Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[C:5]([C@H:11]([NH:13][S@@](C(C)(C)C)=O)[CH3:12])[CH:4]=[N:3]1.[ClH:20]>O1CCOCC1>[ClH:20].[ClH:20].[CH3:1][N:2]1[C:6]([C:7]([F:8])([F:9])[F:10])=[C:5]([C@H:11]([NH2:13])[CH3:12])[CH:4]=[N:3]1
Reactant: C[C@@H](N[S@](=O)C(C)(C)C)c1cnn(C)c1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](N)c1cnn(C)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-N-((R)-1-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (0.135 g, 0.00045 mole) was dissolved in HCl in dioxane (4M, 8 ml) and the solution stirred at room temperature overnight under nitrogen. The solution was evaporated and the residue suspended in ether and the white solid filtered off under a blanket of nitrogen. Yield 120 mg 99% (hygroscopic). 1H NMR (400 MHz CD3OD) 7.74 (s, 1H) 4.67, 4.66, 4.64, 4.62 (q, 1H) 4.02 (s, 3H) 1.63, 1.61 (d, 3H) MS (ESI) m/z 194 (M+H)+177 (M+H—NH3)+TLC CH2Cl2:MeOH:NH4OH 95:5:0.5 0.2 UV−ve KMnO4+ve [α]D=+2.87° (c=2.003, CH3OH)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[N+:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([O-:34])=[O:33].O>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:43][CH:42]=3)[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 59.3 %

Procedure:
11.2 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 120 ml of acetone, and 7.56 g of sodium bicarbonate are added thereto. 6.4 g of 4-nitrobenzoyl chloride are added to the mixture under ice-cooling and under stirring, and said mixture is stirred at room temperature for 2 hours. After the reaction, 10 ml of water are added to the mixture to dissolve inorganic materials, and said mixture is evaporated under reduced pressure to remove acetone. The oil thus obtained is extracted with ethyl acetate, and the extract is washed with water, dried and then eveporated to remove solvent. 9.3 g of (+)-cis-2-(4-methoxyphenyl)-3-(4-nitrobenzoyloxy)-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: COC[N:4]1[C:8]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[CH:7][C:6]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:33]=[C:32]([C:34]4[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=4)[N:31](COC)[N:30]=3)[CH2:24][CH2:23]2)=[N:5]1.C(OCC)(=O)C.[ClH:55]>C(Cl)(Cl)Cl>[ClH:55].[ClH:55].[CH3:45][O:44][C:36]1[CH:35]=[C:34]([C:32]2[NH:31][N:30]=[C:29]([CH2:28][N:25]3[CH2:24][CH2:23][N:22]([CH2:21][C:6]4[CH:7]=[C:8]([C:9]5[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=5)[NH:4][N:5]=4)[CH2:27][CH2:26]3)[CH:33]=2)[CH:39]=[C:38]([O:40][CH3:41])[C:37]=1[O:42][CH3:43]
Reactant: COCn1nc(CN2CCN(Cc3cc(-c4cc(OC)c(OC)c(OC)c4)n(COC)n3)CC2)cc1-c1cc(OC)c(OC)c(OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2cc(CN3CCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)[nH]n4)CC3)n[nH]2)cc(OC)c1OC
Reaction time: 3 h

Procedure:
N,N′-Bis[[1-methoxymethyl-5-(3,4,5-trimethoxy-phenyl)pyrazol-3-yl]methyl]piperazine (71 mg) was dissolved in chloroform (3 mL), and to the solution an ethyl acetate solution (0.7 mL) of 4 M hydrochloric acid was added at room temperature, and the mixture was stirred for 3 hours. After concentrating the reaction mixture, the residue was sufficiently dried and recrystallized from methanol-diisopropyl ether to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][NH2:18]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([NH:18][CH3:17])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Product: CNC(=O)C1(c2ccc(F)cc2)CCCCC1
Yield: 86 %

Procedure:
The title compound was synthesized from 1-(4-fluorophenyl)cyclohexane-carboxylic acid (222 mg, 1 mmol) and methylamine (1 mL, 1M in THF, 1 eq) according to General Procedure G. The crude product was purified by silica gel column chromatography to give the amide (202.6 mg, 86%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([OH:5])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:20][C@H:21]1[C:29]2[C:24](=[C:25]([C:30]3[N:34]=[C:33]([C:35]4[CH:36]=[CH:37][C:38]([O:43][CH:44]([CH3:46])[CH3:45])=[C:39]([CH:42]=4)[C:40]#[N:41])[O:32][N:31]=3)[CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1>CN(C=O)C.CC(=O)OCC>[C:40]([C:39]1[CH:42]=[C:35]([C:33]2[O:32][N:31]=[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:24]=3[CH2:23][CH2:22][C@H:21]4[NH:20][C:3](=[O:5])[CH2:2][OH:1])[N:34]=2)[CH:36]=[CH:37][C:38]=1[O:43][CH:44]([CH3:46])[CH3:45])#[N:41]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Reactant: O=C(O)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NC(=O)CO)no2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
Prepared using General Procedure 7. To 2-hydroxyacetic acid (7 mg, 0.08 mmol) in DMF (2 mL) was added HOBt (12 mg, 0.09 mmol) and EDC (17 mg, 0.09 mmol). The reaction mixture was stirred at room temperature for 0.5 h until the acid was fully activated. (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (25.0 mg, 0.07 mmol) was added in one portion and the reaction was stirred at room temperature for 12 h. The reaction mixture was diluted with EA and washed with NaHCO3. The combined aqueous layers were back-extracted with EA. The resulting combined organic layers were dried over Na2SO4 and concentrated to a brown oil which was purified by chromatography (MeOH/DCM) to provide 14 mg (48%) of (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxy acetamide 65 as a white solid. LCMS-ESI (m/z) calculated for C22H22N4O4: 418.5. found 419.0 [M+H]+, tR=2.47 min. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=2.2 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.45 (d, J=7.5 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 5.61 (d, J=8.1 Hz, 1H), 4.80 (dt, J=12.2, 6.1 Hz, 1H), 4.20 (s, 2H), 3.49 (m, 1H), 3.23 (dd, J=17.1, 8.5 Hz, 1H), 2.80-2.60 (m, 1H), 1.93 (dd, J=13.0, 8.4 Hz, 1H), 1.47 (t, J=5.6 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 173.11, 171.21, 168.78, 162.78, 144.48, 143.21, 134.11, 133.88, 128.56, 127.42, 126.83, 123.29, 116.76, 115.26, 113.55, 103.90, 72.77, 62.25, 54.00, 33.52, 31.71, 21.72.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[C:15]2[O:14][CH2:13][C:12](=[O:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:2].[BrH:18].[NH+]1C=CC=CC=1.O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[C:15]2[O:14][CH:13]([Br:18])[C:12](=[O:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1cccc2c1OCC2=O
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)COc1cccc2c1OC(Br)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl[(3-oxo-2,3-dihydrobenzofuran-7-yl)oxy]acetate (1.00 g, 4.23 mmol) in chloroform (30 mL) was added pyridinium hydrobromide perbromide (1.35 g, 4.23 mmol) at 0° C. and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water. The organic layer was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 1.20 g of ethyl[(2-bromo-3-oxo-2,3-dihydrobenzofuran-7-yl)oxy]acetate. A mixture of this compound (1.20 g, 3.80 mmol) and 1-phenyl-2-thiourea (580 mg, 3.80 mmol) in acetic acid (20 mL) was refluxed for 3 hours. The solvent was then distilled off under reduced pressure. To that residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane=1:5) to provide 180 mg of the title compound. Yield 12%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[C:8]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:3][CH2:2]1.CC(O)=O.[OH-].[Na+].[CH3:34][C:35]([CH3:37])=O>>[CH3:34][CH:35]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=3)[C:8]=2[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[CH2:3][CH2:2]1)[CH3:37]
Reactant: FC(F)(F)c1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)N1CCC(c2[nH]nc(-c3ccc(C(F)(F)F)cc3)c2-c2ccncc2)CC1
Reaction time: 120 h

Procedure:
To a solution of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-(trifluoromethyl)phenyl]pyrazole (Example C-83) (300 mg, 0.7 mmol) in 50 mL of acetone was added 1 mL of AcOH and NaBH(OAc), (15 g, 70.8 mmol). The mixture was warmed to reflux and was stirred for 5 days, The reaction mixture was poured onto 100 mL of 2.5 N NaOH and was extracted with ethyl acetate (2×100 mL). The extracts were combined and washed with brine (1×100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to afford the title compound: MS (M+H): 415 (base peak).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C@H:20]2[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([OH:28])[C@@H:22]([CH2:29][OH:30])[O:21]2)=[CH:16][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH2:9][C:8]2=[O:15].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C@H:20]2[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([OH:28])[C@@H:22]([CH2:29][OH:30])[O:21]2)=[CH:16][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH2:9][CH:8]2[OH:15]
Reactant: O=C1CCOc2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)C(O)CCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h

Procedure:
To a solution of 6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman-4-one (0.1 g, 0.23 mmol) in methanol (3 mL) was added sodium borohydride (0.017 g, 0.46 mmol). The reaction mixture was stirred for 2 h and quenched by the addition of water (10 mL) and extracted with ethyl acetate (150 mL×3), solvent was removed under reduced pressure to get crude (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-hydroxy-chroman-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol which was further purified by preparative HPLC (Yield=30 mg).
Reaction SMILES: Br[CH2:2][C:3]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>CN(C=O)C>[C:13]([O:16][CH2:2][C:3]1[C:4]([C:5]#[N:6])=[C:7]([Cl:12])[CH:8]=[C:9]([Cl:11])[N:10]=1)(=[O:15])[CH3:14]
Reactant: N#Cc1c(Cl)cc(Cl)nc1CBr
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc(Cl)cc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(bromomethyl)-4,6-dichloronicotinonitrile (354.8 mg, 1.334 mmol) in DMF (7 ml) was charged with sodium acetate (198 mg, 2.414 mmol) and stirred at RT for 2 hr. The reaction was quenched with water, extracted twice with Et2O. The organics was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give (4,6-dichloro-3-cyanopyridin-2-yl)methyl acetate. MS ESI calc'd. For C9H7O2N2O2 [M+I-1]+ 245. found 245.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21]CC)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=3)=[CH:5][C:4]=2[N:3]=1.B(Br)(Br)Br.CO>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([CH3:17])([OH:18])[CH3:19])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4ccc(F)c(F)c4)cnc3c2n1CC(C)(C)O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(C)(O)Cn1c(CO)nc2c(N)nc3cc(-c4ccc(F)c(F)c4)cnc3c21
Temperature: 0 °C
Reaction time: 22.5 h
Yield: 36.4 %

Procedure:
A suspension of 1-[4-amino-7-(3,4-difluorophenyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (0.790 g, 1.85 mmol), obtained from the filtrate from the trituration in Example 59, in dichloromethane (20 mL) was cooled to 0° C. Boron tribromide (5.54 mL of a 1 M solution in dichloromethane) was added dropwise, and the reaction was stirred at room temperature for 22.5 hours. An analysis by LC/MS indicated the reaction was incomplete, and additional boron tribromide (2.7 mL) was added. The reaction was stirred for three hours at room temperature, and then methanol (25 mL) was carefully added. The resulting solution was stirred at room temperature for one hour and concentrated under reduced pressure. A solution of ammonia in methanol (30 mL of 2 M) was added, and the mixture was stirred for 30 minutes and then diluted with methanol (50 mL) and dichloromethane (50 mL). Silica gel was added, and the mixture was concentrated under reduced pressure. The residue was purified by chromatography according to the method described in Example 62. The resulting solid was triturated with acetonitrile, isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to provide 269 mg of 1-[4-amino-7-(3,4-difluorophenyl)-2-(hydroxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a light yellow solid, mp 256-258° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:13])[N:4]=1.[C:14]1([CH:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH2:8][CH:9]([OH:13])[CH2:10][N:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[CH:20]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27]2)[N:4]=1
Reactant: O=C(C(c1ccccc1)c1ccccc1)N1CCNCC1
Reactant: CSc1ccc2c(O)cccc2n1
Product: CSc1ccc2c(OCC(O)CN3CCN(C(=O)C(c4ccccc4)c4ccccc4)CC3)cccc2n1

Procedure:
An epoxy compound was prepared from 2-methylthio-5-hydroxyquinoline in accordance with the same procedure as in Example 1-(a), and reaction and treatment were then carried out using this epoxy compound and N-(α,α-diphenylacetyl)piperazine to obtain the desired compound.
Reaction SMILES: [Li+].[OH-].[C:3]([NH:6][C@@H:7]1[C@H:16]([O:17]C(=O)C)[C@@H:15]([O:21]C(=O)C)[C@H:14]([CH2:25][O:26]C(=O)C)[O:13][C@@H:8]1[O:9]C(=O)C)(=[O:5])[CH3:4]>C1COCC1.O>[C:3]([NH:6][C@@H:7]1[C@H:16]([OH:17])[C@@H:15]([OH:21])[C@H:14]([CH2:25][OH:26])[O:13][C@@H:8]1[OH:9])(=[O:5])[CH3:4]
Reactant: CC(=O)N[C@H]1[C@@H](OC(C)=O)O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@@H]1O
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of aqueous LiOH (0.3M, 20 mL) was added dropwise to a solution containing Compound 10 (0.52 g, 1.34 mmol) in THF-H2O (3:1, 22 mL). From TLC, the reaction was complete within 30 minutes. Dowex® 50W-X8[H+] was added to neutralize the solution, then the resin was filtered off, and the filtrate was concentrated. The product was purified by flash column chromatography with CHCl3—MeOH (3.5:1) to obtain 0.29 g (1.3 mmol) of Compound 11 (97 percent yield). Further purification was carried out with Bio Gel P-2 chromatography using water as eluent.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.OC(C(F)(F)F)=O.[F:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=1>C(#N)C>[Br:1][C:22]1[C:17]([F:16])=[CH:18][C:19]([NH2:23])=[N:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(F)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Nc1cc(F)c(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
N-Bromosuccinimide (126 mg, 0.71 mmol) was added to a solution of 4-fluoropyridin-2-amine TFA salt (162 mg, 0.72 mmol) in acetonitrile (4 mL) in an aluminum foil-wrapped flask in a darkened hood. The reaction solution was stirred at room temperature in darkness for 2 hours. After evaporation of the solvent, the crude product was purified on a silica gel column eluting with EtOAc to give 5-bromo-4-fluoropyridin-2-amine as an ivory solid (92 mg, 67%). LC/MS (m/z): 190.9/192.9 (MH+), Rt 1.02 minutes.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[CH:10]=2)[C:5]1=[O:20]>CC(O)=O>[Br:1][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[CH:10]=2)[C:5](=[O:20])[N:4]([CH3:3])[CH:13]=1
Reactant: BrBr
Reactant: Cn1cc(-c2ccc3c(=O)n(C)ccc3c2)cn1
Solvent: CC(=O)O
Product: Cn1cc(-c2ccc3c(=O)n(C)cc(Br)c3c2)cn1

Procedure:
Bromine (1.8 g, 11.25 mmol) in HOAc (6 mL) was added to the title compound of 2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one (3 g, 12.5 mmol) in HOAc (24 mL) at 0° C. The mixture was stirred at 30° C. for 15 min, quenched with H2O (100 mL), and the resulting yellow solid was collected by filtration to give the title compound (2.04 g, 56%). 1H NMR (CDCl3, 400 MHz) δ 8.42 (d, J=8.4 Hz, 1H), 7.87 (d, J=28.8 Hz, 2H), 7.82 (d, J=15.6 Hz, 2H), 7.65 (d, J=8 Hz, 2H), 7.38 (s, 1H), 4.00 (s, 3H), 3.61 (s, 3H). LCMS: 318.0 (M+H)+
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[N:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])=[N:13][CH:14]=2)[CH2:4]1.C(N(CC)C(C)C)(C)C.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:30][O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][N:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[N:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])=[N:13][CH:14]=2)[CH2:4]1
Reactant: COC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)cn1
Reactant: COc1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3OC)C2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a suspension of methyl (2E)-3-{5-[(3R)-3-pyrrolidinylamino]-2-pyrazinyl)acrylate dihydrochloride (260 mg) in CH2Cl2 (2.6 mL) was added N,N-diisopropylethylamine (282 uL), 2-methoxybenzaldehyde (121.2 mg), and sodium triacetoxyborohydride (343 mg), which was stirred at room temperature for 1 hour. To the resultant was added sat. NaHCO3 aq., which was stirred for 20 min. The mixture was extracted with CH2Cl2. The organic phase was washed with brine and dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give methyl (2E)-3-(5-{[(3R)-1-(2-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (193 mg) as a yellow amorphous.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:11]([F:12])=[C:10]2[O:13][CH2:14][O:15][C:9]2=[CH:8][C:5]=1[CH:6]=[O:7]>CO>[F:3][C:4]1[C:11]([F:12])=[C:10]2[CH:9]=[CH:8][C:5]=1[CH:6]([OH:7])[O:15][CH2:14][O:13]2
Reactant: O=Cc1cc2c(c(F)c1F)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1OCOc2ccc1c(F)c2F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A solution of sodium borohydride (5 g) in methanol was added to a solution of 2,3-difluoromethylenedioxybenzaldehyde (36 g) in methanol with cooling so that the temperature did not exceed 10 ° C. The reaction mixture was then allowed to warm to ambient temperature and stirred for 1 hour. Most of the methanol was evaporated and the residue was poured into cold 20% sodium hydroxide solution, extracted with ether, separated and washed with brine (until neutral), dried and the solvent removed to yield the title compound as a colourless oil (33.7 g), NMR (CDCl3): 2.10(br, 1H), 4.80(d,2H), 7.00(m, 1H), 7.10(m,2H).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:8][C:9]=1[O:10]C.[BrH:30]>[PH2](O)=O>[BrH:30].[BrH:30].[F:3][C:4]1[CH:5]=[C:6]([CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: COc1ccc(CCNCCCCCCNCCc2ccccc2)cc1F
Agent: Br
Agent: Cl
Agent: O=[PH2]O
Product: Oc1ccc(CCNCCCCCCNCCc2ccccc2)cc1F

Procedure:
The product from step (b) (1.8 g) in 48% hydrobromic acid (18 ml) containing hypophosphorous acid (10 drops) was boiled at reflux under nitrogen for 5.5 hr. The solid which separated on cooling the solution was collected and recrystallised from water giving the dihydrobromide salt of the title compound as colourless needles (1.3 g) mp 240.5-142°-5°.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15])[CH2:2][CH2:3][CH2:4][CH3:5].Br[CH2:17][CH2:18]Br.[H-].[Na+].[NH4+].[Cl-]>CN(C)C=O.CO>[CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:18][CH2:17]2)[C:7]1=[O:15])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: BrCCBr
Reactant: CCCCCN1C(=O)Cc2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCCN1C(=O)C2(CC2)c2ccccc21
Temperature: 15 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 1-pentyl-1,3-dihydro-indol-2-one (Farmaco, Ed. Sci. 1977, 32, 703-712) (22 g) and 1,2-dibromoethane (14.1 ml; 162 mmol) in dry N,N-dimethylformamide (180 ml) is added sodium hydride (60% in mineral oil, 13 g; 325 mmol) in small portions over a period of 15 min. The resulting mixture is stirred at 15° C. for 1 h. MeOH (50 ml) and saturated NH4Cl solution (200 ml) is added and the aqueous phase is extracted with Et2O. The combined organic layer is washed with water, brine and dried over MgSO4. The compound (24.8 g) is obtained after evaporation.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:20]=[C:21]([C:22]#[N:23])[C:4]=2[N:3]=1.[C:30]([NH:33][NH2:34])(=O)[CH3:31].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(O)CCC.O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:20]=[C:21]([C:22]3[NH:34][N:33]=[C:30]([CH3:31])[N:23]=3)[C:4]=2[N:3]=1
Reactant: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Reactant: CC(=O)NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Solvent: ClCCl
Product: Cc1n[nH]c(-c2cc(N3CCOCC3)cc3c2nc(C)n3Cc2cccc3ccccc23)n1
Yield: 26.1 %

Procedure:
To the suspension of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carbonitrile (120 mg, 0.314 mmol) in n-butanol (15 mL) was added in acetic hydrazide (232 mg, 3.14 mmol) and potassium carbonate (434 mg, 3.14 mmol). The reaction was stirred at reflux temperature for 4 days. DCM (50 mL) and water (50 mL) were added in. The organic phase was washed with Brine (50 mL×3), dried (MgSO4), and the solvent was removed. The crude was purified by reverse phase purification to provide the desired product (36 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (br. s., 3H), 1.78 (br. s., 3H), 2.21-2.37 (m, 4H), 2.90-3.08 (m, 4H), 5.20 (s, 2H), 5.74 (d, J=7.33 Hz, 1H), 6.17 (br. s., 1H), 6.51 (t, J=7.71 Hz, 1H), 6.75-6.95 (m, 3H), 7.04 (d, J=8.08 Hz, 1H), 7.17 (d, J=8.08 Hz, 1H), 7.43 (d, 1H). MS (ES+) m/e 439.1[M+H]+.