Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][CH:19]=[CH:18][C:17]4[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:30].[Na+].OO>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][CH2:19][CH:18]([OH:30])[C:17]4[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [OH-]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC=Cc1ccccc1-3
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCC(O)c1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
BH3Me2S (1.6 eq, 2M solution in THF) was added to a 0.2M solution of methyl 14-cyclohexyl-7,8-dihydroindolo[2,1-a][2]benzazocine-11-carboxylate in THF, and the mixture was stirred for 2 h at RT. 3M aq NaOH (3 eq) and 35% H2O2 (3 eq) were added at 0° C., and stirring was continued overnight at RT. After dilution with sat NaHCO3 the aq. phase was extracted with EtOAc, the organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give mainly methyl 14-cyclohexyl-5-hydroxy-5,6,7,8-tetrahydroindolo[2,1-a][2]benzazocine-11-carboxylate (with traces of its regioisomer methyl 14-cyclohexyl-6-hydroxy-5,6,7,8-tetrahydroindolo[2,1-a][2]benzazocine-11-carboxylate).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C@H:5]1[CH2:8][C@H:7]([CH2:9][O:10]CC2C=CC=CC=2)[CH2:6]1>C(OC(=O)C)C.[Pd]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C@H:5]1[CH2:8][C@H:7]([CH2:9][OH:10])[CH2:6]1
Reactant: COC(=O)C[C@H]1C[C@H](COCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H]1C[C@H](CO)C1

Procedure:
Prepared from trans-(3-benzyloxymethyl-cyclobutyl)-acetic acid methyl ester (980 mg, 3.95 mmol) by hydrogenation 16 hours at room temperature using Pd/C (10%) (420 mg) in ethylacetate (20 ml).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.N1C=CC=CC=1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14]>C1COCC1>[O:1]1[CH2:4][CH:3]([O:5][C:13](=[O:14])[O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH2:2]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OC1COC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COC1
Temperature: 25 °C

Procedure:
A solution of Oxetan-3-ol (0.100 g, 1.35 mmol) and pyridine (0.13 mL, 1.62 mmol) in THF (2.5 mL) was cooled to 0° C. with an external ice bath, stirring. A solution of 4-Nitrophenyl chloroformate (0.299 g, 1.485 mmol) in THF (2 mL) was added at 0° C. and the solution was allowed to warm to room temperature. The crude reaction was purified by normal phase silica gel (0-100% ethyl acetate:hexanes) chromatography to give Carbonic acid 4-nitro-phenyl ester oxetan-3-yl ester. LCMS-ESI+: calc'd for C10H9NO6: 239.04 (M+); Found: 239.97 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C[Si](Cl)(C)C.C(N(CC)CC)C.CC([O:28][C:29]1[C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=[CH:31][CH:30]=1)=O>C(Cl)Cl>[C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)(=[O:36])[C:34]1[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=1)[OH:28]
Reactant: CC(C(=O)O)c1ccc(N)cc1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(=O)O)c1ccc(NC(=O)c2ccccc2O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 52.4 %

Procedure:
A slurry of 58.6 g (0.355 mol) of 2-(4-aminophenyl)propionicacid and 500 ml of methylene chloride was treated with 90.11 ml (77.13 g, 0-710 mol) of trimethylsilyl chloride and was heated to reflux for 120 min. The reaction mixture was cooled to 0° C. and treated with 184.44 ml (107.77 g, 1.065 mol) of triethylamine. After stirring for 5 minutes, this mixture was treated with a solution of 70.45 g (0.355 mol) of O-acetylsalicyloyl chloride and 150 ml of methylene chloride. The reaction mixture was warmed to 25° C. and stirred for 64 hr. The volatiles were removed in vacuo. The residue was stirred in 2N aqueous sodium hydroxide for one hour and acidified with 2 M aqueous sulfuric acid. The solid was recrystallized twice from ethanol/water to give a tan solid. Isolation by filtration afforded 53.05 g of (52% yield) of 2-(4-(N-salicyloyl)aminophenyl)propionic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[N:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:13]=2)[S:9][CH:10]=1)=[O:5])C.[OH-].[K+]>CO>[CH3:21][C:18]([C:16]1[C:15]([OH:22])=[C:14]([C:23]([CH3:24])([CH3:25])[CH3:26])[N:13]=[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[N:17]=1)([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1csc(Nc2nc(C(C)(C)C)c(O)c(C(C)(C)C)n2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1nc(Nc2nc(C(=O)O)cs2)nc(C(C)(C)C)c1O
Reaction time: 3.5 h

Procedure:
A solution of 2-([4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]amino)-4-thiazolecarboxylic acid ethyl ester (0.5 g, 1.3 mmol) in 20 mL of methanol is treated with 10 mL of 1.0N KOH (aq) at room temperature. After 3.5 hours, the methanol is removed under reduced pressure, and the aqueous solution is acidified to pH 4 with concentrated HC1. The resulting precipitate is collected by filtration and recrystallized from MeOH/water. Yield of 2-([4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]amino)-4-thiazolecarboxylic acid is 0.09 g (26%); mp 251°-253° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[O:7][CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:4].[F:25][C:26]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:27]=1[CH2:28][NH:29][CH2:30][CH2:31][CH3:32].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[F:25][C:26]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:27]=1[CH2:28][N:29]([CH2:30][CH2:31][CH3:32])[C:16](=[O:18])[CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][O:7][C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:20][CH:19]=1
Reactant: CCCNCc1ccc(F)cc1F
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
(4-{2-[2-(Methoxycarbonyl)phenoxy]ethyl}phenoxy)acetic acid (0.150 g, 0.454 mmol) was dissolved in DMF (10 ml), N-(2,4-difluorobenzyl)-N-propylamine (0.084 g, 0.454 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.160 g, 0.499 mmol) and N-ethyl-N,N-diisopropylamine (0.123 g, 0.954 mmol) was added. The solution was stirred for two hours at room temperature. EtOAc (20 ml) was added and the organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation to give 0.220 g of methyl 2-[2-(4-{2-[(2,4-difluorobenzyl)(propyl)amino]-2-oxoethoxy}phenyl)-ethoxy]benzoate (yield 97.4%).
Reaction SMILES: [OH:1][C:2]1[C:19]2[CH2:18][C@@:17]([OH:24])([C:20](=[O:23])[CH2:21][OH:22])[CH2:16][C@H:15]([O:25][C@@H:26]3[O:40][C@@H:39]([CH3:41])[C@H:29]4[O:30][C@H:31]5[N:36]([C@H:28]4[CH2:27]3)[CH2:35][CH2:34][O:33][C@@H:32]5[O:37][CH3:38])[C:14]=2[C:13]([OH:42])=[C:12]2[C:3]=1[C:4](=[O:46])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:44][CH3:45])[C:10]=1[C:11]2=[O:43].[CH2:47]([O:49][C:50](=[O:59])[CH2:51][O:52][C:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH:54]=1)[CH3:48].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[O:23]=[C:20]([C@@:17]1([OH:24])[CH2:16][C@H:15]([O:25][C@@H:26]2[O:40][C@@H:39]([CH3:41])[C@H:29]3[O:30][C@H:31]4[N:36]([C@H:28]3[CH2:27]2)[CH2:35][CH2:34][O:33][C@@H:32]4[O:37][CH3:38])[C:14]2[C:19](=[C:2]([OH:1])[C:3]3[C:4](=[O:46])[C:5]4[C:10]([C:11](=[O:43])[C:12]=3[C:13]=2[OH:42])=[C:9]([O:44][CH3:45])[CH:8]=[CH:7][CH:6]=4)[CH2:18]1)[CH2:21][O:22][C:53]1([O:52][CH2:51][C:50]([O:49][CH2:47][CH3:48])=[O:59])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: CCOC(=O)COC1=CCCCC1
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COC1(OCC(=O)[C@]2(O)Cc3c(O)c4c(c(O)c3[C@@H](O[C@H]3C[C@H]5[C@H](O[C@@H]6[C@@H](OC)OCCN65)[C@H](C)O3)C2)C(=O)c2c(OC)cccc2C4=O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of (8S,10S)-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione (50 mg, 0.078 mmol) [PNU-159682, compound IIA, prepared as reported in WO 9802446] in 2 ml of dry dimethylformamide kept under argon, (Cyclohex-1-enyloxy)-acetic acid ethyl ester (0.5 mL, [prepared as reported in J. Org. Chem. (1978) 43:1244-1245] and p-toluenesulfonic acid monohydrate (5 mg, 0.026 mmol) were added. The reaction mixture was stirred overnight at room temperature, sodium bicarbonate saturated solution was added (20 mL) and the product extracted with dichloromethane (2×20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, the solvent removed under vacuum and the residue partially purified by flash chromatography (DCM/MeOH 97.5:2.5) to give 30 mg (37%) of the ester intermediate that was used as such in step 2. MS (ESI): 826 [M+H]+. Retention time=7.48 min. method 2
Reaction SMILES: [OH:1][C@@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].ClC(Cl)(Cl)C(=N)O[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.FC(F)(F)S(O)(=O)=O>C1CCCCC1.C(Cl)Cl>[CH2:13]([O:1][C@@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C[C@H](C)O
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: COC(=O)C[C@H](C)OCc1ccccc1
Reaction time: 1 h

Procedure:
Methyl (S)-(+)-3-hydroxybutyrate (17) (2.223 g, 18.82 mmol) and benzyl 2,2,2-trichloroacetimidate (4.2 mL) were dissolved into 37.5 mL of cyclohexane/methylene chloride (2:1). After the addition of 0.2 mL of trifluoromethane sulfonic acid the reaction was stirred under nitrogen for one hour. The reaction was diluted with 75 mL of cyclohexane/methylene chloride (2:1) and filtered. The organic layer was washed with 50 mL of saturated sodium bicarbonate and 50 mL of distilled water. After drying with anhydrous sodium sulfate the solution was filtered and the solvents were removed on a rotovap. The resulting solid was purified using silica gel and elution with ether/hexane (1:4).
Reaction SMILES: [CH:1]([NH:3][CH:4]([P:18]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])=[S:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][C:42](=[O:46])[CH2:43][O:44][CH3:45]>CC(C)=O>[N+:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][C:5]([CH:4]([P:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:19])[N:3]=[CH:1][S:2][CH2:41][C:42](=[O:46])[CH2:43][O:44][CH3:45])=[O:6])=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: COCC(=O)CCl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C(NC=S)P(=O)(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCC(=O)CSC=NC(C(=O)OCc1ccc([N+](=O)[O-])cc1)P(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of p-nitrobenzyl α-thioformamidodiphenylphosphonoacetate (2.43 g), powdered potassium carbonate (0.73 ), 1-chloro-3-methoxy-2-propanone (0.63 g), and acetone (25 ml) is stirred in a capped flask at room temperature for 16 hours. The mixture is filtered and the filtrate is evaporated in vacuo to afford 3-methoxy-2-oxopropyl N-(p-nitrobenzyloxycarbonyl-diphenylphosphonomethyl)thioformimidate.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:25]4[CH:26]=[CH:27][C:22]([C:19](=[O:21])[CH3:20])=[CH:23][CH:24]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CC(=O)c1ccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)cc1
Temperature: 90 °C

Procedure:
Following the similar procedure described for Example 401(c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 (b), 0.73 g, 2.1 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (0.12 g, 0.11 mmol), 4-actylphenylboronic acid (Aldrich Chemical Company) (0.41 g, 2.5 mmol) and 1,2-dimethoxyethane (20 mL) gave, after heated at 90° C. overnight and purification on a Biotage 40M column (3:1 hexane:EtOAc), the title compound as a light-orange solid. MS (ESI, pos. ion) m/z: 347 (M+1). Mp: 178.0-180.5° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([CH2:17][CH2:18][CH3:19])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:25][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([CH2:17][CH2:18][CH3:19])=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCC1
Reactant: CCCc1nn2ccccc2c1-c1ccnc(F)c1
Product: CCCc1nn2ccccc2c1-c1ccnc(NC2CCCC2)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 3-(2-fluoropyridin-4-yl)-2-propylpyrazolo[1,5-a]pyridine (126 mg, 0.49 mmol) in cyclopentylamine (5 mL) was heated in a sealed vessel at 150° C. for 18 h. The mixture was cooled to room temperature and concentrated in vacuo and the residue was purified by flash chromatography on silica gel (2:1 hexane-ethyl acetate) to give N-cyclopentyl-4-(2-propylpyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine (155 mg, 98%) as a yellow solid. 1H NMR (CDCl3) δ 8.41 (d, 1H), 8.07 (d, 1H), 7.58 (d, 1H), 7.14 (t, 1H), 6.74 (td, 1H), 6.66 (dd, 1H), 6.45 (s, 1H), 5.01 (broad, 1H), 3.95 (m, 1H), 2.91 (t, 2H), 2.04 (m, 2H), 1.80–1.50 (m, 8H), 0.98 (t, 3H); MS m/z 321 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([OH:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+:25].[Na+]>CC(C)=O.O>[CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([O-:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:3])[CH3:4].[Na+:25]
Reactant: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 185.6 %

Procedure:
(2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]-carbamoyl]oxirane-2-carboxylic acid (48.59 g) was dissolved in acetone (245 mL), and sodium carbonate (8.51 g) dissolved in water (32.9 mL) was slowly added. The solution was stirred at room temperature to 50° C. for three hours until the deposited inorganic salt was dissolved. While the temperature was kept, acetone (200 mL) was dropped and a seed crystal was placed in the solution, and then the solution was stirred for 30 minutes. Acetone (510 mL) was again dropped, and the solution was stirred for 1 hour while the temperature was kept. While the solution was gradually cooled to room temperature, it was stirred overnight. The precipitated crystalline product was collected by filtration, washed with a mixture of 3% water-acetone (70 mL), dried in air to obtain white solid sodium (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (46.1 g, 87.9%). The NMR data of the solid product were the same as those in Example 9.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[N:14](C(OC(C)(C)C)=O)[NH:15]C(OC(C)(C)C)=O>C(OCC)(=O)C>[ClH:1].[NH:14]([C:10]1[N:9]([CH3:8])[CH:13]=[CH:12][N:11]=1)[NH2:15]
Reactant: Cn1ccnc1N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1ccnc1NN
Temperature: 22 °C
Reaction time: 20 h

Procedure:
4 M Hydrogen chloride in dioxane (50 mL, 200.00 mmol) was added to di-tert-butyl 1-(1-methyl-1H-imidazol-2-yl)hydrazine-1,2-dicarboxylate (Intermediate AV3) (5.9 g, 18.89 mmol) in ethyl acetate (50 mL) at 22° C. The resulting solution was stirred at 22° C. for 20 hours. The reaction mixture was evaporated to dryness to afford the product (2.80 g) which was used without purification. 1H NMR (400 MHz, DMSO) δ 3.38 (3H, s), 6.90 (1H, d), 6.96 (1H, d).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8][C:7]=2[CH:14]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1C=CC=CC=1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH:10]([NH:13][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:9][CH2:8][C:7]=2[CH:14]=1
Reactant: CCOC(=O)CBr
Reactant: NC1CCc2ccc(C(F)(F)F)cc2CC1
Solvent: c1ccccc1
Product: CCOC(=O)CNC1CCc2ccc(C(F)(F)F)cc2CC1
Yield: 85.9 %

Procedure:
458.5 g (2 mols) of 2-trifluoromethyl-7-amino-6,7,8,9-tetrahydro-[5H]-benzocycloheptene are dissolved in 2000 ml of anhydrous benzene. One mol of ethyl bromoacetate is added thereto and the whole is heated under reflux. A precipitate forms. The refluxing is maintained for 4 hours, then the mixture is allowed to return to room temperature. The hydrobromide precipitate of the starting amine is filtered off and washed in benzene then ether. The solvent is distilled off from the filtrate. The oil obtained is used as such for the subsequent hydrolysis. Ultimately 271 g of 2-trifluoromethyl-7-(N-ethoxycarbonylmethylamino)-6,7,8,9-tetrahydro-[5H]-benzocycloheptene are obtained. (Yield 86%), a sample of which is purified in the form of the hydrochloride, which sublimes towards 270°-280° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[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:27](=[O:29])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][C@@H:15]3[CH2:16][C@@H:14]3[CH:11]3[CH2:10][CH2:9][N:8]([C:5]4[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=4)[CH2:13][CH2:12]3)=[CH:21][C:22]=2[F:30])[CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F
Reactant: C1CNC1
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: O=C(Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F)N1CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of [4-(2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorophenyl]acetic acid (100 mg, 0.230 mmol) in 1 ml of anhydrous DMF at RT was added azetidine (13.2 mg, 0.230 mmol) and N,N-diisopropylethylamine (0.201 ml, 1.15 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (175 mg, 0.461 mmol) was added to the solution and the mixture stirred at RT for 4 hrs. The mixture was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-75% acetonitrile in 0.1% formic acid in water gradient) to give the title compound. LC/MS (m/z): 473.1 (M+H)+. GPR119 Human EC50: 0.19 nM
Reaction SMILES: FC1C=C([C:9]2[CH:10]=[C:11]([C:20]#[N:21])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14]([OH:19])[CH:13]=3)C=CC=1O.[CH3:22]OC1C=C2C(CCCC2=O)=CC=1>C1(C)C=CC=CC=1>[CH3:22][O:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[CH:9][CH:10]=[C:11]2[C:20]#[N:21])=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: N#Cc1cc(-c2ccc(O)c(F)c2)cc2ccc(O)cc12
Solvent: Cc1ccccc1
Product: COc1ccc2cccc(C#N)c2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In a highly preferred aspect of this invention illustrated in Scheme 1, there is provided a new and improved process for the large-scale production of 3-(3-fluoro-4-hydroxyphenyl)-7-hydroxy-1-naphthonitrile (1). Commercial material 3,4-dihydro-7-methoxy-1(2H)-naphthalenone (7-methoxy-1-tetralone) may be transformed into an unsaturated nitrile (3) as shown on Scheme 1. The reaction is performed in toluene solution. Upon the completion of the reaction, it is quenched by caustic solution. The reaction mixture is extracted with toluene. After washing the toluene solution, the crude unsaturated nitrile (3) is aromatized directly in this toluene solution by stirring with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) at 60° C. for 2 h. The solid is removed by filtration and the filtrate is washed with sodium hydroxide solution and brine and respectively. Most of the solvent is removed by distillation and heptane is added to precipitate the product. 7-methoxy-1-naphthonitrile (4) is isolated. The expected yield over these two steps is at least 70-75%. By performing two reactions in the same solvent, isolation of the low melting point intermediate (3) can be avoided, improving efficiency and yield.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[Li+].[OH-].Cl>C1COCC1>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:16])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(4-chlorophenoxy)isobutyric acid ethyl ester (1.0 g, 4.12 mmol) in THF (10 mL) was treated with 1N aqueous LiOH (10 mL) and stirred overnight at room temperature. The mixture was acidified with 1N aqueous HCl to pH 3-4 and extracted three times with EtOAc. The combined organic layers were dried and concentrated to give the title compound.