Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:16][CH2:15][C@:14]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])[N:18]([C:30]3[C:31]4[C@H:38]([CH3:39])[CH2:37][C@@H:36]([OH:40])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:17]2)[CH2:13]1)C1C=CC=CC=1>CO.[Pd]>[CH:27]([NH:26][CH2:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]2[N:18]([C:30]3[C:31]4[C@H:38]([CH3:39])[CH2:37][C@@H:36]([OH:40])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:17][C@@:14]3([CH2:15][CH2:16][NH:12][CH2:13]3)[C:24]=12)([CH3:29])[CH3:28]
Reactant: CC(C)NCc1cccc2c1[C@]1(CCN(Cc3ccccc3)C1)CN2c1ncnc2c1[C@H](C)C[C@H]2O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)NCc1cccc2c1[C@]1(CCNC1)CN2c1ncnc2c1[C@H](C)C[C@H]2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pd/C (35.2 mg, 0.017 mmol) and ammonium formate (52.2 mg, 0.827 mmol) was added to a solution of (5R,7R)-4-((S)-1′-benzyl-4-((isopropylamino)methyl)spiro[indoline-3,3′-pyrrolidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (40.0 mg, 0.083 mmol) in MeOH (3 mL). The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated and purified by Analogix chromatography (DCM/MeOH/1% NH4OH gradient) to give (5R,7R)-4-((S)-4-((isopropylamino)methyl)spiro[indoline-3,3′-pyrrolidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol. This material was converted to the bis-HCl salt by dissolving the material in DCM and adding HCl (4N in dioxane) and concentrating the mixture (9.0 mg, 0.022 mmol, 27%). 1H NMR (400 MHz, d6-DMSO) δ 10.05 (br s, 1H), 9.92 (br s, 1H), 9.58 (br s, 1H), 9.47 (br s, 1H), 8.89 (s, 1H), 8.10 (d, J=8.2 Hz, 1H), 7.66 (s, J=7.8 Hz, 1H), 7.46 (t, J=8.2 Hz, 1H), 5.30 (t, J=7.8 Hz, 1H), 4.83 (d, J=10.5 Hz, 1H), 4.35 (t, J=10.5 Hz, 1H), 4.20 (d, J=7.8 Hz, 1H), 4.14 (d, J=10.9 Hz, 1H), 3.96-3.85 (m, 1H), 3.71-3.67 (m, 4H), 3.43 (dd, J=10.9, 3.9 Hz, 2H), 3.41-3.31 (m, 2H), 2.63-2.58 (m, 1H), 2.35-2.33 (m, 1H), 2.18-2.13 (m, 2H), 1.41 (d, J=6.2 Hz, 6H), 1.18 (d, J=6.4 Hz, 2H), 1.12 (d, J=6.6 Hz, 3H). LCMS (APCI+) M+H+394 (100%); Rt=1.72 min. HPLC purity at 254 nm >99%, Rt=1.63 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:30]=[CH:29][C:15]([CH2:16][NH:17][C:18]([NH:20][NH:21]C(OC(C)(C)C)=O)=[O:19])=[CH:14][C:13]=2[F:31])[N:9]=1)(=[O:3])[CH3:2].O1CCOCC1.[ClH:38]>O1CCOCC1>[ClH:38].[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:30]=[CH:29][C:15]([CH2:16][NH:17][C:18]([NH:20][NH2:21])=[O:19])=[CH:14][C:13]=2[F:31])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(CNC(=O)NNC(=O)OC(C)(C)C)cc2F)cs1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(CCc2ccc(CNC(=O)NN)cc2F)cs1
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.7 %

Procedure:
To a solution of tert-butyl 2-[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}-3-fluorobenzyl)carbamoyl]hydrazinecarboxylate (12.3 mg, 0.027 mmol) in dioxane (1.2 ml) was added 4M hydrogen chloride dioxane solution (0.1 ml), and the mixture was stirred at room temperature for 17 hr, and concentrated under reduced pressure.The residue was suspended in ethyl acetate (2 ml), and the mixture was filtered. The filtered product was washed 3 times with ethyl acetate, and dried under reduced pressure to give the title compound (10.2 mg, 0.026 mmol, yield 96.7%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2([C:22]([O:24]C)=[O:23])[CH2:21][CH2:20]2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20]2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C2(C(=O)O)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl 1-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}cyclopropanecarboxylate (Example 70, 0.417 g, 1.21 mmol) in THF (5 mL) stirring at 0° C. was added 1 M lithium hydroxide solution (5 mL, 5 mmol). After 3 h, it was warmed to room temperature and kept stirring for another 3 h. The reaction mixture was acidified with 1 M hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated in vacuum to provide 1-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}cyclopropanecarboxylic acid. (0.307 g, 77%) as a white powder.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([C:30]([F:33])([F:32])[F:31])[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24](F)=[C:25]([CH:28]=3)[C:26]#[N:27])[CH2:17]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1.O>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([C:30]([F:32])([F:33])[F:31])[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)=[C:25]([CH:28]=3)[C:26]#[N:27])[CH2:17]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: N#Cc1cc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To the solution of 1H-1,2,4-triazole (0.06 g) in DMF was added sodium hydride (0.04 g) while cooling with ice, and the mixture was warmed to room temperature and then stirred for 0.5 hr. To this solution was added the solution of 5-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]2-fluorobenzonitrile (0.30 g) in DMF, and the mixture was heated to reflux for 6 hours. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 5-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.18 g). 1H-NMR (DMSO-d6) δ: 2.62-2.73 (1H, m), 2.95-3.03 (1H, m), 3.49-3.55 (2H, m), 3.90 (1H, d), 4.31 (1H, d), 7.09 (1H, dd), 7.29 (1H, d), 7.61 (1H, d), 7.68 (2H, d), 7.71 (1H, t), 8.26 (1H, s), 8.98 (1H, s)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[B:15]([O:24]C(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>CCCCCC.C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([O:16][B:15]([OH:24])[OH:20])[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1cc(F)cc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)Oc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To a mixture of 1-bromo-3,5-difluorobenzene (743 mmol) and 500 ml of THF was added dropwise 500 ml of a solution of n-butyl lithium (corresponding to 780 mmol) in hexane at −78° C. in 1.6 hours, and stirred at the same temperature for 1.5 hours. To this solution was wadded dropwise 200 ml of a solution of triisopropyl borate (1,486 mmol) in THF, the solution was gradually warmed up to room temperature, and then the solution was stirred overnight. After 750 ml of 7.3% hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted twice with diethyl ether, washed thrice with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was recrystallized from about 1,000 ml of toluene to give a white solid of 3,5-difluorophenyl boric acid (520 mmol).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]([NH:35][NH2:36])([CH3:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2C3C(=CC=CC=3)C(=O)O2)=[C:8]([O:23][CH:24]2C3C(=CC=CC=3)C(=O)O2)[CH:7]=1.[Li+].[OH-]>O.CO.C1COCC1>[CH3:24][O:23][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([NH:35][NH2:36])([CH3:34])[C:3]([OH:37])=[O:2])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COC(=O)C(C)(Cc1ccc(OC2OC(=O)c3ccccc32)c(OC2OC(=O)c3ccccc32)c1)NN
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC(C)(NN)C(=O)O)cc1OC

Procedure:
Following the procedure for preparation of compound 119, and treatment of the resulting 120 with 0.33M of LiOH in H2O/MeOH/THF before Boc removal by TFA, provided the title compound 121. 1H NMR (CD3OD, 400 MHz): 1.49 (s, 3H), 3.05 (dd, 2H), 3.80 (2 s, 6H), 6.77–6.92 (m, 3H). MS (ESI) m/z 255.25 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]([F:34])([F:33])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:19][S:16]([CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH2:22][C:21]([F:20])([F:34])[F:33])[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:18])=[O:17]
Reactant: OB(O)c1ccccc1OCC(F)(F)F
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccccc3OCC(F)(F)F)n2)c1

Procedure:
Example 16 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and [2-(2,2,2-trifluoroethoxy)phenyl]boronic acid (Combi-Blocks Inc.). The batch was purified by preparative HPLC:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:32][CH:31]2[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:26]([F:38])[CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:32][CH:31]4[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:26]([F:38])[CH:25]=3)[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C1CC1c1ccc(N)cc1F
Reactant: CCOCCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(C4CC4C(=O)OCC)c(F)c3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A mixture of 4′-(2-ethoxyethoxy)-2′,6′-dimethyl-3-biphenylcarbaldehyde (0.313 g, 1.05 mmol), ethyl 2-(4-amino-2-fluorophenyl)cyclopropanecarboxylate (0.234 g, 1.05 mmol), acetic acid (0.126 g, 2.10 mmol) and 1,2-dichloroethane (5 mL) was stirred under a nitrogen atmosphere at room temperature for 3 hr. Sodium triacetoxyborohydride (0.445 g, 2.10 mmol) was added to the reaction mixture by small portions, and the mixture was stirred for 3.5 hr. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-30:70) to give the title compound (0.456 g, yield 86%) as a yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[BrH:14]>>[BrH:14].[OH:2][C:3]1[CH:13]=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCNCC2
Agent: Br
Product: Oc1ccc2c(c1)CCNCC2
Temperature: 100 °C
Reaction time: 4 h

Procedure:
7-Methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (10 g) in 48% aqueous hydrobromic acid (350 ml) was allowed to stir at 100° C. for 4 h. The mixture was cooled to 20° C. then evaporated to dryness in vacuo to give the title compound (14.5 g) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([OH:17])=[C:12]([F:18])[CH:11]=2)=[O:9])[CH:7]=1.IC.[C:22](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([C:8]([C:10]2[CH:11]=[C:12]([F:18])[C:13]([O:17][CH3:22])=[C:14]([F:16])[CH:15]=2)=[O:9])[CH:7]=1
Reactant: O=C(c1cc(F)c(O)c(F)c1)c1cc(Br)ccc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(F)cc(C(=O)c2cc(Br)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
To a solution of (5-bromo-2-chlorophenyl)(3,5-difluoro-4-hydroxyphenyl)methanone (600 mg, 1.7 mmol) in acetone (5 mL) was added iodomethane (50 μL, 2.6 mmol) and potassium carbonate (470 mg, 3.4 mmol), and the mixture was stirred overnight at 25° C. After the volatiles were removed under reduced pressure, the residue was dissolved in ethyl acetate (30 mL), washed with brine, and concentrated to give 629 mg of crude product, which was used in the next step without further purification.
Reaction SMILES: COC[O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:13][O:14][N:15]=[C:16]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[N:19]=1)[CH3:17].Cl.[OH-].[Na+]>O1CCCC1>[OH:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:13][O:14][N:15]=[C:16]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[N:19]=1)[CH3:17]
Reactant: COCOc1c(CON=C(C)c2cc(C)cc(C)n2)cccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(CON=C(C)c2cc(C)cc(C)n2)c1O
Temperature: 25 °C

Procedure:
1.77 g (5.14 mmol) of 1-(4,6-dimethyl-2-pyridinyl)ethanone O-[(2-methoxymethoxy-3-methoxyphenyl)methyl] oxime was dissolved in 20 ml of tetrahydrofuran, and the resultant solution was added with 10 ml of 1N-hydrochloric acid. The obtained mixture was then heated to reach the reflux temperature and further stirred for an hour. Then, the mixture was cooled to a room temperature, neutralized with aqueous solution of 1N-sodium hydroxide and subjected to an extraction with diethyl ether. The resultant nonaqueous layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate and then condensed under reduced pressure to thereby obtain the target compound in an amount of 1.6 g.
Reaction SMILES: [H-].[Na+].COC(=O)[CH2:6][CH2:7][C:8]1[N:13]=[CH:12][C:11]2[O:14][CH2:15][CH2:16][C:10]=2[C:9]=1[C:17]([O:19]C)=O.Cl>O1CCCC1.CO>[CH2:16]1[C:10]2=[C:9]3[C:17](=[O:19])[CH2:6][CH2:7][C:8]3=[N:13][CH:12]=[C:11]2[O:14][CH2:15]1
Reactant: COC(=O)CCc1ncc2c(c1C(=O)OC)CCO2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCc2ncc3c(c21)CCO3
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
To a suspension of 65% sodium hydride (1.38 g, 37.4 mmol) in tetrahydrofuran (10 mL) were added a solution of methyl 5-(3-methoxy-3-oxopropyl)-2,3-dihydrofuro[2,3-c]pyridine-4-carboxylate (1.98 g, 7.46 mmol) in tetrahydrofuran (80 mL) and methanol (0.2 mL), and the mixture was stirred at 80° C. for 10 min. 12M Hydrochloric acid (40 mL) was added thereto under ice-cooling, and the organic solvent was evaporated under reduced pressure. The residual aqueous solution was stirred at 150° C. for 20 min, the reaction mixture was basified with 8M aqueous sodium hydroxide solution under ice-cooling, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (886 mg, yield 68%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][NH:4][C@H:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6]1.[C:14]([OH:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([OH:24])=[O:23])([C:18]([OH:20])=[O:19])[OH:17]>>[CH:1]#[C:2][CH2:3][NH:4][C@H:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6]1.[C:14]([O-:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([O-:24])=[O:23])([C:18]([O-:20])=[O:19])[OH:17]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C#CCN[C@@H]1CCc2ccccc21
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
The experiments conducted in this example are listed below in Table 3. In each of the experiments, rasagiline free base, excipient, and citric acid were combined and mixed. A solid dispersion was prepared from the mixture by dry milling, wet milling, or cryo-grinding the mixture at conditions listed in Table 3 below.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])([O-:3])=[O:2].[CH:12](=O)[CH2:13][CH2:14][CH3:15].[NH4+].[OH-]>O=P(Cl)(Cl)Cl>[N+:1]([C:4]1[C:5]2[N:11]=[C:12]([CH2:13][CH2:14][CH3:15])[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: CCCC=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc2c([N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
3-Nitro-benzene-1,2-diamine (1.0 g, 6.54 mmol) and butyraldehyde (630 μL, 7.19 mmol) were stirred in POCl3 (10 mL) at 85° C. for 3 hours. The reaction was cooled to ambient temperature and poured over ice. The resulting mixture was basified with NH4OH. The precipitate was filtered and washed with ice water to give 1.17 g of the sub-title compound that was used without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25](B(O)O)[C:20]=2[N:19]=[CH:18]1>O1CCOCC1.C([O-])(O)=O.[Na+].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]>[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:2]3[N:11]=[CH:10][C:9]4[NH:8][C:7](=[O:12])[CH:6]5[CH2:13][O:14][CH2:15][CH2:16][N:5]5[C:4]=4[N:3]=3)[C:20]=2[N:19]=[CH:18]1
Reactant: OB(O)c1cccc2[nH]cnc12
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: O=C1Nc2cnc(-c3cccc4[nH]cnc34)nc2N2CCOCC12

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 84 using 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x1, 50 mg, 0.208 mmol), 1H-benzo[d]imidazol-4-ylboronic acid (71.5 mg, 0.441 mmol), and PdCl2(dppf) (7.60 mg, 10.39 μmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 3.10-3.19 (m, 1 H), 3.50-3.59 (m, 2 H), 3.99 (d, J=3.28 Hz, 1 H), 4.18 (dd, J=11.24, 3.66 Hz, 1 H), 4.43 (dd, J=10.61, 3.79 Hz, 1 H), 4.59-4.71 (m, 1 H), 7.49-7.67 (m, 1 H), 7.90 (d, J=8.08 Hz, 1 H), 8.03 (s, 1 H), 8.39 (d, J=7.83 Hz, 1 H), 9.23 (br s, 1 H), 11.03 (s, 1 H). ESI-MS m/z [M+H]+ calc'd for C16H14N6O2, 323.12; found 323.2.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.P(Br)(Br)([Br:19])=O>C1(C)C=CC=CC=1.C(#N)C>[Br:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)c1cc(O)c2ccccc2n1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Br)c2ccccc2n1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-hydroxyquinoline-2-carboxylate (10.0 g, 46.0 mmol) and phosphorus oxybromide (13.2 g, 46.0 mmol) in 100 mL of toluene and 10.0 mL acetonitrile was heated at 75° C. for 1.5 h. The reaction mixture was cooled to room temperature, quenched slowly with water, and extracted with ethyl acetate. The organic fraction was washed with brine, dried over sodium sulfate, filtered, and concentrated. The resultant residue was subjected to silica gel chromatography eluting with 0-50% ethyl acetate in hexanes to afford ethyl 4-bromoquinoline-2-carboxylate that gave a mass ion (ES+) of 280.1 (79Br) for M+H+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:18])([F:17])[F:19])=[CH:14][N:15]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2Cl)c1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
First, 0.15 g of 3-(2,4-dichloro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-357) was dissolved in 0.90 ml of N,N-dimethylformamide, to which 92 mg of potassium carbonate and 82 mg of ethyl bromoacetate were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 179 mg (yield, 96%) of 3-{2,4-dichloro-5-[(ethoxycarbonyl)methoxy]phenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-380).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][O:33][Si](C(C)(C)C)(C)C)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][OH:33])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCCCN1Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCC1CCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
To an ice-cooled THF solution of tetrabutylammonium fluoride (1M, 3.2 ml) was dropwise added a THF (2 ml) solution of 1-benzyl-2-(tert-butyldimethylsilyloxymethyl)-piperidine (1.00 g, 3.2 mmol). After stirring at room temperature for 2 hours, a reaction solution was poured onto water followed by extraction with ethyl acetate (30 ml). The extract was washed successively with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The crude product thus obtained was purified by a column chromatography on silica gel (SiO2 : 20 g, CHCl3) to afford 0.41 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C)=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.O.[OH-].[K+]>CO>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:16])[CH3:1])=[CH:4][C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(=O)Nc1ccc(N(C)C)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)c1ccc(N)c([N+](=O)[O-])c1
Reaction time: 5 h
Yield: 65 %

Procedure:
To a solution of N-[4-(dimethylamino)-2-nitrophenyl]acetamide obtained in step 11 above (1.0 eq) in MeOH and water was added KOH (1.5 eq) at room temperature and stirred for 5 hrs. Water was added to the reaction mixture and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired N-(4-amino-3-nitrophenyl)-N,N-dimethylamine. (Yield=65%).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:24]([N:26]([CH2:35][CH3:36])[C:27]([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])=[O:28])[CH3:25]>>[CH2:35]([N:26]([CH2:24][CH3:25])[C:27](=[O:28])[CH2:29][CH2:30][CH2:31][C:32]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:33])[CH3:36]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCN(CC)C(=O)CCCC(=O)O
Product: CCN(CC)C(=O)CCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-diethylcarbamoyl-butyric acid to yield (3aR,4S,7aR)-methyl 4-(5-(diethylamino)-5-oxopentanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [2M+NH4]=982; RT=1.23 min; UPLC Method I