Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)([CH3:11])[CH3:10].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:9]([CH3:11])[CH3:10])[CH:17]=2)=[CH:7][N:6]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CC(C)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cccc(-c2ccc(Cl)nc2)c1
Temperature: 80 °C
Yield: 58.6 %

Procedure:
To a stirred solution of 5-bromo-2-chloropyridine (1.27 g, 6.63 mmol) in toluene (30 mL) was added an ethanolic solution (10 mL) of 3-isopropyl-phenylboronic acid (1.8 g, 11.28 mmol) followed by water (10 mL) and potassium carbonate (2.76 g, 20.0 mmol). The resulting mixture was degassed for 15 min (by purging with argon). At this time, Pd(PPh3)4 (0.613 g, 0.53 mmol) was added under argon and the reaction mixture was heated at 80° C. for 4 h. The reaction mixture was then cooled to room temperature and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (2×10 mL), dried over Na2SO4 and concentrated in vacuo to obtain the crude product, which was purified over silica gel (Biotage column chromatography, 2% ethyl acetate in hexane) to afford 0.900 g (59%) of 2-chloro-5-(3-isopropyl-phenyl)-pyridine.
Reaction SMILES: O=[C:2]([CH2:5][CH2:6][CH2:7][CH3:8])[CH:3]=O.O=C(C)C=O.CC1[N:16]=[C:17]([OH:24])[C:18]([C:21]([NH2:23])=[O:22])=[N:19]C=1.NC(C(N)=O)C(N)=O>>[CH2:5]([C:2]1[N:16]=[C:17]([OH:24])[C:18]([C:21]([NH2:23])=[O:22])=[N:19][CH:3]=1)[CH2:6][CH2:7][CH3:8]
Reactant: Cc1cnc(C(N)=O)c(O)n1
Reactant: CCCCC(=O)C=O
Agent: CC(=O)C=O
Agent: NC(=O)C(N)C(N)=O
Product: CCCCc1cnc(C(N)=O)c(O)n1

Procedure:
2-Oxohexanal (F. Ballistreri, et al., J. Organic Chem., 53, 830 (1988) is reacted (according to the method described by F. L. Muehlmann and A. R. Day in J. American Chem. Soc., 78, 242-4(1956) substituting 2-oxohexanal for the 2-oxopropanal used in the synthesis of 5-methyl-3-hydroxypyrazine-2-carboxamide) with aminomalonamide to give 5-n-butyl-3-hydroxypyrazine-2-carboxamide. The amide is hydrolyzed with sodium hydroxide in water at 95° C. to give 5-n-butyl-3-hydroxypyrazine-2-carboxylic acid. The acid is converted to the corresponding ester with methanol and hydrochloric acid and the ester is chlorinated with phosphorous oxychloride (according to the method described by G. Dick and H. Wood in J. Chem. Soc., 1955, 1379-82) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH3:11])[CH2:5]OS(C)(=O)=O.[N-:13]=[N+:14]=[N-:15].[Na+].C(OC(=O)CC(C)=O)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH3:11])[CH2:5][N:13]=[N+:14]=[N-:15]
Reactant: COC(=O)[C@H](C)COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(=O)CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)CN=[N+]=[N-]
Reaction time: 24 h
Yield: 32 %

Procedure:
(R)-3-methanesulfonyloxy-2-methyl-propionic acid methyl ester was dissolved in 100 mL of dimethylformamide, and then 8.2 g (126 mmol) of sodium azide was added thereto at 60° C., followed by stirring for 24 hours. After addition of 400 mL of ethylacetoacetate and washing with water, an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by column chromatography to give 2 g (13.9 mmol) of the title compound in a yield of 32%.
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N=C=NC(C)C)(C)C.[CH2:21]([O:24][C:25](=[O:53])[C:26]1[CH:31]=[CH:30][C:29]([N:32]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=2)=[C:28]([NH2:52])[CH:27]=1)[CH:22]=[CH2:23]>C(Cl)Cl>[CH2:21]([O:24][C:25](=[O:53])[C:26]1[CH:31]=[CH:30][C:29]([N:32]([C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:42])[F:43])=[CH:36][CH:35]=2)=[C:28]([NH:52][C:9](=[O:11])[CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:27]=1)[CH:22]=[CH2:23]
Reactant: C=CCOC(=O)c1ccc(N(Cc2ccc(OC(F)(F)F)cc2)C(=O)OC(C)(C)C)c(N)c1
Reactant: O=C(O)COc1ccccc1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: C=CCOC(=O)c1ccc(N(Cc2ccc(OC(F)(F)F)cc2)C(=O)OC(C)(C)C)c(NC(=O)COc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
318 mg of phenoxyacetic acid were dissolved in methylenchloride and 0.36 ml of diisopropylcarbodiimide added. 950 mg of 3-amino-4-[tert-butoxycarbonyl-(4-trifluoromethoxy-benzyl)-amino]-benzoic acid allylester were added and the reaction mixture stirred at room temperature for 16 h. The product was extracted from methylenchloride/water without further characterization.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:12]=1[C:13]([OH:15])=[O:14].O>ClCCl>[F:10][C:11]1[C:12]([C:13]([OH:15])=[O:14])=[C:16]([C:20]([F:21])([F:22])[F:23])[C:17]([N+:1]([O-:4])=[O:2])=[CH:18][CH:19]=1
Reactant: O=C(O)c1c(F)cccc1C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1c(F)ccc([N+](=O)[O-])c1C(F)(F)F
Temperature: 0 °C

Procedure:
1.05 ml (23.3 mmol) of concentrated nitric acid (65%), which also was precooled to 0° C., is instilled in a solution of 17.5 ml of concentrated sulfuric acid and 2.5 g (12.0 mmol) of 2-fluoro-6-trifluoromethyl-benzoic acid, cooled to 0° C. It is allowed to stir for one more hour at 0° C. and then overnight at room temperature. It is then poured in a mixture of ice, water and dichloromethane, the organic phase is separated and the aqueous phase is extracted with dichloromethane. The organic solutions are combined, washed with saturated sodium chloride solution, dried on sodium sulfate and evaporated to dryness in a vacuum. The title compound is obtained in crystalline form.
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11](O)=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)CCl.C1C=[N:23]C2N(O)N=NC=2C=1.C(=O)([O-])O.[NH4+]>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]([C:11](=[O:12])[NH2:23])[CH3:10])[CH3:14])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: On1nnc2cccnc21
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@@H](C(N)=O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
Boc-N-methyl-L-alanine (3.12 g, 15.3 mmol), EDC (2.94 g, 15.3 mmol), HOAt (2.09 g, 15.3 mmol) and ammonium hydrogencarbonate (3.63 g, 45.9 mmol) were added to DMF (20 mL) and stirred at ambient temperature overnight. The mixture was partitioned between EtOAc and water. The EtOAc layer was washed with aqueous potassium hydrogen sulfate solution (×2), dilute aqueous sodium carbonate solution and brine. The EtOAc was evaporated to give the title compound as a white solid (1 g). 1H NMR (400 MHz, DMSO-d6): 7.19 (1H, br), 6.95 (1H, br), 4.60-4.20 (1H, m), 2.73 (3H, s), 1.39 (9H, s), 1.24 (3H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:16])[C:12]=1[C:13](=[O:15])[CH3:14].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[Br:41]Br>C(Cl)(Cl)Cl>[Br:41][CH2:14][C:13]([C:12]1[N:11]([CH3:16])[N:10]=[N:9][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:15]
Reactant: CC(=O)c1c(-c2ccccc2Cl)nnn1C
Reactant: BrBr
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: ClC(Cl)Cl
Product: Cn1nnc(-c2ccccc2Cl)c1C(=O)CBr
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A solution of 1-(4-(2-chlorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)ethanone (1.02 g, 4.33 mmol) was dissolved in chloroform (7 mL) and acetic (0.136 mL) was heated to reflux and then a solution of bromine (0.234 mL, 4.54 mmol) in chloroform (3 mL) was added dropwise within 10 min at and after 1 h bromine (0.09 mL, 1.73 mmol) in chloroform (2 mL) was added and heated under reflux for 1 h. After cooling to room temperature the mixture was poured onto ice-water and the mixture extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 10 to 60% ethyl acetate in heptane) afforded the title compound (988 mg, 73%) as an off white solid. MS: m/e=313.9/315.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[OH:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:17]I>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[O:16][CH3:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CI
Reactant: N#Cc1ccc(O[C@@H]2CCC[C@@H]2O)cc1Cl
Product: CO[C@H]1CCC[C@H]1Oc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
2-Chloro-4-(cis-2-hydroxy-cyclopentyloxy)-benzonitrile (76 mg, 0.32 mmol) was added to a flame dried round bottom flask under nitrogen containing 2 mL of dry DMF and 8.5 mg of 60% sodium hydride as an oil dispersion (0.35 mmol). The reaction was stirred at room temperature for 1 h, after which time methyl iodide (54 mg, 0.38 mmol) was added. The mixture was stirred for 16 h, quenched by the dropwise addition of 5 mL of water, and extracted with ether (2×). The combined organic phases were washed with brine, dried (MgSO4), concentrated and purified by reverse phase HPLC (Shimadzu) to give 35 mg of the title compound. GC/MS: 251 (M/Z for C13H14ClNO2)—
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:21])[CH2:4][C@H:3]1[OH:22].[Cl:23][C:24]1[CH:25]=[C:26]([CH:32]=O)[CH:27]=[N:28][C:29]=1[CH2:30][OH:31]>ClCCCl.CO>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:32][NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:21])[CH2:4][C@H:3]2[OH:22])[CH:27]=[N:28][C:29]=1[CH2:30][OH:31]
Reactant: O=Cc1cnc(CO)c(Cl)c1
Reactant: N[C@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Solvent: CO
Solvent: ClCCCl
Product: O=c1ccc2ncc(F)cc2n1CCN1CC[C@H](NCc2cnc(CO)c(Cl)c2)[C@H](O)C1

Procedure:
A mixture of 1-{2-[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one (Intermediate 31 as a free base: 60 mg, 0.196 mmol) and 5-chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde (Intermediate 39: 33.6 mg, 0.196 mmol) in DCE (5 ml) and Methanol (0.5 ml) was stirred at rt for 5 h. LCMS showed desired compound Rt 2.16 [M+H]+ 460 and not starting material, sodium triacetoxy borohydride (125 mg, 0.588 mmol) was added. The mixture was stirred under nitrogen at room temperature overnight. LCMS showed desired compound and imine. An excess of sodium triacetoxy borohydride (62.3 mg, 0.294 mmol) was added. The mixture was stirred at room temperature for 3 h. Full conversion to the amine was observed by LCMS desired compound Rt 2.02 [M+H]+ 462. It was quenched with saturated NaHCO3, extracted with dichloromethane, dried (MgSO4), filtered, and concentrated affording 78.5 mg of crude material. Purification by manual flash chromatography using a 5 g Merck silica gel cartridge, and DCM/MeOH 9/1 as eluent afforded 1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one (35 mg, 0.072 mmol, 36.8% yield) as a white solid.
Reaction SMILES: C[C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:11]Br)[C:5]([CH2:9]Br)=[C:6]([Br:8])[CH:7]=1.BrC1C=CC(OC)=C(C)C=1C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC#N>[CH2:26]([N:33]1[CH2:9][C:5]2[C:4](=[C:3]([O:13][CH3:14])[CH:2]=[CH:7][C:6]=2[Br:8])[CH2:11]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: COc1c(C)cc(Br)c(CBr)c1CBr
Agent: COc1ccc(Br)c(C)c1C
Solvent: CC#N
Product: COc1ccc(Br)c2c1CN(Cc1ccccc1)C2
Temperature: 60 °C
Yield: 55 %

Procedure:
To a solution of methyl 1-bromo-2,3-bis(bromomethyl)-4-methoxybenzene (prepared as described in J. Org. Chem. 1992, 57, 6374, from commercially available 1-bromo-4-methoxy-2,3-dimethylbenzene) in CH3CN (0.1 M) were added 2.5 eq of KHCO3 and the mixture heated at 60° C. Then 1 eq. of benzylamine in CH3CN (0.9 M) was added within 15 minutes and the mixture was heated to reflux for 2 h. The reaction mixture was allowed to cool, filtered over celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (5% EtOAc in petroleum ether, then 10%) to afford the title compound (55%). 1H NMR (300 MHz, CDCl3, ppm) δ 3.77 (s, 3H), 3.92 (s, 2H), 3.98 (s, 2H), 4.01 (s, 2H), 6.60 (d, J 8.6, 1H), and 7.22-7.46 (m, 6H). MS (ES+) m/z 318, 320 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:14]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:21](=[O:23])[CH3:22].[O:24]=[C:25]1[NH:34][C:33]2[N:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][CH:39]=O)[CH:30]=[CH:29][C:28]=2[CH:27]=[CH:26]1>>[C:21]([C:10]1[C:9]([Cl:8])=[C:14]([N:15]2[CH2:20][CH2:19][N:18]([CH2:39][CH2:38][CH2:37][CH2:36][O:35][C:31]3[N:32]=[C:33]4[C:28]([CH:27]=[CH:26][C:25](=[O:24])[NH:34]4)=[CH:29][CH:30]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=1)(=[O:23])[CH3:22]
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: CC(=O)c1cccc(N2CCNCC2)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cccc(N2CCN(CCCCOc3ccc4ccc(=O)[nH]c4n3)CC2)c1Cl

Procedure:
In a manner similar to that of other examples above, 1-(2-chloro-3-piperazin-1-yl-phenyl)-ethanone trifluoroacetate was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound, mp 108–110° C. MS: APCI: M+1: 455.2 (Exact Mass: 454.18).
Reaction SMILES: [NH:1]1[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>O>[C:16]([N:1]1[CH2:9][CH:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CC(O)C[C@H]1C(=O)O
Reaction time: 0.75 h
Yield: 64.4 %

Procedure:
A solution of 100 g (0.76 mol) of L-hydroxyproline and 540 ml of water was cooled to 10° and 297 ml (3.7 mol) of pyridine was added. The temperature was lowered to 5° and 151.2 ml (1.6 mol) of acetic anhydride was slowly added. The reaction was stirred at 0°-5° for 45 min and 81 ml (0.97 mol) of pyridine was added followed by 42.7 ml (0.45 mol) of acetic anhydride. The reaction was stirred overnight in an ice bath allowing the bath to come to room temperature. The reaction was evaporated and the residue was dissolved in ethanol and evaporated to an oily residue. This step was repeated a number of times, and the residue was dissolved in acetone, seeded, and cooled. The white crystals were filtered and recrystallized from ethanol-ether and dried under vacuum at 40° to give 84.8 g of N-acetyl-4-hydroxy-L-proline; mp 124°-131°; [α]D23 -117° (cl, water).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[C:16]2[C:23]([CH3:24])=[N:22][N:21]([CH3:25])[C:17]2=[N:18][C:19]=1[Cl:20])[C:8]1[N:9]=[N:10][NH:11][N:12]=1.[H-].[Na+].[CH3:37]I.O>CN(C=O)C>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:28]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[C:16]2[C:23]([CH3:24])=[N:22][N:21]([CH3:25])[C:17]2=[N:18][C:19]=1[Cl:20])[C:8]1[N:9]=[N:10][N:11]([CH3:37])[N:12]=1
Reactant: Cc1nn(C)c2nc(Cl)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C)c2nc(Cl)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 121.4 %

Procedure:
A mixture of (3,5-bis-trifluoromethyl-benzyl)-(6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-ylmethyl)-(2H-tetrazol-5-yl)-amine (8.5 g, 10 mmol) and sodium hydride (0.81 g, 30 mmol) in DMF (150 mL) was stirred at 0° C. for 20 minutes. Thereafter, methyl iodide (3.5 g, 20 mmol) was added and the resulting mixture was stirred at 0-10° C. for 30 minutes. Water (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography over 230-400 mesh silica gel. Elution of the column with 10% acetone in hexanes gave the pure product as a colorless solid (6.3 g), yield: 75%.
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.C(N(CC)CC)C.Cl[C:39]1[O:40][C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=1>C1COCC1>[O:40]1[C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=[C:39]1[NH:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]([CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:21]2[C:30]3[N:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNc2nc3ccccc3o2)cc1)Cc1nc2ccccc2[nH]1
Yield: 50.4 %

Procedure:
Using the General N-Alkylation Procedure: To a stirred solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (128 mg, 0.32 mmol) and triethylamine (100 ul, 0.72 mmol) in THF (5 mL) was added 2-chlorobenzoxazole (50 uL, 0.44 mmol) and the mixture was stirred at reflux for 16 h. Purification of the crude material by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 125:1:1) afforded the desired amine (83 mg, 37%) as a yellow foam.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1B(O)O>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[C:13]([O:17][CH3:18])[CH:12]=1
Reactant: N#Cc1cccnc1Cl
Reactant: COc1cccc(F)c1B(O)O
Product: COc1cc(F)ccc1-c1ncccc1C#N
Yield: 85 %

Procedure:
Prepared in 85% yield from 2-chloronicotinonitrile and 2-fluoro-6-methoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 228.9 (M+H)+; 1H NMR (CDCl3) δ 6.82-6.88 (m, 2H), 7.38-7.46 (m, 2H), 8.07 (dd, J=7.8, 1.7 Hz, 1H), 8.91 (dd, J=4.9, 1.9 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9]O)[CH2:4]1)[CH3:2].C(Br)(Br)(Br)[Br:12]>O1CCCC1>[Br:12][CH2:9][CH:5]1[CH2:6][CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4]1
Reactant: CCN1CCCC(CO)C1
Reactant: BrC(Br)(Br)Br
Solvent: C1CCOC1
Product: CCN1CCCC(CBr)C1
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To mixture of (1-ethylpiperidin-3-yl)methanol (430 mg) and polymer bound triphenylphoshphine (2 g) in tetrahydrofuran (30 mL) was added carbon tetrabromide (1 g). The mixture was stirred for 8 hours before polymer bound triphenylphoshphine (1 g) and carbon tetrabromide (0.5 g) were added. The reaction was stirred overnight at room temperature. The mixture was filtered and evaporated and the residue was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in dichloromethane to give the title compound as a yellow oil (430 mg, 69%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]([CH3:20])=[C:18]2[C:14]([C:15]3[CH2:24][CH2:23][O:22][C:21]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH2:25][CH2:26][CH3:27])[C:16]=3[NH:17]2)=[C:13](Br)[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36]1C(=O)CCC1.C([Cu])#N.O>CCOC(C)=O>[CH2:1]([O:8][C:9]([C:11]1[C:19]([CH3:20])=[C:18]2[C:14]([C:15]3[CH2:24][CH2:23][O:22][C:21]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH2:25][CH2:26][CH3:27])[C:16]=3[NH:17]2)=[C:13]([C:35]#[N:36])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)c(C(=O)OCc3ccccc3)cc(Br)c21
Reactant: CN1CCCC1=O
Agent: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)c(C(=O)OCc3ccccc3)cc(C#N)c21
Temperature: 190 °C
Reaction time: 0.75 h
Yield: 81.8 %

Procedure:
A 500 mL RBF was charged with 5-bromo-1-ethoxycarbonylmethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid benzyl ester (12.00 g, 23 mmol), NMP (100 mL), and CuCN (20.34 g, 0.227 mol). The reaction was heated to 190° C. with vigorous stirring for 45 minutes. The reaction was then cooled to ambient temperature, diluted with EtOAc followed by water (300 mL). A 1:1 mixture of Celite/silica gel were added to the mixture. This suspension was stirred for several minutes and filtered through a pad of Celite. The Celite pad was washed with EtOAc, and the filtrate was washed with water (5×) and saturated NaCl (1×), dried over MgSO4, and concentrated. Upon trituration with hexanes, 8.82 g (81.8%) of a light tan solid was obtained. 1H NMR (CDCl3) δ 10.11 (br s, 1H), 8.12 (s, 1H), 7.40 (m, 5H), 5.37 (s, 2H), 4.22 (m, 2H), 3.95 (m, 2H), 3.00 (m, 4H), 2.83 (s, 3H), 2.00 (m, 2H), 1.30 (m, 5H), 0.89 (t, J=7.6 Hz, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].C1O[C:30]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)([CH2:31][CH2:32][CH2:33][Cl:34])[O:29]C1.O>C(O)CCC>[ClH:34].[F:41][C:38]1[CH:37]=[CH:36][C:35]([C:30]([CH2:31][CH2:32][CH2:33][N:2]2[CH2:3][CH2:4][C:5]3([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[O:14][C:15]4[C:20]3=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:6][CH2:7]2)=[O:29])=[CH:40][CH:39]=1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Reactant: c1ccc2c(c1)Oc1ccccc1C21CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: O=C(CCCN1CCC2(CC1)c1ccccc1Oc1ccccc12)c1ccc(F)cc1
Yield: 32.5 %

Procedure:
A mixture of xanthene-9-spiro-4'-piperidine hydrochloride (1 g.), potassium carbonate (1.2 g.) and γ-chloro-p-fluorobutyrophenone ethylene ketal (1.03 g.) in n-butanol is heated under reflux for 48 hours. The mixture is poured into water, extracted with ether, the ether solution evaporated and the residue warmed with 3 N hydrochloric acid for 1 hour to hydrolyse the ketal. The acidic solution is extracted with ethyl acetate, the solvent evaporated and the residue recrystallised from ethyl acetate to give 1'-[3-(p-fluorobenzoyl)propyl]xanthene-9-spiro-4'-piperidine hydrochloride (0.51 g.), m.p. 219°-222° C.