Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.[C:10]1(=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[O:11]1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([N:9]2[C:10](=[O:11])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:19])[CH:3]=1
Reactant: Cc1cnc(N)cc1C
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cnc(N2C(=O)c3ccccc3C2=O)cc1C
Temperature: 90 °C
Yield: 33.7 %

Procedure:
To a solution of 4,5-dimethylpyridin-2-amine (2.1 g, 0.02 mol) in acetic acid (40 mL) was added isobenzofuran-1,3-dione (2.5 g, 0.02 mol) at the room temperature. The mixture was heated at 90° C. overnight. The resulting solution was basified by saturated solution of NaHCO3 and extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give 2-(4,5-dimethylpyridin-2-yl)-isoindoline-1,3-dione (1.7 g, 40%) 1H NMR (300 MHz, DMSO) δ 8.33 (s, 1H), 7.97-7.91 (m, 4H), 7.32 (s, 1H), 2.30 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: C(OC(=O)C)(=[O:3])C.[CH:8]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11]>C(O)=O>[C:10]([O:9][CH:8]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])(=[O:3])[CH3:11]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOC(OCC)OC(C)=O
Yield: 54.5 %

Procedure:
Acetic anhydride (550 g), formic acid (275 g) and triethyl orthoformate (740 g) were reacted as is described in DeWolfe, Synthesis, 1974, 153-172 (scaled up five fold). The product had a b.p. of 77°-78° C. at 25 mmg/Hg, and was obtained in a yield of 54.5%.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][O:8][CH2:7][CH:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:5]1)=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[NH2:1][CH:4]1[CH2:9][O:8][CH2:7][CH:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:5]1
Reactant: CC(C)(C)OC(=O)NC1COCC(N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1COCC(N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a solution of tert-butyl 5-azido-tetrahydro-2H-pyran-3-ylcarbamate (1 g, 4.13 mmol) in 30 mL of ethyl acetate was added Pd/C (10%, 1 g), the reaction mixture was stirred overnight at room temperature under a hydrogen filled balloon. The reaction mixture was filtered over celite, the filtrate was concentrated to give tert-butyl 5-amino-tetrahydro-2H-pyran-3-ylcarbamate (188 mg, 21%) as white solid. LCMS: (M+H)+=217; 1H NMR (300 MHz, CDCl3): δ 3.84-3.57 (m, 4H), 3.19-3.05 (m, 2H), 2.21-1.65 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Br:10]Br>C(Cl)(Cl)(Cl)Cl>[Br:10][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[S:1][CH:5]=1
Reactant: BrBr
Reactant: c1ccc2sccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1csc2ccccc12
Yield: 48408 %

Procedure:
Dissolve benzo[b]thiophene (23 g, 0.170 mmol) in carbon tetrachloride (80 mL). Add, by dropwise addition, a solution of bromine (26.85 g, 0.168 mmol) in carbon tetrachloride (30 mL) and stir at room temperature for 2 days. Quench with a 1M solution of sodium thiosulfate and separate the organic phase. Extract the aqueous phase with carbon tetrachloride, combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo and purify by distillation to give 3-bromobenzo[b]thiophene as a pale yellow liquid (17.33 g, 48%); bp 64°-72° C. @ 0.02 mm Hg.
Reaction SMILES: Cl[C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[N:5]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:7]=1.[CH2:20]1[CH:27]2[NH:28][CH:22]([CH2:23][C:24]([CH2:26]2)=[O:25])[CH2:21]1.Cl.C(N(CC)CC)C>C(O)C.C(OCC)(=O)C.O>[CH:8]1([C:6]2[N:7]=[C:2]([N:28]3[CH:22]4[CH2:21][CH2:20][CH:27]3[CH2:26][C:24](=[O:25])[CH2:23]4)[C:3]3[C:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:12][S:11][C:4]=3[N:5]=2)[CH2:10][CH2:9]1
Reactant: O=C1CC2CCC(C1)N2
Reactant: Clc1nc(C2CC2)nc2scc(-c3ccccc3)c12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1CC2CCC(C1)N2c1nc(C2CC2)nc2scc(-c3ccccc3)c12
Temperature: 140 °C
Yield: 129.9 %

Procedure:
A mixture of 4-chloro-2-cyclopropyl-5-phenyl-thieno[2,3-d]pyrimidine (0.30 g, 1.05 mmol, ex Enamine), nortropinone hydrochloride (0.25 g, 1.57 mmol) and triethylamine (0.44 mL, 3.14 mmol) in ethanol (4 mL) was heated to 140° C. for 30 min in a microwave. Heating was repeated. Further portions of triethylamine (0.44 mL, 3.14 mmol) and nortropinone hydrochloride (0.25 g, 1.57 mmol) were added and the mixture was stirred at room temperature for 3 nights. It was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated and the aqueous was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (1×20 mL), dried (magnesium sulfate, filtered and evaporated to give a brown oil (512 mg). This was purified by silica chromatography (10 g cartridge; eluent petroleum ether 40-60/ethyl acetate 0 to 100%; all output collected) to give 8-(2-cyclopropyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-oneas a yellow solid (0.15 g). m/z [M+H]+ 376.0. Retention time 4.98 min (LCMS method+ve 6 min).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13][C:12]=2[CH:24]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][C:12]=2[CH:24]=1)[CH3:2]
Reactant: CCOc1ccccc1COc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccccc1COc1ccc2c(c1)C=C(C(=O)O)CCS2(=O)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 73.5 %

Procedure:
Into a solution of methyl 7-[(2-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (220 mg) in THF-methanol (5-2.5 ml) was added at room temperature an aqueous solution (1.0 ml) of potassium carbonate (151 mg), and the resulting mixture was stirred at 60° C. for 20 hours. After cooling to room temperature, the reaction mixture was mixed with 1 N hydrochloric acid (10 ml) and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[(2-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (156 mg) as colorless crystals.
Reaction SMILES: [OH-].[Na+].[SH:3][CH2:4][C:5]([OH:7])=[O:6].Cl[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO>[CH2:9]([S:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)CS
Reactant: ClCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CSCCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 1 L flask, solid sodium hydroxide (10.50 g, 0.263 mol) was dissolved in MeOH (150 ml), and then slowly combined with 2-mercaptoacetic acid (11.51 g, 0.125 mol). The mixture was then treated in portions with (2-chloroethyl)benzene (19.33 g, 0.138 mol), heated at reflux for 10 hours, stirred for 6 hours at ambient temperature, concentrated to dryness on a rotovap, treated with water (500 mL) and extracted with Et2O (2×150 mL). These Et2O extractions were discarded. The aqueous layer was acidified to pH ˜2 with concentrated HCl and extracted with Et2O (2×150 mL). These Et2O extractions were combined, washed with brine, dried (MgSO4), filtered and concentrated to provide the title compound. 1H NMR (CDCl3) δ 2.93 (s, 4H), 3.25 (s, 2H), 7.17-7.34 (m, 5H); MS (M+NH4)+ m/z 214.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:41]=[CH:40][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:41][CH:40]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: COc1cccc(C[C@H]2CN[C@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)C2)c1
Agent: Cl
Product: COc1cccc(C[C@@H]2C[C@@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)N(C(=O)Cn3cncn3)C2)c1
Yield: 82 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(3-methoxybenzyl)pyrrolidine-2-carboxamide, gave Compound 70, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(3-methoxybenzyl)pyrrolidine-2-carboxamide (160 mg, 82%). 1H-NMR (400 MHz, CDCl3): σ 9.00 (s, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.41 (d, 2H), 7.00 (t, 2H), 6.93-6.89 (m, 4H), 6.80-6.73 (m, 4H), 5.03 (d, 1H), 4.95 (d, 1H), 4.80 (d, 1H), 3.81 (s, 3H), 3.63 (dd, 1H), 3.27-3.16 (m, 1H), 3.02-2.88 (m, 2H), 2.68-2.59 (m, 2H), 1.76-1.68 (m, 1H). MS (EI) for C29H28FN5O4. found 530.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12](F)=[CH:13][C:14]=3[O:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:9]=2)[CH:5]=[C:4]([CH3:30])[N:3]=1.[CH3:31][O-:32].[Na+].CO.O>CN(C=O)C.C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:32][CH3:31])=[CH:13][C:14]=3[O:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:9]=2)[CH:5]=[C:4]([CH3:30])[N:3]=1
Reactant: C[O-]
Reactant: Cc1cc(-c2nc3cc(F)cc(OCCOc4ccccc4)c3c(=O)[nH]2)cc(C)n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OCCOc2ccccc2)c2c(=O)[nH]c(-c3cc(C)nc(C)c3)nc2c1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a suspension of 2-(2,6-dimethylpyridin-4-yl)-7-fluoro-5-(2-phenoxyethoxy)-3H-quinazolin-4-one (0.59 g, 1.45 mmol) in DMF (10 mL) was added a solution of sodium methoxide in methanol (25 wt %, 3.15 g, 14.5 mmol) and the reaction mixture was stirred at approximately 70-80° C. for 48 hours, then cooled to room temperature. Water (1 mL) was added, the mixture was neutralized to pH approximately 6-7 with acetic acid, concentrated, dissolved in DCM, washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was passed through a column (eluted with 2% methanol in DCM), to give 0.12 g of the desired product. The crude product was washed with acetonitrile, then solubilized in dioxane, and precipitated by adding water to afford the title compound as a white solid. Yield: 70 mg (11%). 1H NMR (400 MHz, DMSO-d6): δ 12.08 (br s, 1H), 7.77 (s, 2H), 7.31 (t, J=7.81 Hz, 2H), 7.04 (d, J=8.20 Hz, 2H), 6.96 (t, J=7.42 Hz, 1H), 6.83 (d, J=1.56 Hz, 1H), 6.69 (s, 1H), 4.40-4.53 (m, 2H), 3.90 (s, 3H), 3.33 (s, 6H). MS (ES+) m/z: 418.14 (M+1)+; MP 172.3-173.2° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[C:32](O)[CH:31]=[CH:30][C:29]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][O:22][C:32]3[CH:31]=[CH:30][C:29]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:28]([F:27])[CH:33]=3)=[CH:19][CH:20]=2)[N:12]=[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cc(OCc2ccccc2)n(Cc2ccc(CO)cc2)n1
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(C(C)(C)C)cc3OCc3ccccc3)cc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a mixture of (4-([5-(benzyloxy)-3-tert-butyl-1H-pyrazol-1-yl]methyl)phenyl)methanol (0.60 g, 1.7 mmol), ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (0.40 g, 1.9 mmol), tributylphosphine (0.85 mL, 3.4 mmol) and tetrahydrofuran (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.86 g, 3.4 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, diisopropyl ether was added to the residue, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:4) to give the title compound (0.82 g, yield 88%) as a colorless oil. MS: m/z 545 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>>[CH2:17]([N:19]([CH2:20][CH3:21])[C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:16])[CH3:18]
Reactant: CCNCC
Reactant: COc1ccc(-c2oncc2C(=O)O)cc1
Product: CCN(CC)C(=O)c1cnoc1-c1ccc(OC)cc1

Procedure:
The title compound was prepared from 5-(4-methoxyphenyl)isoxazole-4-carboxylic acid (11.0 mg, 0.050 mmol) and diethylamine (4.4 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method A to give a solid (7.8 mg). MS (pos) m/z 275.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C[O-].[Na+].C[CH2:22][O:23]C(C)=O>CS(C)=O.CO>[CH3:22][O:23][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-1,3-dinitro-5-trifluoromethyl-benzene (5.43 g, 20.1 nunol) was dissolved in 10 mL anhydrous DMSO. Sodium methoxide (5.85 mL of a 25% w/w solution in methanol) was added by syringe. The yellow solution immediately turned pink-orange, with heat evolved. The reaction was left stirring overnight at room temperature, then EtOAc (300 mL) was added and the mixture was washed once with dilute HCl aqueous solution, thrice with water and once with brine. The organic solution was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified through a short plug of silica gel and 4.65 g of 2-methoxy-1,3-dinitro-5-trifluoromethylbenzene was isolated as a yellow solid.
Reaction SMILES: CN(C)C=O.[CH2:6]([O:13][C@@H:14]1[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:18]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:17]([CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:16][C@H:15]1[C:45]1[CH:50]=[C:49]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][C:53]=2[CH3:59])[C:48]([CH3:60])=[CH:47][C:46]=1[O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:70][CH2:71][N:72]1[C:76](=[O:77])[C:75]2=[CH:78][CH:79]=[CH:80][CH:81]=[C:74]2[C:73]1=[O:82].C(=O)([O-])[O-].[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].O>[CH2:6]([O:13][C@@H:14]1[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:18]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@@H:17]([CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:16][C@H:15]1[C:45]1[CH:50]=[C:49]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH2:70][CH2:71][N:72]3[C:73](=[O:82])[C:74]4[C:75](=[CH:78][CH:79]=[CH:80][CH:81]=4)[C:76]3=[O:77])=[CH:54][C:53]=2[CH3:59])[C:48]([CH3:60])=[CH:47][C:46]=1[O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cc(O)ccc1Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(OCc2ccccc2)cc1C
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCCN2C(=O)c3ccccc3C2=O)ccc1Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(OCc2ccccc2)cc1C
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 14.8 %

Procedure:
To a N,N-dimethylformamide solution (5.0 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-hydroxy-2-methylbenzyl)-4-methylphenyl]-D-glucitol (340 mg, 0.40 mmol) and N-(2-bromoethyl)phthalimide (1.02 g, 4.0 mmol) were added potassium carbonate (553 mg, 4.0 mmol) and n-Bu4NI (14 mg, 0.038 mmol). The reaction mixture was stirred at 80° C. for 3.5 hours. After the mixture was cooled to room temperature, water was added thereto, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain a residue. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (60 mg, 15%) as a pale yellow oily compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[C:14]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:13]=[CH:12][N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccnc(-c3ccc(C(C)C)cc3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(-c2nccc(-c3ccc(C(=O)O)cc3)n2)cc1
Reaction time: 12 h
Yield: 41 %

Procedure:
Part B. A solution of ethyl 4-[2-(4-isopropyl-phenyl)-pyrimidin-4-yl]-benzoate in THF-water-ethanol (2 mL/2 mL/1 mL) is treated with lithium hydroxide hydrate (60 mg) and stirred for 12 h. The solution is evaporated, and the residue is partitioned between 1 M aq. HCl and ethyl acetate. The organic phase is washed with water (20 mL), dried over magnesium sulfate, filtered and evaporated to afford the title compound as a white solid (65 mg, 41%), m.p. 262-264° C. 1H NMR (300 MHz, acetone-d6): δ 8.96 (1H, d, J=6 Hz), 8.48 (2H, d, J=9 Hz), 8.23 (2H, d, J=9 Hz), 8.12 (2H, d, J=9 Hz), 7.98 (1H, d, J=6 Hz), 7.44 (2H, d, J=9 Hz), 3.02 (1H, heptet, J=7 Hz), 1.33 (6H, d, J=7 Hz). MS (ES+): m/e 320 (20), 319 (100). MS (ES−): m/e 318 (20), 317 (100).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:6]#[N:7].[CH2:12]([OH:14])[CH3:13].C(OCC)C>C1C=CC=CC=1>[I:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:6](=[NH:7])[O:14][CH2:12][CH3:13]
Reactant: CCO
Reactant: Cc1ccc(C#N)cc1I
Agent: Cl
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=N)c1ccc(C)c(I)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 189.8 %

Procedure:
Hydrogen chloride gas was bubbled over a period of 35 minutes into a stirred solution of 3-iodo-4-methylbenzonitrile (preparation 51a, 2.00 g, 8.2 mmol) and ethanol (0.70 mL, 12.3 mmol) in benzene at 0° C. The mixture was stirred for 30 minutes at room temperature and then the mixture was placed in the refrigerator and left overnight. Diethyl ether (200 mL) was then added and a white solid precipitated. After leaving the mixture a further night in the refrigerator the precipitate was filtered. Dichloromethane and saturated aqueous potassium carbonate solution were added to the solid with stirring. The organic layer was dried (MgSO4) and evaporated to give the title compound (4.50 g, 80%) as an 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: O=C=NC1CCCC1
Reactant: CCOC(=O)CCCCCCc1cccc(C(N)(Cc2ccccc2)c2cc(F)cc(C(F)(F)F)c2)c1
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.