Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([NH:8][C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]1[CH2:24][C:25]([NH:27][CH:28]([CH:35]([CH3:37])[CH3:36])[CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31])=[O:26]>CO.ClCCl>[O:1]=[C:2]1[C:7]([NH:8][C:9](=[O:17])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=[C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:3]1[CH2:24][C:25]([NH:27][CH:28]([CH:35]([CH3:37])[CH3:36])[C:29](=[O:34])[C:30]([F:32])([F:31])[F:33])=[O:26]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)Cc2ccccc2)c1=O)C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)Cc2ccccc2)c1=O)C(=O)C(F)(F)F

Procedure:
Using a similar procedure to that described in Example 1, using methanol:dichloromethane (1:99) as the chromatography solvent, 2-(2-oxo-6-phenyl-3-phenylacetylamino-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide was oxidized to afford the title product; HPLC: tR =6.92, FR=2.0, column A, water:acetonitrile (55.45); MS: m/z=514(M+1).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:35])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:34])[CH:17]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])=[N:23][O:24][C:25]=3[CH3:26])=[O:20])[C@H:5]2[S:4]1.[CH3:36][N:37]1[C:41]([SH:42])=[N:40][N:39]=[N:38]1>P([O-])([O-])([O-])=O.CC(C)=O>[CH3:36][N:37]1[C:41]([S:42][CH2:2][C:3]2([CH3:35])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]3[C:16](=[O:34])[CH:17]([NH:18][C:19]([C:21]4[C:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[Cl:33])=[N:23][O:24][C:25]=4[CH3:26])=[O:20])[C@H:5]3[S:4]2)=[N:40][N:39]=[N:38]1
Reactant: Cn1nnnc1S
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(CBr)S[C@H]12
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(CSc3nnnn3C)S[C@H]12

Procedure:
By treating in the similar manner as described in Example 11 using 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate and 1-methyl-1H-tetrazole-5-thiol in a mixture of pH 6.85 phosphate buffer and acetone, there was obtained amorphous 2,2,2-trichloroethyl 2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+].C(=O)=O>CS(C)=O>[CH2:12]([N:2]([CH2:9][C:5]1[CH:6]=[CH:10][CH:11]=[CH:3][CH:4]=1)[C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc2sccc2c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C=O
Solvent: CS(C)=O
Product: c1ccc(CN(Cc2ccccc2)c2ccc3sccc3c2)cc1
Reaction time: 8 h
Yield: 121.4 %

Procedure:
A stirred solution of 5-aminobenzo[b]thiophene hydrochloride (4.65 g, 0.025 mole) in dry DMSO (40 ml) was treated with benzyl bromide (6 ml, 0.05 mole) followed by solid NaHCO3 (6.3 g, 0.075 mole). After the immediate, vigorous evolution of CO2, the mixture set to a solid mass. This was held at ambient temperature overnight and the solid then was collected and recrystallized from CH3CN to obtain 5.0 g (61%) of 5-(dibenzyl)aminobenzo[b]thiophene, m.p. 114°-117° C. A sample recrystallized from ethyl acetate-hexane melted at 115°-117° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)([N:25]1C=CN=C1)=O.N>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[NH2:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCC(=O)O
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCCCCCCCCC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
A mixture of 12-tert-butoxycarbonylaminododecanoic acid (3) (202 mg, 0.64 mmol) and 1,1′-Carbonyldiimidazole (114 mg, 0.70 mmol) in anhydrous THF (6 mL) was stirred at room temperature for 1 hour. Methanolic ammonia (7 M, 3 mL, 21 mmol) was then added via syringe and the reaction mixture stirred at room temperature for 16 hours. The solvent was removed by rotary evaporation and the resulting residue was subjected to Biotage silica gel column chromatography, eluting with 5% to 36% ethyl acetate in hexanes followed by 50% ethyl acetate in dichloromethane, to give the desired amide 7 (90.0 mg, 45%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.25 (m, 14H), 1.46 (s, 9H), 1.63 (m, 4H), 2.22 (t, 2H), 3.10 (m, 2H), 4.50 (br, 1H), 5.40 (br, 2H). m/z (ESI) 337 [C17H34N2O3+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[N+:18]([O-])([O-:20])=[O:19].[K+]>>[Cl:1][C:2]1[C:10]([N+:18]([O-:20])=[O:19])=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(Cl)c(C(=O)O)cc1C
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(C(=O)O)c(Cl)c([N+](=O)[O-])c1C

Procedure:
31.6 g of 2-chloro-4,5-dimethylbenzoic acid are initially introduced into 94 ml of H2SO4. 19 g of KNO3 are added in portions, while cooling with ice. The mixture is subsequently warmed to 50° for a further 2 hours and then poured onto ice. The product is isolated and recrystallized from toluene. Yield: 25.3 g, melting point: 160°-63°.
Reaction SMILES: [C:1]1([C:7]2([CH:13]=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([C:7]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC1(c2ccccc2)CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a stirred solution of 1-phenyl-cyclohexanecarbaldehyde (250) (16.4 g, 87.1 mmol) in methanol (200.0 mL) was added NaBH4 (6.62 g, 174.2 mmol) portion-wise at 0° C. The reaction mixture was then stirred at room temperature for 2 h. After completion of the reaction, the solvent was concentrated and the crude product was extracted with ethyl acetate. The organic layer was then washed with water and brine and dried over sodium sulfate and concentrated under reduced pressure to get (1-phenyl-cyclohexyl)-methanol (251) (15.2 g, 91.7%) as a white solid which was sufficiently pure to be used for the next step.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[CH:10]=[C:11]([CH:13]=[C:14]([CH3:16])[CH:15]=1)[NH2:12].NC1C=CC=CC=1.[OH-].[Na+]>C1COCC1>[CH3:8][C:9]1[CH:10]=[C:11]([NH:12][C:5](=[O:7])[CH3:6])[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(C)cc(C)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
Acetic anhydride (2.84 mL, 30 mmol) was dissolved in dry THF (10 mL), purged with N2 and brought to 0° C. 3,5-Dimethylaniline (1.25 mL, 10 mmol) was then added dropwise. After the addition of the aniline, the reaction was allowed to warm to room temperature and stirred for an additional hour. The solution was then poured over ice and 1 M NaOH (aq) was added until the pH was between 12 and 14. The precipitate was filtered, dissolved in DCM and dried over Na2SO4. The drying agent was filtered and solvent was removed under reduced pressure to afford pure product in 99% yield as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25][CH3:26])=[CH:9]2)=[N:6][CH:7]=1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25][CH3:26])=[CH:9]2)=[N:6][CH:7]=1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: OB(O)c1ccccc1Cl
Product: CSc1cn(-c2ncc(-c3ccccc3Cl)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Synthesized according to general procedure 1 from (1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (1.0 g, 2.30 mmol, 1.0 eq) and (2-chlorophenyl)boronic acid (0.429 g, 2.77 mmol, 1.2 eq). Yield: 0.7 g (65% of theory).
Reaction SMILES: [C:1]1(=[O:10])[N:5]([CH2:6][CH2:7][OH:8])[C:4](=[O:9])[CH:3]=[CH:2]1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH:13]=[CH:12]1.[CH:18]12[CH2:24][CH:21]([CH:22]=[CH:23]1)[CH2:20][CH:19]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C([C:34]12[CH2:40][CH:37]([CH:38]=[CH:39]1)[CH2:36][CH:35]2[C:41]([O:43]O)=[O:42])C.[CH:45]12[CH2:51][CH:48]([CH:49]=[CH:50]1)[CH2:47][CH:46]2[C:52]([OH:54])=[O:53].CC(N=NC(C#N)(C)C)(C#N)C>C1COCC1>[C:4]1(=[O:9])[N:5]([CH2:6][CH2:7][OH:8])[C:1](=[O:10])[CH:2]=[CH:3]1.[C:14]1(=[O:15])[O:16][C:11](=[O:17])[CH:12]=[CH:13]1.[CH:18]12[CH2:24][CH:21]([CH:22]=[CH:23]1)[CH2:20][CH:19]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].[CH:34]12[CH2:40][CH:37]([CH:38]=[CH:39]1)[CH2:36][CH:35]2[C:41]([O:43][CH2:46][CH2:52][OH:53])=[O:42].[CH:45]12[CH2:51][CH:48]([CH:49]=[CH:50]1)[CH2:47][CH:46]2[C:52]([OH:54])=[O:53]
Reactant: CCC12C=CC(CC1C(=O)OO)C2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)(C)OC(=O)C1CC2C=CC1C2
Agent: O=C(O)C1CC2C=CC1C2
Solvent: C1CCOC1
Product: O=C(OCCO)C1CC2C=CC1C2

Procedure:
2-Maleimidylethanol (12) (0.3 to 1 mol), 0.05 to 1 mol of maleic anhydride, 0.1 to 1 mol of t-butyl 5-norbornene-2-carboxylate (19), 0.05 to 1 mol of 2-hydroxyethyl 5-norbornene-2-carboxylate (21), and 0.01 to 0.3 mol of 5-norbornene-2-carboxylic acid (20) were dissolved in 180 to 230 g of THF to which was added 0.5 to 20 g of AIBN as a polymerization initiator. The reaction mixture was allowed to react at 60° C. to 75° C. for 4 to 24 hours under a nitrogen atmosphere. The resulting crude resin was precipitated with ethyl ether and dried to obtain poly[2-maleimidylethanol/maleic anhydride/t-butyl 5-norbornene- 2-carboxylate/2-hydroxyethyl 5-norbornene-2-carboxylate/5-norbornene-2-carboxylic acid] copolymer resin. The NMR spectral data of the resulting resin is shown in FIG. 6.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([C:10]2[O:14][N:13]=[C:12]([CH2:15][O:16]C(=O)C)[CH:11]=2)[O:8][C@@H:7]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([Cl:30])=[N:24][C:25]=3Cl)[C@@H:6]1[O:31]C(=O)C)(=O)C.[NH2:35][CH2:36][CH:37]([C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1)[C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1>>[OH:44][C:41]1[CH:42]=[CH:43][C:38]([CH:37]([C:45]2[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=2)[CH2:36][NH:35][C:25]2[N:24]=[C:23]([Cl:30])[N:22]=[C:21]3[C:26]=2[N:27]=[CH:28][N:20]3[C@H:7]2[C@H:6]([OH:31])[C@H:5]([OH:4])[C@@H:9]([C:10]3[O:14][N:13]=[C:12]([CH2:15][OH:16])[CH:11]=3)[O:8]2)=[CH:39][CH:40]=1
Reactant: CC(=O)OCc1cc([C@H]2O[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1
Reactant: NCC(c1ccc(O)cc1)c1ccc(O)cc1
Product: OCc1cc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)on1

Procedure:
The title compound is prepared from acetic acid (2R,3R,4R,5S)-4-acetoxy-5-(3-acetoxymethyl-isoxazol-5-yl)-2-(2,6-dichloro-purin-9-yl)-tetrahydro-furan-3-yl ester (WO 99/38877) analogously to (2R,3R,4S,5S)-2-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(3-hydroxymethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol (Intermediate CG) by replacing 2,2-diphenylethylamine with 4,4′-(2-aminoethylidene)bisphenol (Intermediate A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[N:14][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:16][C:11]=2[N:10](C(OC(C)(C)C)=O)[N:9]=1>C[O-].[Na+].CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[N:14][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:16][C:11]=2[NH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccccc2Cl)c2cnc(Oc3ccc(F)cc3F)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(Oc2cc3[nH]nc(-c4ccccc4Cl)c3cn2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
A mixture of 3-(2-chlorophenyl)-6-(2,4-difluorophenoxy)-pyrazolo[4,3-c]pyridine-1-carboxylic acid, tert-butyl ester (14.0 mg) in 3 mL of 0.5 M sodium methoxide solution in methanol was stirred for 30 minutes at room temperature. The resulting solution was concentrated and the residue was extracted with ethyl acetate, washed, dried and concentrated to give 10.0 mg of 3-(2-chlorophenyl)-6-(2,4-difluorophenoxy)-1H-pyrazolo[4,3-c]pyridine (91% yield). Mass Spec. M+H=356.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]2[CH:16]=[C:17]([C:33]([O:35]C)=[O:34])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][C@H:27]([CH3:31])[CH2:26]2)=[CH:21][C:20]3=[O:32])[CH:7]=[CH:8][CH:9]=1.Cl>CO>[F:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]2[CH:16]=[C:17]([C:33]([OH:35])=[O:34])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][C@H:27]([CH3:31])[CH2:26]2)=[CH:21][C:20]3=[O:32])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(C2CCCN2c2cccc(F)c2)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)O)cc(C4CCCN4c4cccc(F)c4)c3o2)CCO1
Temperature: 40 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
An aqueous NaOH 2N (0.804 ml, 1.61 mmol) solution was added to methyl 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (0.25 g, 0.54 mmol) suspended in MeOH (4 mL). The solution was stirred at 40° C. overnight then cooled to 0° C. and an aqueous HCl 2N (0.670 ml, 1.34 mmol) solution was added dropwise to the reaction mixture until pH ˜3. The resulting precipitate was collected by filtration, washed with water and dried under vacuum at 50° C. in presence of P2O5 to a constant weight to afford 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (201 mg, 83%) as a beige solid. Mass Spectrum: m/z [M+H]+=453.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:14][N:13]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:12]2[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=2[NH:10][C:9]1=[O:24])(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[NH2:7][C@@H:8]1[C:9](=[O:24])[NH:10][C:11]2[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=2[N:13]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(CC(F)(F)F)c2ccccc2NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CN(CC(F)(F)F)c2ccccc2NC1=O

Procedure:
In an analogous procedure to that described in Example 1d), the treatment of the [(S)-4-oxo-1-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester with hydrochlorid acid (37%) in dioxane yielded the title compound as a light yellow solid; MS (m/e): 260 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]3([CH3:26])[CH2:25][CH2:24]3)=[O:21])[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:27][C:28]([OH:30])=O.[NH:31]1[CH2:34][CH2:33][CH2:32]1.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=O)C>[N:31]1([C:28](=[O:30])[CH2:27][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]4([CH3:26])[CH2:24][CH2:25]4)=[O:21])[CH2:18][CH2:19]3)=[CH:7][C:2]=2[F:1])[CH2:34][CH2:33][CH2:32]1
Reactant: C1CNC1
Reactant: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2-fluoro-4-{2-[(1S,2R)-2-(1-{[(1-methylcyclopropyl)oxy]carbonyl}piperidin-4-yl)cyclopropyl]ethoxy}phenyl)acetic acid (100 mg, 0.238 mmol) in 1 ml anhydrous DMF at RT was added azetidine (16.3 mg, 0.286 mmol) and N,N-diisopropylethylamine (0.125 ml, 0.715 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (181 mg, 0.477 mmol) was added into the solution and stirred at RT for 4 hrs. The reaction mixture was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-95% acetonitrile in 0.1% formic acid in water gradient) to give the title compound. LC/MS (m/z): 459.3 (M+H)+. GPR119 Human EC50: 3.3 nM
Reaction SMILES: [Cl-].[Cl-].[Ca+2].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].[Cl:15][C:16]([Cl:21])([Cl:20])[CH:17](O)O.OS(O)(=O)=O>>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12]([CH:17]([C:16]([Cl:21])([Cl:20])[Cl:15])[O:10][C:9]2=[O:11])=[CH:13][CH:14]=1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: COc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [Cl-]
Product: COc1ccc2c(c1)C(=O)OC2C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.7 %

Procedure:
A oven-dried 25 mL three neck round-bottomed flask containing a stirring bar was fitted with a drying tube (CaCl2) and was charged with m-methoxybenzoic acid (5.04 g, 17.91 mmol) followed by chloral hydrate (2.96 g, 17.91 mmol). Concentrated H2SO4 (12.0 mL) was added and the reaction mixture was left stirring at room temperature for 24 h. It was then poured onto ice, a thick precipitate formed and the mixture was left stirring vigorously until the ice was dissolved. The precipitate was filtered, washed with water and dried. The solid was recrystallised from ethanol, the crystals were then filtered and dried to yield 6-methoxy-3-(trichloromethyl)isobenzofuran-1(3H)-one as off-white needles (3.16 g, 63%). Spectral data for this compound were consistent with those in the literature. M.p. 134-136° C. (lit. m.p. 136-137° C.); 1H NMR (400 MHz, DMSO-d6): δ=7.88 (d, J=8.3 Hz, 1H), 7.49-7.39 (m, 2H), 6.54 (s, 1H), 3.90 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=[O:5].[CH3:16][NH:17][CH3:18]>C1COCC1>[CH3:16][N:17]([CH3:18])[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=[O:5]
Reactant: O=C(CCCl)Nc1cccc([N+](=O)[O-])c1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-chloro-N-(3-nitrophenyl)propanamide (4.6 g, 20 mmol) in THF (50 mL) was added dropwise N,N-dimethyl amine (2M solution in THF) (1.8 g, 20 mL, 40 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight and then evaporated to dryness under reduced pressure. The residue was triturated with 5% NH3 (aqueous, 50 mL) and the solid product was collected by filtration, washed with water followed by hexane, and dried to give 3-(dimethylamino)-N-(3-nitrophenyl)propanamide, 4.1 g (87%), mp 80-81° C. 1H NMR (DMSO-d6) δ: 2.17 (6H, s, CH3), 2.47-2.50 (2H, t, J=6.4 Hz, CH), 2.56-2.59 (2H, t, J=6.8 Hz, CH), 7.57-7.62 (1H, t, J=8.2 Hz, Ar—H), 7.88-7.91 (2H, dd, J=8.1 and 2.2 Hz, Ar—H), 8.63-8.64 (1H, t, J=2.0 Hz, Ar—H), 10.49 (1H, brs, NH).
Reaction SMILES: [C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([OH:3])=O.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[N:27]1([C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[N:9]=[C:8]2[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:3])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C1CCNC1
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 103.2 %

Procedure:
To a stirring solution of (RS) 1-[3-carboxybutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (0.700 g, 1.9 mmol) in N,N-dimethylformamide (40 ml) were added sequentially pyrroldine (155 mg, 1.1 eq), 1-hydroxybenzotriazole (282 mg, 1.1 eq), and dicyclohexylcarbodiimide (431 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concentrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 0.835 grams of the title product as a white foam.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:21]([NH2:23])=[N:20][CH:19]=[N:18][C:17]=3[NH:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27].O>CN(C)C=O>[CH:26]([S:29]([N:16]1[C:17]2[N:18]=[CH:19][N:20]=[C:21]([NH2:23])[C:22]=2[C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)=[CH:15]1)(=[O:31])=[O:30])([CH3:28])[CH3:27]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)S(=O)(=O)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21

Procedure:
5-(4-Phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (1.57 g) was dissolved in dry dimethylformamide (30 ml) and then sodium hydride (0.22 g of a 60% dispersion in mineral oil) was added with stirring. The mixture was stirred for 30 minutes and then isopropylsulphonyl chloride (0.74 g) was added and the mixture was stirred at ambient temperature for 18 hours. Water was added to the mixture until no further precipitation occurred. The solid was collected by filtration and purified by flash column chromatography on silica using dichloromethane/methanol (9:1) as the mobile phase to give a solid which was further purified by flash column chromatography on silica using ethyl acetate as the mobile phase to give 7-isopropylsulphonyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 162-162.5° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[N:7][NH:6][C:5](=O)[CH:4]=1.O=P(Cl)(Cl)[Cl:14]>O1CCOCC1>[Cl:14][C:5]1[N:6]=[N:7][CH:8]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=1
Reactant: O=c1cc(C(F)(F)F)cn[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1cnnc(Cl)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
5-(Trifluoromethyl)pyridazin-3(2H)-one (20.0 g, 111 mmol) was dissolved in 1,4-dioxane (222 mL) and POCl3 (31.0 mL, 333 mmol) added. The reaction was left to stir at 80° C. for 3 h. After consumption of the starting material, the reaction was cooled to room temperature. The reaction mixture was added to ice and quenched with ammonium hydroxide. The aqueous layer was extracted with dichloromethane (×3) and the organic layers combined, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound as an orange oil. 1H NMR (500 MHz, CDCl3) δ 9.37 (s, 1H); 7.76 (s, 1H).