Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:3]=1
Reactant: COC(=O)c1ccc2c(c1)c(Br)nn2-c1ccc(C)cc1
Reactant: OB(O)c1ccccc1Cl
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)c(-c1ccccc1Cl)nn2-c1ccc(C)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
Methyl 3-bromo-1-(4-methylphenyl)-1H-indazole-5-carboxylate (150.3 mg, 0.435 mmol), 2-chlorophenylboronic acid, pinacol ester (210.4 mg, 0.882 mmol), palladium(II) acetate (5.2 mg, 0.023 mmol), copper(I) chloride (88.5 mg, 0.894 mmol), cesium carbonate (431.8 mg, 1.325 mmol), and 1,1′-bisdiphenylphosphino ferrocene (26.4 mg, 0.048 mmol) were dissolved in N,N-dimethylformamide (2200 μl) at 25° C. under Ar. The reaction mixture was warmed to 100° C. and allowed to stir for 3 h. The reaction was stopped, cooled to room temperature, quenched by addition of saturated aqueous ammonium chloride (10 mL), and extracted with ethyl acetate (3×10 mL). The combined organic phases washed with saturated aqueous ammonium chloride (2×10 mL) and saturated aqueous sodium chloride (1×10 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. Crude product purified by flash chromatography (RediSep SiO2, 24 g column) on a CombiFlash Rf purification system eluting with ethyl acetate-hexanes (0-30%). The title compound (117.4 mg, 0.312 mmol, 71.6% yield) was recovered as a light yellow/white solid. LC-MS: [M+1]=377.1.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[NH:10][N:9]2[CH:13]=[CH:14][CH:15]=[C:8]2[C:7]=1[OH:16])=[O:5])C.[NH2:17][CH2:18][C:19]([O-:21])=[O:20].[Na+]>COCCO>[OH:16][C:7]1[C:8]2[N:9]([CH:13]=[CH:14][CH:15]=2)[NH:10][C:11](=[O:12])[C:6]=1[C:4]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:5]
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c2cccn2[nH]c1=O
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2cccn2[nH]c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.) in 2-methoxyethanol. ESI (m/z): 252 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Cl-].Cl[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH+:19]([CH3:21])[CH3:20].O.[OH-].[Na+]>CS(C)=O>[CH3:20][N:19]([CH3:21])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][S:8][C:6]1[NH:5][C:4](=[O:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Reactant: C[NH+](C)c1ccccc1CCl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(=O)[nH]c(SCc2ccccc2N(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
After dissolving 0.71 g (5 mmol) of 6-methyl-2-thiouracil [Ann. 236, 1 (1986)] and 1.03 g (5 mmol) of (2-chloromethylphenyl)-dimethylammonium chloride (J. Chem. Soc. 1954, 4127) in 10 ml of dimethylsulfoxide, the reaction mixture is stirred at room temperature for 1 hour and then poured into 60 ml of water. After adjusting the pH value of the mixture to 6-8 by adding aqueous 1 N sodium hydroxide solution the precipitate is filtered and the crude base (1.3 g) is recrystallized from benzene to give 1.08 g (78.4%) of the title compound, m.p.: 152°-154° C. (white crystals).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.BrBr.[CH3:11][C:12]1[C:20]([C:21](=[S:23])[NH2:22])=[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]2[N:13]=1>C(O)(=O)C>[CH3:11][C:12]1[C:20]([C:21]2[S:23][C:3]3[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=3[N:22]=2)=[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]2[N:13]=1
Reactant: Cc1nn2ccccc2c1C(N)=S
Reactant: O=C1CCCCC1=O
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1nn2ccccc2c1-c1nc2c(s1)CCCC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
In a 250 mL round bottomed flask were placed 1,2-cyclohexanedione (1.32 g, 11.8 mmol) and acetic acid (30 mL). To the solution was added dropwise a solution of bromine (1.67 g, 10.4 mmol) in acetic acid (20 mL). The mixture was stirred for 30 min at rt. To the mixture was added 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide (1.92 g, 10.0 mmol) and the resulting suspension was stirred for 1 hr at 120° C. After 30 min the suspension turned into a clear brown solution. After 1 hour the mixture was allowed to cool to rt during which time an off-white solid precipitated. The mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (100 mL) and a saturated aqueous solution of NaHCO3 (100 mL). The resulting bi-phasic mixture was vigorously stirred for 30 min at rt. The aqueous phase was separated and the organic phase was washed with a 10% aqueous solution of NaHSO3 (50 mL), then a saturated aqueous solution of NaHCO3 (50 mL). The organic phase was dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was recrystallized from EtOAc and ether to yield the title compound (1.0 g; 35%) as a yellowish off-white crystalline solid. From the mother liquor, a 2nd crop of title compound (1.5 g; 53%) was obtained. LCMS: (FA) ES+ 284; 1H NMR (400 MHz, d6-DMSO) δ ppm 8.75 (dt, 1H), 8.29 (dt, 1H), 7.54 (dd, 1H), 7.07 (td, 1H), 3.16 (t, 2H), 2.65 (s, 3H), 2.60 (dd, 2H), 2.14-2.21 (m, 2H).
Reaction SMILES: [Na].COC([C:6]1[C:7]2[N:8]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:14]=2)[CH:9]=[CH:10][N:11]=1)=O.[CH3:22][CH:23]([OH:25])[CH3:24]>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:14]=[C:7]3[C:6]([O:25][CH:23]([CH3:24])[CH3:22])=[N:11][CH:10]=[CH:9][N:8]3[CH:12]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Reactant: CC(C)O
Agent: [Na]
Product: CC(C)Oc1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of anhydrous IPA (25 mL) and sodium (0.4 g, 17.4 mmol) was heated at reflux until the sodium was consumed. The reaction mixture was cooled to ambient temperature and the 8-chloro-2-(4-fluorophenyl)-imidazo[1,2-a]pyrazine (prepared from general procedure B using 3-chloropyrazin-2-ylamine and 2-bromo-1-(4-fluorophenyl)-ethanone; 2.0 g, 8 mmol) was added. The reaction mixture was heated at reflux for about 2 h, cooled to ambient temperature, and partitioned between EtOAc and water. The layers were separated and the organic phase was dried over MgSO4, filtered, and evaporated. The resulting solid was triturated with heptane to afford 1.52 g (70%) of the title compound: LC/MS (Table 1, Method g) Rt=2.78 min; MS m/z: 272.2 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][CH2:15]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:17][C:18]1[CH:19]=[C:20]([OH:27])[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25].O>CN(C)C=O>[F:17][C:18]1[CH:19]=[C:20]([O:27][CH2:15][CH2:14][CH2:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25]
Reactant: BrCCCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCCc2ccccc2)cc1F
Temperature: 85 °C
Reaction time: 6 h
Yield: 120.6 %

Procedure:
Potassium carbonate (20.7 g, 150 mmol) and 3-phenylpropyl bromide (18.2 mL, 120 mmol) were added to a solution of 3-fluoro-4-nitrophenol (15.7 g, 100 mmol) in N,N-dimethylformamide (200 mL) at room temperature and the mixture was stirred at 85° C. for 6 hr. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted three times with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid and brine and dried over anhydrous sodium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was dried under reduced pressure to afford 2-fluoro-1-nitro-4-(3-phenylpropoxy)benzene as a brown oil (33.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N+:9]=[N-:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:24]2[C@@H:29]3[C@@:27]([C:30]([NH:32][CH3:33])=[O:31])([CH2:28]3)[C@@H:26]([OH:34])[C@H:25]2[OH:35])=[C:17]([NH:36][CH2:37][C:38]#[CH:39])[N:16]=1.O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C(O)(C)(C)C.S([O-])([O-])(=O)=O.[Cu+2].CCCC[Sn](OC(C)=O)(CCCC)CCCC>[Cl:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:24]2[C@@H:29]3[C@@:27]([C:30]([NH:32][CH3:33])=[O:31])([CH2:28]3)[C@@H:26]([OH:34])[C@H:25]2[OH:35])=[C:17]([NH:36][CH2:37][C:38]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=3)[CH:39]=2)[N:16]=1
Reactant: C#CCNc1nc(Cl)nc2c1ncn2[C@H]1[C@H](O)[C@H](O)[C@]2(C(=O)NC)C[C@H]12
Reactant: [N-]=[N+]=Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [Cu+2]
Agent: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Solvent: CC(C)(C)O
Product: CNC(=O)[C@@]12C[C@@H]1[C@@H](n1cnc3c(NCc4cn(-c5ccc(F)c([N+](=O)[O-])c5)nn4)nc(Cl)nc31)[C@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
4-Fluoro-3-nitro-phenylazide (9.7 mg, 0.053 mmol) and TBTA (1 mg, 0.001 mmol) were added to a solution of compound 218 (14.4 mg, 0.038 mmol) in t-butanol (0.8 mL)-water (0.8 mL) at room temperature. Freshly prepared 1M solution of sodium ascorbate (38.2 μL) followed by 7.5% solution of copper sulfate (63 μL, 0.019 mmol) was also added into the reaction mixture stirred at room temperature overnight. Solvent was evaporated, and the residue was purified on flash silica gel column chromatography (CH2Cl2:MeOH=30:1) to give compound 219a (19 mg, 92%) as a syrup. 1H NMR (CD3OD, 400 MHz) δ 8.62-8.61 (m, 2H), 8.27-8.24 (m, 1H), 8.06 (s, 1H), 7.69-7.64 (m, 1H), 5.08 (d, J=6.8 Hz, 1H), 4.94 (br s, 2H), 4.81 (s, 1H), 4.01 (d, J=6.0 Hz, 1H), 2.87 (s, 3H), 2.07-2.04 (m, 1H), 1.82 (t, J=4.8 Hz, 1H), 1.39-1.37 (m, 1H). HRMS calculated for C22H21ClFN10O5 (M+H)+: 559.1369. Found 559.1346.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([OH:25])[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][CH2:36][O:37][CH2:38][CH3:39]>Cl([O-])(=O)(=O)=O.[Ag+]>[CH2:36]([O:37][C@@H:38]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=2)[C@H:35]([CH2:12][O:11][C:10](=[O:13])[CH3:9])[C@@H:15]([CH2:16][O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:25][C@@H:39]1[O:25][C@@H:15]1[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:13][C@H:10]([O:11][CH3:12])[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:16]1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:35]1[CH:31]=[CH:30][CH:29]=[CH:34][CH:33]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CCOCC
Agent: [Ag+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](COC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
Ethereal silver perchlorate (0.08 M, 9.58 ml, 7.67 mmol) is added with stirring at -30° C. to a solution of methyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside (2.592 g, 5.59 mmol), 2,3,6-tri-O-benzyl-1,4-dideoxy-4-acetyloxymethyl-D-gluco-pyranosyl chloride (3.661 g, 6.98 mmol) in ether (20 ml). The mixture is stirred 15 min at -30° C. and silver chloride precipitated. The mixture is filtered through a celite pad, the solids are washed with ether, the filtrate is concentrated under reduced pressure. The residue is dissolved in methylene chloride and the organic layer is washed successively with aqueous sodium thiosulfate and water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure so as to afford a foam. Flash chromatography on silica gel and elution with a graded mixture of hexane and ethyl acetate will afford methyl 4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxymethyl-α-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside as a foam.
Reaction SMILES: [CH2:1]([C:8]1([OH:18])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[CH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:24][C:23]1[CH:25]=[CH:26][C:20]([C:17]#[C:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)([OH:18])[CH2:9][CH2:10]2)=[CH:21][CH:22]=1
Reactant: C#CCCN1CCC(O)(Cc2ccccc2)CC1
Reactant: Nc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Nc1ccc(C#CCCN2CCC(O)(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.9 %

Procedure:
A mixture of 4-benzyl-1-(but-3-yn-1-yl)-4-hydroxypiperidine (243 mg, 1.00 mmol), 4-iodoaniline (219 mg, 1.00 mmol), copper(I) iodide (40 mg), PdCl2(PPh3)2 (50 mg, 0.04 mmol) in 10 mL of Et3N is stirred at room temperature under N2 for 20 hr. The mixture is filtered and washed with Et3N (3×15 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as a brown oil (100 mg, 30%): 1H NMR (CDCl3) 1.49 (m, 3 H), 1.72 (m, 2 H), 2.38 (m, 2 H), 2.55-2.66 (m, 6 H), 2.74 (s, 2 H), 3.75 (s, 2 H), 6.52 (d, J=8.4 Hz, 2 H), 7.15-7.30 (m, 7 H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][C@H:16]([CH2:21][N:22]([CH2:30][C@H:31]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:46][O:47][CH2:48][C:49](O)=[O:50].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:39]([O:38][C@H:31]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[CH2:30][N:22]([CH2:21][C@@H:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([NH:1][C:49](=[O:50])[CH2:48][O:47][CH3:46])(=[O:4])=[O:3])[CH:6]=3)[CH:12]=2)[O:17]1)[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N(C[C@@H]1CCc2cc(-c3cccc(S(N)(=O)=O)c3)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCC(=O)NS(=O)(=O)c1cccc(-c2ccc3c(c2)CC[C@@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)c1

Procedure:
A solution of the compound of Example 281 (60 mg, 0.091 mmol), methoxyacetic acid (13 mg, 0.13 mmol), EDCl (26 mg, 0.14 mmol), and DMAP (11 mg, 0.091 mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated down and the crude product was purified by preparative TLC plate with CH2Cl2:MeOH:NH4OH (90:15:2) to obtain (60 mg). ESLC-MS: m/z=725 (MH+); 1H NMR (MeOH-d4): 8.566˜8.439 (m, 2H), 8.077 (s, 1H), 7.889˜7.780 (m, 1H), 7.675 (m, 1H), 7.453 (m, 2H), 7.313(m, 2H), 6.767 (d, 1H), 5.180˜5.035 (m, 1H), 4.220 (s, b, 1H), 3.907 (s, 2H), 3.760˜3.333 (m, 4H), 2.835 (m, 2H), 2.041 (m, 1H), 1.711 (m, 1H), 1.445 (d, 9H), 0.892 (s, 9H), 0.076 (s, 3H), −0.109 (s, 3H).
Reaction SMILES: [C:1]1([C:11]2([C:16]#N)[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:30])C>ClCCl.CCCCCC>[C:1]1([C:11]2([CH:16]=[O:30])[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2cccc3ccccc23)CCCC1
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: O=CC1(c2cccc3ccccc23)CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98 %

Procedure:
To a solution of 1-naphthalen-1-yl-cyclopentanecarbonitrile (338) (10.5 g, 47.4 mmol) in dichloromethane (150 mL) was added dropwise diisobutylaluminium hydride (25% in toluene, 67.5 mL, 118.6 mmol) at −78° C. and stirred for 2 h at the same temperature (silica TLC, 5% ethyl acetate in hexane; Rf=0.6). The reaction mixture was quenched with a saturated aqueous solution of potassium sodium tarterate (35 mL) and stirred for 17 h at room temperature. The reaction mixture was filtered and the residue was washed with dichloromethane. The organic phase was separated and the aqueous part was back extracted with dichloromethane (100 mL). The combined organic part was dried, filtered and concentrated in vacuo to get a crude mass which was purified by CombiFlash using gradient eluent mixture of ethyl acetate and hexane to obtain pure 1-naphthalen-1-yl-cyclopentanecarbaldehyde (339) (10.4 g, 98%) as a colorless sticky liquid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[CH2:31]([C:35]1[CH:36]=[CH:37][C:38]([CH:41]=O)=[N:39][CH:40]=1)[CH2:32][CH2:33][CH3:34].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:31]([C:35]1[CH:36]=[CH:37][C:38]([CH2:41][NH:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][N:11]([CH2:10][C:2]3[NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[CH:21]3[C:30]4[N:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:24][CH2:23][CH2:22]3)=[CH:18][CH:17]=2)=[N:39][CH:40]=1)[CH2:32][CH2:33][CH3:34]
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: CCCCc1ccc(C=O)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1ccc(CNCc2ccc(CN(Cc3nc4ccccc4[nH]3)C3CCCc4cccnc43)cc2)nc1

Procedure:
Using general procedure B: N-(1H-benzimidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.1258 g, 0.316 mmol) and 5-n-butylpyridine-2-carboxaldehyde (0.0603 g, 0.294 mmol) were reacted with NaBH(OAc)3 (0.0942 g, 0.444 mmol) in CH2Cl2 (2.5 mL). Purification of the crude material by radial chromatography (2 mm TLC plate, 50:1:1 CH2Cl2: CH3OH: NH4OH) provided 0.0713 g (45%) of AMD9398 (free base).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:26](COCC[Si](C)(C)C)[C:25]4[C:24](=[O:35])[N:23]([CH2:36][CH2:37][CH3:38])[C:22]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=5)=[N:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:26][C:25]4[C:24](=[O:35])[N:23]([CH2:36][CH2:37][CH3:38])[C:22]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:46])[F:47])[CH:40]=5)=[N:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCn1c(-c2cccc(C(F)(F)F)c2)nc2nc(-c3ccc(OCC#Cc4ccc(F)cc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Agent: Cl
Solvent: CCO
Product: CCCn1c(-c2cccc(C(F)(F)F)c2)nc2nc(-c3ccc(OCC#Cc4ccc(F)cc4)cc3)[nH]c2c1=O
Temperature: 85 °C
Yield: 46.3 %

Procedure:
A mixture of 8-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.056 g, 0.083 mmol), 2N HCl (2 ml), ethanol (2 ml) was heated at 85° C. for 2 hours. The mixture was cooled and the solvent was evaporated. The residue was washed with n-pentane to obtain 8-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one (0.021 g, 46%) as an off white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:26][CH2:27][O:28][CH2:29][C:30]1[O:31][CH:32]=[CH:33][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CC(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:16]2[N:17]([CH2:26][CH2:27][O:28][CH2:29][C:30]3[O:31][CH:32]=[CH:33][CH:34]=3)[C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCOCc1ccco1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2CCOCc2ccco2)CC1
Reaction time: 21 h

Procedure:
Combine ethyl 2-fur-2-ylmethoxyaceate (1.2 g, 6.5 mmol) and tetrahydrofuran (10 mL). Cool in an ice-bath. Add dropwise a solution of lithium aluminum hydride (8.0 mL, 1.0M in THF, 8.0 mmol). After 2 hours, add water (0.3 mL), add 15% sodium hydroxide solution (0.3 mL), and add water (0.9 mL). Stir vigorously. After 15 minutes, filter the reaction mixture and dry the filtrate over Na2SO4, filter, and concentrate in vacua to give a residue. Chromatograph the residue on silica gel eluting with 2% ethyl acetate/dichloromethane to give fur-2-ylmethyl 2-hydroxyethyl ether: Rf=0.22 (silica gel, 5% acetone/dichloromethane). Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (1.71 g, 5.2 nmol), fur-2-ylmethyl 2-hydroxyethyl ether (0.74 g, 5.2 mmol), and triphenylphosphine (1.67 g, 6.4 mmol) in tetrahydrofuran (20 mL). Add diethyl azodicarboxylate (1.0 mL, 6.35 mmol). After 21 hours, evaporate the reaction mixture in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% acetone/dichloromethane to give 1-(t-butoxycarbonyl)-4-(1-(2-fur-2-ylmethoxy-ethyl)-1H-benzimidazole-2-carbonyl)piperidine: Rf=0.30 (silica gel, 5% acetone/dichloromethane).
Reaction SMILES: [CH3:1][N:2]([CH3:50])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][N:17](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]3=[N:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:38][C:39]([CH:41]1[CH2:46][CH2:45][CH2:44][N:43]([CH:47]([CH3:49])[CH3:48])[CH2:42]1)=[O:40])=[O:4].[OH-].[K+]>CO.CN(C)C=O>[CH3:50][N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:38][C:39]([CH:41]1[CH2:46][CH2:45][CH2:44][N:43]([CH:47]([CH3:48])[CH3:49])[CH2:42]1)=[O:40])=[O:4]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(NC(=O)C4CCCN(C(C)C)C4)c(C(=O)N(C)C)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)C4CCCN(C(C)C)C4)c(C(=O)N(C)C)c3)cc12
Reaction time: 1 h
Yield: 31.6 %

Procedure:
1-iso-Propyl-piperidine-3-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-amide (185.1 mg, 0.27 mmol) was dissolved in methanol (0.5 mL) and dimethylformamide (0.5 mL), cooled to 0° C. and 50% w/v aqueous potassium hydroxide (0.2 mL) was added. After 1 hour, the reaction was quenched by addition of concentrated hydrochloric acid (0.2 mL). The mixture was carefully poured into saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and dried to a residue which was purified by preparative HPLC to afford 1-isopropyl-piperidine-3-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-amide (46.0 mg, 31.9%). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 0.98 (d, J=6.5 Hz, 6H), 1.59 (m, 2H), 1.76 (m, 2H), 2.16 m, 3H, 2.32 (m, 2H), 2.70 (m, 1H, 2.87 (s, 3H), 2.97 (s, 3H, 3.82 (s, 3H), 7.04 (t, J=7.5 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.28 (dt, J=1.5, J=7.5 Hz 1H), 7.61 (dd, J=1.5 Hz, J=7.5 Hz, 1H), 7.59-7.61 (m, 2H), 7.65 (d, J=8.0 Hz, 1H), 7.72-7.74 (m, 2H), 8.54 (d, J=2.5 Hz, 1H), 9.51 (s, 1H), 11.92 (s, 1H). MS: m/z 541 (M+H+).