Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([Cl:23])[CH:14]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[Cl:23][C:15]1[CH:14]=[C:13]([CH:4]([CH2:5][CH:6]2[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2)[C:3]([OH:24])=[O:2])[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: COC(=O)C(CC1CCC(=O)CC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of 2-(3-chloro-4-methylsulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid methyl ester (590 mg, 1.58 mmol) in methanol (7.0 mL) and water (3.0 mL) was treated with lithium hydroxide (980 mg, 31.6 mmol). The reaction mixture was stirred at 25° C. for 2 h and then concentrated in vacuo to remove methanol. The remaining aqueous layer was diluted with water (25 mL) and washed with ethyl acetate (2×50 mL). The aqueous layer was then acidified to pH=3 with a 1N aqueous hydrochloric acid solution and was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 2-(3-chloro-4-methylsulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (550 mg, 97%) as a colorless gum: EI-HRMS m/e calcd for C16H19ClO5S (M+Na)+ 381.0534. found 381.0537.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7](I)=[C:6]([O:11][CH3:12])[CH:5]=1.C(Cl)(Cl)Cl.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[CH2:31]([Zn]Br)[CH2:32][CH2:33][CH3:34]>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CCOCC>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:31][CH2:32][CH2:33][CH3:34])=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: CCCC[Zn]Br
Reactant: COC(=O)c1ccc(I)c(OC)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCc1ccc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Iodo-3-methoxy-benzoic acid methyl ester (292 mg, 1 mmol) and Pd2(dba)3.CHCl3 (25 mg, 0.025 mmol) and P(tBu)3 (0.25 mL, 10% in hexane, 0.08 mmol) and n-BuZnBr (4 mL, 0.5 M in THF, 2.0 mmol) is mixed in N,N-dimethylformamide (4 mL) together and degassed. After stirring at room temperature for 1 hour, analysis of TLC suggested no starting material left and reaction is stopped. Et2O and H2O were then added and the ether layer is washed with water and dried. After the removal of ether, the residue is directly used in the next step after pass through a short column.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[NH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1>C(#N)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]2[NH:13][C:1](=[O:2])[N:21]([CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:27]3)[C:15]=2[CH:16]=1
Reactant: CCOC(=O)N1CCC(Nc2cc(F)ccc2N)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3ccc(F)cc32)CC1
Temperature: 40 °C
Yield: 63.8 %

Procedure:
A solution of 1,1′-carbonyldiimidazole (12.6 g, 78 mmol) in acetonitrile (150 mL) was added portionwise over 10 minutes to a stirred solution of D2 (13.7 g, 49 mmol) in acetonitrile (250 mL) at 40° C. The reaction mixture was heated at 40° C. for 15 hours and then allowed to cool. The precipitate was collected by filtration and washed with acetonitrile (2×50 mL) to give the title compound (9.6 g, 69% yield) as a purple solid that was used without further purification. (Rf: 0.5 (ethyl acetate/hexane 7:8))
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].[CH2:12]([O:14][C:15](=[O:24])[C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([OH:23])[CH:17]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:9]2[C:8]([F:11])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[F:1])[CH:17]=1)[CH3:13]
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Reactant: N#Cc1cc(F)c(F)c(F)c1
Product: CCOC(=O)c1cc(O)cc(Oc2c(F)cc(C#N)cc2F)c1
Yield: 39.4 %

Procedure:
Using 1.5 g (9.55 mmol) of 3,4,5-trifluoro-benzonitrile and 3,5-dihydroxy-benzoic acid ethyl ester (1.73 g, 9.55 mmol) and following the procedure of Example 42(a) afforded 1.2 g of the required product. 1H NMR (DMSO-d6): δ 1.28 (3H, t), 4.27 (2H, q), 6.67 (1H, t), 6.92 (1H, s), 7.18 (1H, s), 8.08 (2H, d), 10.20 (1H, brs).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][C:13](=[O:15])[O:12][C:10](=[O:11])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([OH:24])[CH:18]=1>ClCCl>[OH:24][C:19]1[CH:18]=[C:17]([Cl:16])[CH:23]=[CH:22][C:20]=1[NH:21][C:13](=[O:15])[CH2:14][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: Nc1ccc(Cl)cc1O
Solvent: ClCCl
Product: O=C(O)CC(CC(=O)Nc1ccc(Cl)cc1O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
Prepared by refluxing an equimolar mixture of 3-(4-chlorophenyl)glutaric anhydride and commercial 4-chloro-2-hydroxyaniline in dichloromethane for 0.5 h. After cooling to rt the precipitated product is isolated by suction filtration, washed, and dried to provide 90% of N-(2-hydroxy-4-chlorophenyl)-3-(4-chlorophenyl)glutaramic acid as light red crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1>C(N(CC)CC)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCN(c3ccc(Br)cc3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with 1-(4-bromophenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(4-bromophenyl)-4-(p-nitrobenzyl)piperazine
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][O:7][CH2:8][C@@:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:12][C@H:11]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10]1.NN>C1(C)C=CC=CC=1>[F:1][C:2]([F:38])([F:39])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][O:7][CH2:8][C@@:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Agent: NN
Solvent: Cc1ccccc1
Product: N[C@H]1CC[C@@](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Temperature: 80 °C
Yield: 85.5 %

Procedure:
To a solution of 2-((1S,3S)-3-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-3-phenylcyclopentyl)isoindoline-1,3-dione (69 mg), available from Example 7, in toluene (0.50 mL) was added anhydrous hydrazine (41 μL), and the reaction mixture was heated at 80° C. for 12 h. The precipitate was removed by filtration, and the filtrate was evaporated in vacuo to give the title compound (45 mg). The
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:18][C:26]3[O:27][C:28]4[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=4[N:30]=3)[CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: Clc1nc2ccccc2o1
Reactant: NCCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1ccc(C(OC2CCN(CCNc3nc4ccccc4o3)CC2)c2ccccn2)cc1
Yield: 48 %

Procedure:
To a mixture of 1.12 g (3.24 mmol) of 2-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]ethylamine obtained in Example 12 and 0.60 g (3.91 mmol) of 2-chlorobenzoxazole were added 0.57 g (4.12 mmol) of potassium carbonate and 5 ml of dioxane, and the mixture was stirred under heating at an oil-bath temperature of 80° to 85° C. for 3 hours. After the reaction, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using chloroform as an eluent, and the desired fraction was concentrated under reduced pressure to give 0.72 g (48%) of 2-[2-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]ethylamino]benzoxazole as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][CH2:17][C@@H:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1COC(c2ccccc2OCc2ccccc2)=N1
Reactant: CO
Product: COC(=O)[C@@H]1COC(c2ccccc2OCc2ccccc2)=N1

Procedure:
Compound (3) was esterified with methyl alcohol to provide (4).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:9](C(OCC)=O)[C:10]([O:12]CC)=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>>[Cl:8][C:6]1[CH:7]=[C:2]2[C:3]([CH2:9][C:10](=[O:12])[NH:1]2)=[N:4][CH:5]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Cl)cc1N
Agent: Cl
Product: O=C1Cc2ncc(Cl)cc2N1

Procedure:
A mixture of 3-amino-2-bis(ethoxycarbonyl)methyl-5-chloropyridine and 6N HCl (325 mL) was heated at reflux for 4 hours. After removing the aqueous acid in vacuo, the residue was taken up in water and filtered to remove a small amount of black insoluble material. On adjustment of the filtrate to pH 6.5 with solid NaHCO3, 6-chloro-4-azaoxindole precipitated as a tan solid (2.6 g) which was collected by filtration. The filtrate was extracted with ethyl acetate and the combined extracts were dried (MgSO4) and concentrated to yield an additional quantity of 6-chloro-4-azaoxindole (3.6 g). The total yield was thus 6.2 g (71% overall from 2,5-dichloro-3-nitropyridine).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[C:17]([CH2:18][OH:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)(O)[O-].[Na+].O1CCOCC1>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[C:17]([CH2:18][OH:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: OCc1cccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: OCc1cccnc1-c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 65.3 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of (4-chlorophenyl)boronic acid (1.6 g, 10.23 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), Pd(dppf)Cl2 (570 mg, 0.78 mmol, 0.10 equiv), and sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv) in a solvent mixture of dioxane (10 mL) and water (10 mL). The resulting solution was stirred for 4 h at 70° C., and then it was diluted with 100 mL of H2O. The resulting solution was extracted with 2×200 mL of dichloromethane, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:5) as eluent to yield 1 g (65%) of [2-(4-chlorophenyl)pyridin-3-yl]methanol as a light yellow oil.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1.[NH3:24]>>[NH2:24][C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1
Reactant: N
Reactant: CCCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Product: CCCOc1ccccc1-c1nc2nc(N)nnc2c(=O)[nH]1

Procedure:
In a similar manner to that described in Example 10, 3-methylthio-8-oxo-6-(2-propoxyphenyl)-7,8-dihydropyrimido[4,5-e][1,2,4]triazine (1.42 g) was reacted with ethanolic ammonia (70 ml) for 20 hours to give the crude title compound, (0.80 g) which together with another sample (0.17 g), similarly prepared, was recrystallised from ethanol to afford the title compound, 0.54 g, m.p. 255°-256° C.
Reaction SMILES: [CH2:1]([N:3]([CH3:39])[C@H:4]1[CH2:9][C@@H:8]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17]C)=[O:16])[C@@H:7]([NH:22][C:23](=[O:38])[CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH2:6][CH2:5]1)[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([N:3]([CH3:39])[C@H:4]1[CH2:9][C@@H:8]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([OH:17])=[O:16])[C@@H:7]([NH:22][C:23](=[O:38])[CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=2)[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCN(C)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](CCc2cccc(C(=O)OC)c2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCN(C)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](CCc2cccc(C(=O)O)c2)C1
Yield: 55.3 %

Procedure:
Following the procedure of Example 7e, methyl 3-(2-((1R,2S,5R)-5-(ethyl(methyl)amino)-2-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexyl)ethyl)benzoate (13 mg) was converted to the trifluoroacetic acid salt of the title compound as a white powder (7 mg) after purification by reverse phase HPLC and lyophilization. MS found: (M+H)+=534.4.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[C:5]([CH3:12])[CH:4]=1.Br[C:14]1C=CC(C(O)C)=CC=1C>>[OH:1][CH:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[C:5]([CH3:12])[CH:4]=1)[CH3:14]
Reactant: CC(=O)c1ccc(CO)cc1C
Reactant: Cc1cc(C(C)O)ccc1Br
Product: CC(=O)c1ccc(C(C)O)cc1C
Yield: 49 %

Procedure:
1-[4-(1-Hydroxy-ethyl)-2-methyl-phenyl]-ethanone is prepared following preparation 1a employing 1-(4-bromo-3-methyl-phenyl)-ethanol instead of (4-iodo-3-methyl-phenyl)methanol.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH2:19][CH:20]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>O1CCOCC1.O.C1(C)C=CC=CC=1>[CH:31]1[C:32]2[CH:20]([CH2:19][O:18][C:16]([N:5]3[CH2:6][CH:2]([OH:1])[CH2:3][CH:4]3[C:7]([OH:9])=[O:8])=[O:17])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C(O)C1CC(O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
Trans-4-hydroxyproline (5.0 g, 38.1 mmoles) is suspended in a mixture of dioxane (75 mL) and water (75 mL), and stirred briskly at ambient temperature. Sodium bicarbonate (8.0 g, 95.2 mmoles) is added. And the mixture is stirred until all solids dissolve. A solution of 9-fluorenylmethyl chloroformate (11.4 g, 44.0 mmoles) in toluene (25 mL) is added slowly dropwise. The mixture is then stirred for 16 hours. Water (50 mL) and saturated aqueous sodium bicarbonate (50 mL) are added to the reaction mixture, which is then poured into a separatory funnel and washed with diethyl ether (100 mL). The layers are separated, and the aqueous layer is titrated to a pH of about 2 (as determined using pH paper) with concentrated aqueous hydrochloric acid. Ethyl acetate (150 mL) is added to the acidic solution; the mixture is shaken well, and then poured into a separatory funnel. The layers are separated and the aqueous layer extracted again with ethyl acetate (150 mL). The combined ethyl acetate extracts are dried over anhydrous sodium sulfate, filtered and evaporated to a white glassy foam. The crude product is purified on silica gel (400 mL bed volume) eluting with ethyl acetate:acetic acid (100:2 [v/v], 1800 mL), then ethyl acetate:methanol:acetic acid (95:5:2 [v/v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to a clear colorless syrup. The syrup is co-evaporated three time with toluene (150 mL each) to remove residual acetic acid. The resulting amorphous white solid is dried well in vacuo. The yield is 12.0 g (89%).
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][N:13](C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CN(C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:6][C:5]1[C:4]([O:10][CH3:11])=[CH:3][C:2]([C:12]#[N:13])=[C:8]([F:9])[CH:7]=1
Reactant: COc1cc(Br)c(F)cc1N
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C#N)c(F)cc1N
Temperature: 100 °C
Reaction time: 6 h
Yield: 492.4 %

Procedure:
To a pressure tube was added 4-bromo-5-fluoro-2-methoxyaniline (0.24 g, 1.1 mmol), zinc cyanide (0.10 g, 0.87 mmol), Pd2(dba)3 (100 mg, 0.11 mmol), DavePhos (86 mg, 0.22 mmol) and DMF (3 mL). The reaction was sealed and stirred at 100° C. for 6 hours. The reaction was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to give 4-amino-2-fluoro-5-methoxybenzonitrile (0.18 g, 77%).
Reaction SMILES: [CH2:1]([C:8]1[C:13]2[CH2:14][O:15][CH2:16][C:12]=2[C:11]([OH:17])=[C:10]([CH3:18])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][CH2:20][CH2:21][CH2:22][Cl:23].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:19][CH2:20][CH2:21][CH2:22][Cl:23].[Cl:19][CH2:20][CH2:21][CH2:22][O:17][C:11]1[C:12]2[CH2:16][O:15][CH2:14][C:13]=2[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:10]=1[CH3:18]
Reactant: Cc1nc(Cc2ccccc2)c2c(c1O)COC2
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCCl
Solvent: Cc1ccccc1
Product: Cc1nc(Cc2ccccc2)c2c(c1OCCCCl)COC2
Temperature: 90 °C
Yield: 96.6 %

Procedure:
A mixture of 24.2 g (100 millimoles) of 4-benzyl-6-methyl-1,3-dihydro-furo[3,4-c]pyridin-7-ol, 113 g (1 mole) of 1,3-dichloropropane, 2 g of benzyltriethylammonium chloride, 100 ml of toluene and 100 g of 50% strength sodium hydroxide solution is heated for 3 hours at 90° C., whilst stirring. The organic phase is separated off and washed with 50 ml of water. After stripping off the solvent and the excess 1,3-dichloropropane, 30.7 g of 4-benzyl-6-methyl-1,3-dihydro-furo[3,4-c]pyridin-7-yl 3-chloropropyl ether are obtained; this material contains a small proportion of 1,3-bis-(4-benzyl-6-methyl-1,3-dihydro-furo[3,4-c]pyridin-7-oxy)-propane which does not interfere with the subsequent reaction.
Reaction SMILES: [C:1]([CH2:11][C:12]1([CH:18]([C:20]([O:22]C)=[O:21])[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([CH2:11][C:12]1([CH:18]([C:20]([OH:22])=[O:21])[CH3:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COC(=O)C(C)C1(CC(=O)OCc2ccccc2)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C(=O)O)C1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C

Procedure:
To the above 1-carbobenzoxymethyl-1-carbomethoxyethylcyclohexane (40.4 g) in dioxane (300 ml) was added 1N NaOH (150 ml) dropwise over 2 hours with stirring at room temperature. After 6 hours the reaction was neutralized with 1N HCl then the dioxane was evaporated. The cloudy solution was diluted with water, acidified with 1N HCl, then extracted two times with ethyl acetate, washed with saturated NaCl (aqueous), dried with MgSO4, filtered and then concentrated to an oil. By 1H NMR no mono-methyl ester could be seen in the crude reaction mixture, the major by product being the di-acid. The product was purified by flash chromatography (silica gel, eluted with CHCl3, MeOH,HOAc 99:1:0.1) then distilled free of the residual benzyl alcohol to give 1-carbobenzoxymethyl-1-carboxyethylcyclohexane. (29.6 g, 76%) 1H-NMR (CDCl3): δ7.05(s,5H); 4.9(s,2H); 2.35-2.1(m,2H); 2.2(s,2H); 1.85-1.55(m,2H); 1.35(br s,10H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:22][NH:23]4)=[CH:19][C:18]=3[F:33])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][NH:23]4)=[CH:19][C:18]=3[F:33])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)c(F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ncc(-c2nc(-c3cc4[nH]cc(CCC(=O)O)c4cc3F)no2)cc1Cl
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of ethyl 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D158) (250 mg) in isopropanol (20 mL) and water (4 mL) was added 0.8 mL of 20% NaOH aqueous solution. The mixture was then stirred overnight. Afterwards, the solution was adjusted to pH 3 by addition of concentrated HCl and evaporated in vacuo. The residue was treated with 8 mL DMF. The insolubles were filtered and the filtrate was purified by MDAP. The solvent was freeze dried to give 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoic acid (E111) (80 mg). δH (DMSO-d6, 400 MHz): 1.32 (6H, d), 2.54 (2H, t), 2.88 (2H, t), 5.40 (1H, m), 7.37 (1H, s), 7.48 (1H, d), 8.05 (1H, d), 8.50 (1H, d), 8.87 (1H, d), 11.24 (1H, s), 12.05 (1H, s); δF (DMSO-d6, 376 MHz): −121.6; MS (ES): C21H18ClFN4O4 requires 444; found 445.2 (M+H+).
Reaction SMILES: ClC1C=[CH:38][C:37](F)=[CH:36][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=1)=[O:5].[CH3:41][N:42]1C(C(Cl)=O)=CC(C)=[N:43]1>>[F:35][C:31]1[CH:30]=[C:29]([NH:28][C:24]2[N:23]=[C:22]([C:21]3[C:13]([C:9]4[CH:8]=[C:7]([NH:6][C:4]([C:3]5[N:42]([CH3:41])[N:43]=[C:37]([CH3:38])[CH:36]=5)=[O:5])[CH:12]=[CH:11][CH:10]=4)=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=34)[CH:27]=[CH:26][N:25]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1)c1cc(F)ccc1Cl
Product: Cc1cc(C(=O)Nc2cccc(-c3nn4ccccc4c3-c3ccnc(Nc4cccc(F)c4)n3)c2)n(C)n1

Procedure:
In an analogous procedure to Example 11, 40 mg of the title compound was prepared from 79 mg of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride to give the product as a white solid: 1H NMR (d6-DMSO, 300 MHz) δ 2.23 (s, 3H), 4.02 (s, 3H), 6.62 (d, 1H, J=5.2 Hz), 6.77 (td, 1H, J=9.0 and 2.3 Hz), 6.87 (s, 1H), 7.18 (td, 1H, J=6.9 and 1.3 Hz), 7.29-7.38 (m, 2H), 7.48-7.57 (m, 3H), 7.84 (d, 1H, J=10.8 Hz), 7.93 (d, 1H, J=6.4 Hz), 8.11 (s, 1H), 8.36 (d, 1H, J=5.2 Hz), 8.55 (d, 1H, J=8.8 Hz), 8.90 (d, 1H, J=6.8 Hz), 9.85 (s, 1H), and 10.28 (s, 1H); HRMS calcd for C29H23FN8O: 518.1979, found: 519.2060 (M+H+).