Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([O:23][CH:24]([CH3:27])[CH2:25][NH2:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:10]1([CH:8]([OH:9])[CH:7]([NH:26][CH2:25][CH:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:27])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(CN)OCc1ccccc1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Product: CC(CNC(c1ccccc1)C(O)c1ccccc1)OCc1ccccc1
Temperature: 140 °C
Reaction time: 12 h
Yield: 75.2 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 2-benzyloxypropylamine (2.48 g, 0.015 mol) was heated at 140° C. for 6 hours and then allowed to stand at ambient temperature for 12 hours. The solidified reaction mixture was triturated with petroleum ether and filtered to obtain 2.72 g of a solid. Mass spectral analysis showed starting materials present. Recrystallization from isooctane gave 2.16 g (60%) of the product as a white solid; mp 114°-119° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([N:19]=[CH:20][C:21]([S:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]3)=[N:22]2)=[CH:17][CH:16]=1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:34][CH:31]3[CH2:30][CH2:29][N:28]([CH2:27][CH2:26][S:25][C:21]4[CH:20]=[N:19][C:18]5[C:23](=[CH:24][C:15]([O:14][CH3:13])=[CH:16][CH:17]=5)[N:22]=4)[CH2:33][CH2:32]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Product: COc1ccc2ncc(SCCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)nc2c1

Procedure:
The title compound is prepared as a light yellow oil (2.03 g, 78% yield) following Scheme 3 and in analogy to Example 40 using 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (792 mg, 4.77 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (1.52 g, 4.77 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]([O:18][C:19]([N:21]1[C@@H:25]([C@H:26]([OH:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:23][C@H:22]1[CH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[OH:33][C@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:25]1[CH2:24][CH2:23][C@@H:22]([CH2:34][C:35]2[CH:43]=[CH:42][C:38]([C:39]([N:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:9][CH2:10]3)=[O:40])=[CH:37][CH:36]=2)[N:21]1[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reactant: c1ccc(CN2CCNCC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCN(Cc4ccccn4)CC3)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 0.018 g (0.102 mmol) of (1-(pyridine-2-ylmethyl)piperazine and 0.035 g (0.085 mmol) of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid in 2 mL of N,N-dimethylformamide was added 0.074 mL (0.425 mmol) of N,N-diisopropylethylamine and 0.065 g (0.170 mmol) of HATU. The resulting mixture was stirred under an atmosphere of nitrogen for 3 h and then purified directly by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). LC/MS: m/z (ES) 571.2 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[CH:12]=[O:13].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([NH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[CH:12]=[O:13])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cc(N)c(C=O)c(CC)n1
Solvent: c1ccncc1
Product: CCc1cc(NC(C)=O)c(C=O)c(CC)n1

Procedure:
A mixture of 4-amino-2,6-diethylpyridine-3-carbaldehyde (2.0 g) and acetic anhydride (10 ml) in pyridine (20 ml) was heated at reflux for 3 hours. Volatile material was removed by evaporation and the residue was dissolved in ethyl acetate. The solution was washed with aqueous sodium carbonate solution, followed by saturated sodium chloride solution and then dried (MgSO4). Volatile material was removed by evaporation to give an oil which was purified by flash chromatography, eluting with ethyl acetate/petroleum ether (1:1 v/v) to give 4-acetylamino-2,6-diethylpyridine-3-carboxaldehyde as a yellow solid (0.9 g); m.p. 91°-92° C.; NMR (CDCl3): 1.3(t, 3H), 1.35(t, 3H), 2.26(s, 3H), 2.8(q, 2H), 3.14(q, 2H), 8.38(s, 1H), 10.4(s, 1H), 11.7(broad, 1H); mass spectrum (CI): 221 (M+H)+ ; microanalysis, found: C, 65.3; H, 7.3; N, 12.3%; C12H16N2O2 requires: C, 65.4; H, 7.3; N, 12.7%.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:9][CH2:10]OS(C)(=O)=O)(=O)=O.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>C1COCC1>[CH:22]1([N:25]2[CH2:10][CH2:9][N:8]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:7][CH2:6]2)[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C(=O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(N1CCN(C2CC2)CC1)C(F)(F)F
Temperature: 48 °C

Procedure:
The product prepared as in Example 8 above, methanesulfonic acid 2-[(2-methanesulfonyloxy-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-ethyl ester (3.6 g) was dissolved in THF (18 mL). Cyclopropylamine (1.14 g, 20 mmol) was then added neat to the reaction mixture. The reaction mixture was then heated at 48° C. for 72 hours. The reaction mixture was then concentrated to a thick oil and the oil was chromatographed using 25-35% ethylacetate-hexanes mixture to yield the title compound as the late eluting fraction and isolated as thick brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([F:21])=[CH:23][CH:24]=2)=[O:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Product: CCCN(CC(=O)Nc1ccc(F)cc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-propylglycine and 4-fluoroaniline: MS (APCI) m/z 380 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CC(O)C>CCCCCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]2[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(O)cc1)c1cncn1C
Solvent: CC(C)O
Solvent: CCCCCC
Product: CCOC(=O)C[C@@H](c1ccc(O)cc1)c1cncn1C
Yield: 44 %

Procedure:
Racemic compound 74.4 (680 mg, 2.5 mmol) was separated on a semi-preparatory chiral CHIRALCEL OJ-H column (30×250 mm), using 15% i-PrOH in hexane as eluant. Eluant containing the peak with less retention time was concentrated and compound 74.5 (300 mg, 1.1 mmol) was obtained as off-white solid. The absolute configuration was assigned by analogy to other GPR40 agonist compounds. MS ESI (pos.) m/e 275.2 (M+H).
Reaction SMILES: [ClH:1].[N:2]1([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]3[N:30]=[C:29]([C@@H:31]4[CH2:35][CH2:34][CH2:33][N:32]4C(OC(C)(C)C)=O)[O:28][N:27]=3)[CH2:11]2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1>O1CCOCC1>[ClH:1].[N:2]1([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]3[N:30]=[C:29]([CH:31]4[CH2:35][CH2:34][CH2:33][NH:32]4)[O:28][N:27]=3)[CH2:11]2)=[O:9])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)no1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2noc(C3CCCN3)n2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.36 ml (1.46 mmol) of a 4N solution of hydrogen chloride in dioxane was added to a solution of 84 mg (0.146 mmol) of the compound from Example 91A in 0.7 ml of dioxane, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was then concentrated under reduced pressure, dichloromethane was added and the mixture was concentrated again. Yield: 74 mg (98% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[N:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=1[CH3:21].N1C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([S:8]([NH:20][C:18]2[CH:17]=[CH:16][C:15]([CH3:21])=[C:14]([O:13][CH3:12])[N:19]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1nc(N)ccc1C
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1nc(NS(=O)(=O)c2cccnc2Cl)ccc1C
Yield: 79.8 %

Procedure:
The title compound (1.60 g, 5.10 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.35 g, 6.39 mmol), 6-methoxy-5-methylpyridin-2-amine (IntC10) (970 mg, 7.02 mmol) and pyridine (1.55 mL, 19.2 mmol) in 1,4-dioxane (25 mL) at rt using the methods of (IntC1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[N:9]=2)=[N:4][CH:3]=1.Cl.Cl.[CH3:30][N:31]([CH3:36])[CH:32]1[CH2:35][NH:34][CH2:33]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[C:12]([N:34]3[CH2:35][CH:32]([N:31]([CH3:36])[CH3:30])[CH2:33]3)[N:11]=[C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[N:9]=2)=[N:4][CH:3]=1
Reactant: CN(C)C1CNC1
Reactant: Cc1cnc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)C4CC4)cc3)n2)s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc(Nc2cc(N3CC(N(C)C)C3)nc(Sc3ccc(NC(=O)C4CC4)cc3)n2)s1
Temperature: 90 °C
Yield: 66.7 %

Procedure:
A suspension of N-(4-(4-(5-methylthiazol-2-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)cyclopropanecarboxamide (138 mg, 0.33 mmol), 3-dimethylaminoazetidine dihydrochloride (178 mg, 1.0 mmol), N,N-diisopropylethylamine (0.34 ml, 1.98 mmol) in n-butanol (10 ml) was heated at 90° C. for 17 h. Reaction mixture was then allowed to cool to room temperature, concentrated in vacuo. The crude product was purified on HPLC to give the title compound as an off-white solid (106 mg, 58%). 1H NMR (DMSO) 0.82-0.81 (4H, m), 1.87-1.81 (1H, m), 2.07 (3H, s), 2.78-2.77 (6H, m), 4.20 (5H, s), 5.56 (1H, s), 6.94 (1H, s), 7.52 (2H, d), 7.76 (2H, d), 10.55 (1H, s). MS (ES+): 482.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][OH:51])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cr](O)(O)(=O)=[O:53].CC(O)C>CCOCC>[C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([OH:53])=[O:51])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO
Reactant: O=[Cr](=O)(O)O
Solvent: CC(C)O
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Yield: 89 %

Procedure:
The alcohol (40) (1.73 g, 2.41 mmol) was dissolved in ether (200 ml) at 30° C. and treated with chromic acid (4 ml of a 0.67M solution; 2.68 mmol). The resulting solution was allowed to stir and cool to room temperature over two hours during which time two further 1 ml portions of chromic acid were added. Propan-2-ol (5 ml) was then added and the ethereal solution washed with water four times, then dried, filtered and evaporated to leave the title compound (41) as a white powder (1.57 g; 89%).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=1.[OH-].[Na+].OCl>CO>[CH2:11]([O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:16])=[O:2])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCOc1cccc(C(=O)OC)c1
Agent: OCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCOc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
To 3-amyloxybenzoic acid methyl ester (35 g) in methanol (200 ml) was added 1N-sodium hydroxide aqueous solution (200 ml) and the mixture was stirred for 2 days at room temperature. Hydroxy chloride (20 ml) was added to the raction mixture. The precipitate was filtered and washed with water, acetonitrile and diisopropyl ether to give 3-amyloxybenzoic acid (30 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([NH:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]#[N:19])[CH:7]=1.O.O.[Sn](Cl)[Cl:26].Cl>CCO>[ClH:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:20]=[C:18]([NH2:19])[C:10]3[C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[S:13][C:9]=3[NH:8][C:6]=2[CH:7]=1
Reactant: Cl[Sn]Cl
Reactant: N#Cc1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccccc12
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC1=Nc2ccc(F)cc2Nc2sc3ccccc3c21
Temperature: 25 °C
Yield: 78.7 %

Procedure:
Combine 2-(5-fluoro-2-nitro-phenylamino)-benzo[b]thiophene-3-carbonitrile (2.15 g, 6.87 mmol) and Tin(II) chloride, dihydrate (4.65 g, 20.6 mmol) in a mixed solvent of EtOH (25 mL) and 5.0 N HCl (25 mL), heat the suspension to reflux for 3 hours, cool to RT. Suction filtration obtains the title compound 1.73 g (yield 78%) as a yellow solid by. Mass spectrum: ACPI (m/e): 284((M+1-HCl); 1H NMR (300 MHz, DMSO-d6) δ 11.46 (br, 1H), 10.02 (br, 1H), 9.02 (br, 2H), 7.90-7.87 (m, 1H), 7.71-7.68 (m, 1H), 7.46-7.40 (m, 1H), 7.33-7.28 (m, 1H), 7.12-6.94 (m, 2H), 6.85-6.81(m, 1H).
Reaction SMILES: [P:1]([O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:34][C:35]4[N:36]=[C:37]([C:40]5[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([C:47]([F:50])([F:49])[F:48])[CH:41]=5)[O:38][CH:39]=4)=[CH:28][CH:29]=3)[O:24][CH:23]=2)=[CH:18][CH:17]=1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[P:1]([OH:3])([OH:8])([O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:34][C:35]4[N:36]=[C:37]([C:40]5[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([C:47]([F:50])([F:49])[F:48])[CH:41]=5)[O:38][CH:39]=4)=[CH:28][CH:29]=3)[O:24][CH:23]=2)=[CH:18][CH:17]=1)=[O:2]
Reactant: CC(C)(C)OP(=O)(OCOc1ccc(-c2coc3cc(OCc4coc(-c5cc(F)cc(C(F)(F)F)c5)n4)ccc3c2=O)cc1)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c(-c2ccc(OCOP(=O)(O)O)cc2)coc2cc(OCc3coc(-c4cc(F)cc(C(F)(F)F)c4)n3)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 50 mL round bottomed flask ditert-butyl {4-[7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)-4-oxochromen-3-yl]phenoxy}methyl phosphate (119.1 mg, 0.166 mmol) was treated with trifluoroacetic acid (37.9 mg, 0.332 mmol, 2.0 equiv) in methylene chloride (2 ml). The mixture was stirred at room temperature for 18 hours, methylene chloride (10 ml) added, and the suspension thus obtained was filtered through a glass filter. The residue on the filter was collected to give {4-[7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)-4-oxochromen-3-yl]phenoxy}methyl dihydrogen phosphate.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].C([O-])([O-])=O.[K+].[K+].[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[F:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: Cc1cccc(C)c1CCl
Reactant: CCOC(=O)c1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(F)c(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 4-fluoro-3-hydroxybenzoate (2.814 g, 15.3 mmol), K2CO3 (1.95 g, 14.1 mmol) in DMF (15 ml) was added 2,6-Dimethylbenzyl chloride (2.21 g, 14.3 mmol) at room temperature under argon. The reaction mixture was stirred for 16 hours at the room temperature, diluted with ethyl acetate and washed with water (2×), and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hexane:ethyl acetate, 4:1) to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][CH:17]=[C:10]3[C:11]=2[C:6](=[C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]2=[CH:9]3)[C:5]1=[O:22].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.O>N1C=CC=CC=1>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([O:1][CH2:2][CH2:3][N:4]2[C:13](=[O:14])[C:12]3[CH:15]=[CH:16][CH:17]=[C:10]4[C:11]=3[C:6](=[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]3=[CH:9]4)[C:5]2=[O:22])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=C1c2cccc3cc4ccccc4c(c23)C(=O)N1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN2C(=O)c3cccc4cc5ccccc5c(c34)C2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
A mixture of 1.01 g (3.5 mmol) of 2-(2-hydroxyethyl)-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-dione in 10 ml of pyridine is treated with 0.69 g (3.6 mmol) of p-toluenesulfonyl chloride. The mixture is stirred at room temperature for 24 hours and poured into 50 ml of cold water. The solid is collected, washed with water, dried in vacuo, and crystallized from dimethylformamide water to give 1.2 g (77%) of 2-[2-(p-toluenesulfonyloxy)ethyl]-1,2-dihydro-3H-dibenz-[de,h]isoquinoline-1,3-dione. M.p. 240° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)=[O:23])=[CH:4][CH:3]=1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:39][CH:38]=1>>[CH3:34][O:33][C:31]([CH:27]1[CH2:28][CH2:29][CH2:30][CH:25]([NH:24][C:22]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:12]=2[O:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:39][CH:38]=3)=[CH:3][CH:4]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:23])[CH2:26]1)=[O:32]
Reactant: COC(=O)c1ccc(OCCCc2ccc(O)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Reactant: ClCc1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1ccc(OCCCc2ccc(OCc3ccc(Oc4ccccc4)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Methyl 3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(4-phenoxybenzyl)oxy]phenyl}propoxy)benzoate is prepared in analogy to the process described in Example 34 from methyl 4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate and 1-(chloromethyl)-4-phenoxybenzene.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]=[C:16]1[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH:17]1O>C(Cl)Cl>[ClH:1].[C:2]1([C:8]2([C:12]([O:14][CH:17]3[C:16](=[CH2:15])[CH:21]4[CH2:22][CH2:23][N:18]3[CH2:19][CH2:20]4)=[O:13])[CH2:9][CH2:10][CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccccc2)CCC1
Reactant: C=C1C2CCN(CC2)C1O
Agent: Cl
Solvent: ClCCl
Product: C=C1C2CCN(CC2)C1OC(=O)C1(c2ccccc2)CCC1

Procedure:
The title compound was prepared in an analogous manner to that in Example 36 by reacting 1-phenylcyclobutanecarboxylate hydrochloride with 3-methylidenequinuclidinol. The esterification was carried out in CH2Cl2. The crude was chromatographed on silica gel using toluene-Et3N 88:12 as eluent. The yield was 0.07 g (9%); mp 155-157° C.; 1H NMR (CDCl3) δ 1.80-2.10 (m, 7H), 2.25 (m, 1H), 2.52 (m, 2H), 2.76 (m, 3H), 3.18 (m, 5H), 4.09 (m, 2H), 7.29 (m, 5H), 12.2 (br, 1H). Anal. (C19H25NO2.HCl) H, N; C: calcd, 67.94; found, 67.25.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.[Cu]Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Br:15])[CH:17]=2)=[CH:8][C:7]=1[CH3:13]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: Brc1cccc(I)c1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A solution of 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (5.0 g, 26 mmol), 1-bromo-3-iodobenzene (21.9 g, 77 mmol), copper(I) chloride (1.3 g, 13 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (1.3 mL, 6.5 mmol), and cesium carbonate (12.7 g, 39 mmol) in NMP (100 mL) is heated to 120° C. The reaction is stirred overnight, and then is cooled to room temperature. The reaction is then quenched with 1N aqueous hydrochloric acid and extracted with ethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed. The crude is purified by silica gel column chromatography using 9/1 hexanes/ethyl acetate to elute the pure product. The solvent is removed to afford about 7.86 g (87%) of the desired product. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C17H17BrO3 348, found 349 (M+1, 100%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:14]12[O:9][CH:15]1[CH2:16][CH2:17][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2OC2C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
A solution of m-CPBA (7.53 g, 32.7 mmol) in DCM (10 mL) was added to a solution of tert-butyl 5,6-dihydropyridine-1(2H)-carboxylate (5.00 g, 27.3 mmol) in DCM (20 mL) at 0° C. The reaction was stirred at 0° C. for 15 minutes and then at room temperature for 3 hours. Saturated sodium sulfite solution (20 mL) and saturated sodium bicarbonate solution (30 mL) was added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo to give tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (5.36 g, 99%) as oil.