Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([C:15]1[C:16]([NH:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:17][C:18]([NH:21][C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([CH2:39][OH:40])=[C:31]([CH:34]([O:37][CH3:38])[O:35][CH3:36])[N:32]=3)[CH2:27][CH2:26][CH2:25]2)=[O:23])=[N:19][CH:20]=1)#[N:14]>C1COCC1>[CH3:8][S:9]([O:40][CH2:39][C:30]1[C:31]([CH:34]([O:37][CH3:38])[O:35][CH3:36])=[N:32][C:33]2[N:24]([C:22](=[O:23])[NH:21][C:18]3[CH:17]=[C:16]([NH:41][CH2:42][CH2:43][O:44][CH3:45])[C:15]([C:13]#[N:14])=[CH:20][N:19]=3)[CH2:25][CH2:26][CH2:27][C:28]=2[CH:29]=1)(=[O:11])=[O:10]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CO)c(C(OC)OC)nc32)ncc1C#N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(COS(C)(=O)=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Triethylamine (120 μL, 0.866 mmol) and methanesulfonyl chloride (57 μL, 0.731 mmol) were added to solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 171, 300 mg, 0.657 mmol) in THF (11 ml) at 0° C. The reaction mixture was stirred for approximately 2.5 h at 0° C. and filtered to remove solid impurities. The solid residue was washed with THF and the filtrate was concentrated to yield the title compound as beige solid which was used directly in the next step. (UPLC-MS) ESI-MS 535.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 13.67 (br s, 1H), 8.24 (s, 1H), 7.67 (s, 1H), 7.55 (s, 1H), 5.47 (s, 3H), 5.33 (br s, 1H), 4.08-4.00 (m, 2H), 3.63 (t, 2H), 3.53-3.45 (m, 8H), 3.41 (s, 3H), 3.07 (s, 3H), 2.88 (t, 2H), 2.09-1.94 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1ccco1
Product: CC(=O)NCCc1ccco1
Yield: 41 %

Procedure:
In close analogy to the procedure described above, 2-Furan-2-yl-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH2:26][C@@H:27]([OH:30])[CH2:28][OH:29]>>[OH:30][C@@H:27]([CH2:28][OH:29])[CH2:26][NH:25][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[CH:5]=1
Reactant: NC[C@@H](O)CO
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Product: COc1ccc(C(=O)NC[C@@H](O)CO)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzoic acid obtained in step B of Example 2-2-1 and (R)-3-amino-1,2-propanediol (produced by Wako Pure Chemical Industries) in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.CCN(CC)CC.[CH3:42][O:43][C:44](=[O:61])[CH2:45][NH:46][C:47](=[O:60])[C@H:48]([CH:55]([CH3:59])[CH:56]=C=O)[NH:49]OC(C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:42][O:43][C:44](=[O:61])[CH2:45][NH:46][C:47](=[O:60])[C@H:48]([CH:55]([CH3:56])[CH3:59])[NH:49][C:17](=[O:19])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)CNC(=O)[C@@H](NOC(C)(C)C)C(C)C=C=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(C)C
Reaction time: 0.25 h

Procedure:
A solution of N-benzyloxycarbonyl-L-leucine (2.65 g, 10 mmol) in 15 ml CH2Cl2 was cooled in an ice-water bath and stirred with a magnetic stirrer. A solution of dicyclohexylcarbodiimide (2.58 g, 12.5 mmol) in CH2Cl2 was added, and stirring was continued for 15 minutes. Dicyclohexylurea was filtered. The solvent was evaporated in vacuo or at room temperature. The residue was dissolved in 4 ml DMF(1) and cooled in an ice-water bath. CF3CO2H·H-Val-Gly-OMe(1.51 g, 5 mmol) was dissolved in 7 ml DMF, and Et3N (0.25 g =0.34 ml, 2.5 mmol) was added, whereupon the mixture was added to the solution (1) and Et3N (0.34 ml) was again added. Stirring was continued for 24 hours at room temperature. The reaction mixture was filtered, diluted with water and AcOEt and separated. The water layer was extracted twice with AcOEt. Collected organic phases were washed once with water, once with 0.5M NaHCO3, once with water, once with 1N HCl, and twice with water and dried over anhydrous MgSO4. After filtration the solvent was evaporated in vacuo. The solid residue was triturated with petroleum ether, filtered and dried in vacuo.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:14])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][C@H:3]([OH:14])[CH2:2][NH:1][C:23](=[O:24])[O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:8]=1)#[N:11]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: N#Cc1ccc(OC[C@H](O)CN)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(OC[C@H](O)CNC(=O)OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 4{[(2R)-3-amino-2-hydroxypropyl]oxy}benzonitrile (see step (ii) above; 3.4 g, 17.7 mmol), TEA (2.69 g, 26.6 mmol) and CHCl3 (20 mL) was cooled to 0° C. before N-(benzyloxycarbonyloxy)succinimide (4.86 g, 19.5 mol) in CHCl3 (15 mL) was added slowly. The mixture was allowed to reach rt, and was stirred at that temperature overnight. The solvent was evaporated to give a residue that was dissolved in DCM. This solution was washed with water and brine and then dried (Na2SO4). Evaporation of the solvent gave 5.79 g (100%) of the sub-title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11])[CH:2]=[CH2:3].[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>O.CCOCC>[CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[O:11][C:12](=[O:14])[CH3:13])[CH:2]=[CH2:3]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCc1cc(F)ccc1O
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: C=CCc1cc(F)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To crude (4p), acetic anhydride (36.5 mL, 386.4 mmol) and pyridine (37.5 mL, 463.7 mmol) were added. The resulting mixture was stirred at room temperature for 18 hours, checked by HPLC the next day (reaction appeared mostly complete). The mixture was then poured onto cold H2O/Et2O, the aqueous layer was extracted with Et2O (2×), the combined organic layers were washed sequentially with 10% HCl (3×), saturated NaHCO3 (2×), H2O (2×) and brine, and then dried over anhydrous Na2SO4. After concentration, crude product purity was checked by thin-layer chromatography (hexane/ethyl acetate, 7:3) and HPLC. No mass ion was observed. The crude product (5p) was carried on to next step directly without subsequent purification. 1HNMR (400 MHz, CDCl3) δ 7.04-6.91 (m, 3H), 6.09-5.65 (m, 1H), 5.19-5.06 (m, 2H), 3.27 (d, J=6.26 Hz, 2H), 2.30 (s, CH3).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].C([N-]C(C)C)(C)C.[Li+].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:15]1([N+:21]([O-:23])=[O:22])[CH:16]=[CH:17][C:18]([F:20])=[CH:19][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: OCCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])C1(OCCCl)C=CC(F)=CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A solution of 2-chloro-ethanol (1) (8.3 ml, 120 mmoles) in THF, under nitrogen, was cooled to 0° C., treated dropwise with lithium diisopropylamide (LDA) (60 ml, 120 mmoles, while maintaining the temperature constant at 0° C. The mixture was stirred at 0° C. for 15 minutes, treated with 2,4-difluoro-1-nitro-benzene (1) (11 ml, 100 mmoles), stirred at room temperature overnight, diluted with water and extracted with EtOAc. The extracts were combined, washed with brine, dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off-white solid (20.0 g, 91 mmoles), identified by HNMR and mass spectral analyses.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.C(=O)([O-])[O-].[K+].[K+]>CCOCC>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:9]1[NH:8][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
Trichloroacetyl chloride (45 g, 247 mmol) was dissolved in 100 mL of ether followed by dropwise addition of a solution of 1H-Pyrrole (15.4 g, 230 mmol) in 100 mL of ether and 200 mL of aqueous potassium carbonate (20 g, 145 mmol). Upon completion of the addition, the reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The layers were separated and the organic layer was dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2,2,2-trichloro-1-(1H-pyrrol-2-yl)-ethanone 57b (38 g, yield 77.8%) as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]1[CH:18]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:17][CH2:16][CH2:15][CH:14]1[C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=1.[Li+].[BH4-]>CO>[CH3:25][C:24]1[C:19]([CH:18]2[CH2:17][CH2:16][CH2:15][CH:14]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=3)[N:13]2[CH2:12][C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH2:3][OH:2])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc(C#N)ccc1CN1C(c2ncccc2C)CCCC1c1ncccc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccc(C#N)cc1CO
Reaction time: 3.5 h
Yield: 86 %

Procedure:
To a stirred, room temperature solution of the ester from above (2.05 g, 4.6 mmol) in MeOH (50 mL) was added LiBH4 (1.0 g, 50 mmol) in three portions. Effervescence was observed, and the mixture was stirred for 3.5 hours. The mixture was concentrated and 1 N NaOH (50 mL) was added to the resultant residue. The aqueous mixture was extracted with CH2Cl2 (3×50 mL). The organic extracts were combined, dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (40 g, eluted with 5% NH4OH/5% MeOH/CH2Cl2) provided 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-hydroxymethyl-benzonitrile (1.63 g, 86%) as a pale yellow solid.
Reaction SMILES: C12BC(CCC1)CCC2.[CH:10]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH2:11].Br[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([F:25])[CH:19]=1.[OH-].[Na+]>O1CCCC1.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].C(OCC)(=O)C>[CH:12]1([CH2:10][CH2:11][C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([F:25])[CH:19]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc(Br)cc1F
Reactant: C=CC1CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(CCC2CCCC2)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.8 %

Procedure:
9-Borabicyclo[3,3,1]nonane (9-BBN) (tetrahydrofuran solution, 0.5 mol/L, 33 mL, 16.5 mmol) was added dropwise to a solution of vinylcyclopentane (1.59 g, 16.5 mmol) in tetrahydrofuran (7.5 mL) at 0° C. under a nitrogen atomosphere. The mixture was warmed gradually to room temperature and stirred for 15 hr. To the reaction mixture were added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (367 mg, 0.45 mmol), 4-bromo-2-fluoroaniline (2.85 g, 15.0 mmol) and 3 mol/L aqueous sodium hydroxide solution (15 mL, 45.0 mmol), and the mixture was heated to reflux for 10 hr. After cooling, ethyl acetate was added thereto, the mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. Water was added thereto, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to afford the title compound as a pale yellow oil (3.01 g).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20](B(O)O)[CH:19]=[CH:18][N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:16]1[C:21]([C:2]2[N:6]3[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: FC(F)(F)c1ccc2ncc(Br)n2c1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc2ncc(-c3cccnc3Cl)n2c1
Temperature: 95 °C

Procedure:
To a solution of 3-Bromo-6-trifluoromethyl-imidazo[1,2-a]pyridine (1 eq, 2.9 mmol, 0.77 g), 2-chloropyrid-4-yl boronic acid (1.05 eq, 3.05 mmol, 0.478 g), Na2CO3 (2 eq, 5.81 mmol, 0.616 g) in dioxane (45 ml) and water (13.5 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (0.1 eq, 0.03 mmol, 200 mg). The reaction mixture is heated at 95° C. for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound; [M+H]+=297/299.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:31]=[C:30]([C:32]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([OH:42])[CH:37]=2)=[O:33])[CH:29]=[C:28]([CH3:43])[C:10]=1[C:11]([NH:13][C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:15][NH:16]C(OC(C)(C)C)=O)=[O:12].Cl.C(#N)C>ClCCl>[ClH:8].[NH2:16][CH2:15][C@@H:14]([C:24]([O:26][CH3:27])=[O:25])[NH:13][C:11](=[O:12])[C:10]1[C:28]([CH3:43])=[CH:29][C:30]([C:32]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([OH:42])[CH:37]=2)=[O:33])=[CH:31][C:9]=1[Cl:8]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CN)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (20 mL) was added to a solution of N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester (800 mg, 1.54 mmol) in dichloromethane (20 mL). The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated, azeotroped three times with dichloromethane/hexanes, and then held under high vacuum for 35 min. 1 M HCl (4.6 mL, 4.6 mmol) was added, along with acetonitrile (4 mL) and the mixture was freeze-dried overnight to give crude 3-amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-L-alanine, methyl ester hydrochloride (0.85 g, 120% of the theoretical amount).
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:17].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>ClCCl>[Br:17][CH2:15][C:14]([C:11]1[CH:12]=[N:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][CH:10]=1)=[O:16]
Reactant: CC(=O)c1cnc(Oc2ccccc2)nc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(CBr)c1cnc(Oc2ccccc2)nc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
To a solution consisting of 1-(2-phenoxypyrimidin-5-yl)ethanone (Step B, 400 mg, 1.87 mmol) in dichloromethane (14 mL) was added tetrabutylammonium tribromide (990 mg, 2.05 mmol). The reaction mixture was sealed with a screw top and warmed at 40° C. overnight and allowed to cool to room temperature. Hexane (4 mL) was subsequently added. After three hours and little precipitation, additional (150 mg) tetrabutylammonium tribromide was added and the reaction mixture was stirred overnight at room temperature. The pale yellow precipitate that formed was collected on a filter and washed with 1:1 dichloromethane-hexane to afford the title intermediate (375 mg, 68%); Rf 0.43 with 3:1 v/v hexanes-ethyl acetate; MS (ESI+) m/z 295, 293 (M+1, Br isotopes).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([C:12]([F:15])([F:14])[Cl:13])[N:10]([OH:11])[C:3]=12.[OH-].[NH4+:17]>>[NH2:17][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([C:12]([F:15])([F:14])[Cl:13])[N:10]([OH:11])[C:3]=12
Reactant: [NH4+]
Reactant: On1c(C(F)(F)Cl)nc2nccc(Cl)c21
Agent: [OH-]
Product: Nc1ccnc2nc(C(F)(F)Cl)n(O)c12

Procedure:
7-Chloro-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo-(4,5-b)pyridine is reacted with ammonium hydroxide to obtain 7-amino-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine which is oxidized to the corresponding 7-nitro-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine. Also, the 7-amino-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)-pyridine is treated with sodium nitrite and subsequently sodium cyanide to obtain the corresponding 7-cyano-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine. On treatment with 70 percent sulphuric acid the corresponding 7-carboxy-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine is prepared. On further treatment with SF4 and HF, there is obtained 7-(trifluoromethyl)-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=[O:18])[NH:6][N:5]=1)([CH3:3])[CH3:2].Br[CH2:20][CH2:21][CH2:22][Cl:23].C(Cl)(Cl)Cl.CO>CN(C)C=O>[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=[O:18])[N:6]([CH2:20][CH2:21][CH2:22][Cl:23])[N:5]=1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(C(C)C)n[nH]c(=O)c2cc1OC
Reactant: ClCCCBr
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cc2c(C(C)C)nn(CCCCl)c(=O)c2cc1OC

Procedure:
1-[4-Isopropyl-6,7-dimethoxy-1(2H)-phthalazinone-2-yl]-3-chloro-propane was prepared analogous to Example 1 (a) by reaction of 4-isopropyl-6,7-dimethoxy-1(2H)-phthalazinone with 1-bromo-3-chloro-propane in dimethylformamide. Rf -value (chloroform/methanol = 50/1) : 0.5.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH2:19])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[C:20](Cl)(=[O:22])[CH3:21]>CN(C)C=O.N1C=CC=CC=1>[C:20]([O:9][CH2:8][C@H:6]1[O:7][C@@H:1]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH2:19])[C@@H:2]([OH:3])[C@@H:4]1[OH:5])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H](O)[C@@H]1O

Procedure:
To a stirred mixture of 2.67 g. of 9-(β-D-arabinofuranosyl)adenine and 100 ml. of 1:1 dimethylformamide-pyridine is added 0.79 g. of acetyl chloride at 25° C. The mixture is stirred, while being protected from moisture, for 1.5 hours, then treated with 50 g. of crushed ice and evaporated at reduced pressure. The residue is added to a 3× 40 cm. column of dry silica gel and the column is eluted sequentially with 500-ml. portions of 5, 10, 15 and 20% (v/v) methanol in chloroform. Two fractions of eluate (the 15 and 20% methanol in chloroform eluates) are combined and evaporated at reduced pressure to give the desired product 9-(5-O-acetyl-β-D-arabinofuranosyl)adenine; m.p. 197.5°-198.5° C. after crystallization from ethanol, [α]D23 = +23.6° (c = 1% in methanol), λmaxCH3OH = 258 nm (ε = 15,000), water solubility: 9.9 mg./ml.
Reaction SMILES: COC[O:4][C:5]1[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[CH:27]=[CH:26][C:6]=1[C:7]([NH:9][C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:13])=[O:8].C(O)(C(F)(F)F)=O.O>ClCCl>[OH:4][C:5]1[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[CH:27]=[CH:26][C:6]=1[C:7]([NH:9][C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:13])=[O:8]
Reactant: COCOc1cc(C(C)C)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
To a stirring solution of 2-[2-methoxymethyloxy-4-isopropylbenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (5.74 g, 12.6 mmol) in dichloromethane (20 mL) was added TFA (100 mL) followed by water (100 mL). After stirring for 15 min, the solvents were removed in vacuo and the residue was partitioned between ethyl acetate (500 mL) and water (200 mL). At this point, the mixture was filtered to give 1.13 g (22%) of white solid. The filtrate was returned to a separatory funnel and the layers were separated. The organic phase was then washed with 1 M citric acid, once with brine, twice with saturated aq sodium bicarbonate, and once again with brine. The organic phase was then dried with MgSO4, filtered and concentrated to a volume of about 50 mL in vacuo. At this point, a significant amount of precipitate had formed; so the mixture was sonicated and filtered to give another 2.76 g (53%) of the title compound.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][N:2]1[C:14]([CH:16]1[CH2:21][CH2:20][N:19](C(OCC2C=CC=CC=2)=O)[CH2:18][CH2:17]1)=[O:15])=[CH:12][CH:11]=[CH:10][CH:9]=3.CO.C>ClCCl>[NH:19]1[CH2:20][CH2:21][CH:16]([C:14]([N:2]2[CH2:3][CH2:4][C:5]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[CH2:1]2)=[O:15])[CH2:17][CH2:18]1
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)N2CCc3c([nH]c4ccccc34)C2)CC1
Solvent: CO
Solvent: ClCCl
Product: O=C(C1CCNCC1)N1CCc2c([nH]c3ccccc23)C1
Reaction time: 18 h

Procedure:
32 g (76.65 mmol) of benzyl 4-[(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl)carbonyl]-1-piperidinecarboxylate, 300 ml of methanol, 300 ml of dichloromethane and 9 g of palladinized charcoal (10% palladium) are introduced into a Parr apparatus, and a hydrogenolysis is performed under approximately 0.41 MPa for 18 h.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH:3]=[C:4]([C:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH:13]=1)[C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1>O1CCCC1.CO.[Pd]>[CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([C:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH:13]=1)[C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc(C(=CC(C)C)c2cc3cccnc3[nH]2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(C(CC(C)C)c2cc3cccnc3[nH]2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.8 %

Procedure:
A solution of 2-(3-methyl-1-m-tolylbut-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.30 g, 4.70 mmol) in tetrahydrofuran (20 mL) and methanol (40 mL) was treated with 10% palladium on carbon (260 mg). The reaction was stirred at 25° C. under hydrogen atmosphere for 2 d. The reaction mixture was filtered and washed with tetrahydrofuran (2×15 mL). The filtrate was concentrated in vacuo. Silica gel column chromatography (300-400 mesh, 11% ethyl acetate/petroleum ether) afforded 2-(3-methyl-1-m-tolylbutyl)-1H-pyrrolo[2,3-b]pyridine (1.07 g, 81.3%) as light oil: 1H NMR (300 MHz, d6-DMSO): δ ppm 11.54 (s, 1H), 8.09 (d, 1H, J=3.6 Hz), 7.80 (d, 1H, J=7.5 Hz), 7.19-7.16 (m, 3H), 6.98-6.94 (m, 2H), 6.26 (d, 1H, J=1.5 Hz), 4.13 (t, 1H, J=8.1 Hz), 2.27 (s, 3H), 2.09-2.05 (m, 1H), 1.86-1.81 (m, 1H), 1.41-1.36 (m, 1H), 0.90 (s, 3H), 0.89 (s, 3H.