogenated on a Parr shaker at 25° C. under 40 psi hydrogen for 15 minutes. The mixture is filtered through a bed of Supercel and washed with additional ethyl acetate. The combined filtrate is evaporated in vacuo to give 4-(2-acetoxyethyl)-2-azetidinone (10.0 g) as a crystalline solid. Recrystallization from ether affords white crystals: M.P. 44-7°; ir (CHCl3)μ5.66, 5.74; nmr (CDCl3)τ3.44 (broad s, 1, NH), 5.82 (m, 2, CH2OCOCH3), 6.29 (m, 1, C-4H), 6.87 (1/2 AB pattern further split in four by C-4H and NH, 1, Jgem =12.8 Hz, J=4.5H JNH =1.9 Hz, 7.38 (1/2 AB pattern further split in four by C-4H and NH, 1, Jgem =12.8 Hz, J=2.3 Hz, JNH =1.0 Hz), 7.93 and 8.02 (s on m, total 5, OCOCH3, and CH2CH2OCOCH3, respectively).