Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20]([OH:22])=O)=[C:15]([O:24][CH3:25])[CH:14]=1.[NH2:26][C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=1>>[CH2:32]([N:30]1[CH:31]=[C:27]([NH:26][C:20](=[O:22])[CH:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[N:8]=[CH:7][CH:6]=3)=[CH:14][C:15]=2[O:24][CH3:25])[CH3:23])[CH:28]=[N:29]1)[CH3:33]
Reactant: CCn1cc(N)cn1
Reactant: COc1cc(Oc2ccnc3ccc(F)cc23)ccc1C(C)C(=O)O
Product: CCn1cc(NC(=O)C(C)c2ccc(Oc3ccnc4ccc(F)cc34)cc2OC)cn1
Yield: 39 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-[4-(6-fluoroquinolin-4-yloxy)-2-methoxyphenyl]propionic acid was reacted with 4-amino-1-ethylpyrazole. The resultant mixture was evaporated and the residue was purified by preparative HPLC using a Waters ‘Xterra’ reversed-phase column (5 microns silica, 30 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound as a solid in 39% yield; 1H NMR: (DMSOd6) 1.32 (t, 3H), 1.38 (d, 3H), 3.81 (s, 3H), 4.02-4.11 (m, 3H), 6.7 (d, 1H), 6.85 (m, 1H), 7.0 (d, 1H), 7.38-7.44 (m, 2H), 7.75 (m, 1H), 7.90 (s, 1H), 7.96 (m, 1H), 8.12 (m, 1H), 8.69 (d, 1H), 9.97 (s, 1H); Mass Spectrum: M+H+ 435.
Reaction SMILES: ClC1C=CC(C2C3C=CC=CC=3C3=C(C)ON=C3C[N:9]=2)=CC=1.O[CH2:24][C:25]1[O:29][N:28]=[C:27]([CH3:30])[C:26]=1[C:31]1[N:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:32]=1[C:33](OC)=[O:34].ClC1C=CC(C(C2C=CC=CC=2C2C(CO)=NOC=2C)=O)=CC=1.[N-]=[N+]=[N-]>CO>[CH3:42][O:41][C:39]1[CH:38]=[CH:37][C:32]2[C:33](=[O:34])[NH:9][CH2:24][C:25]3[O:29][N:28]=[C:27]([CH3:30])[C:26]=3[C:31]=2[N:40]=1
Reactant: Cc1onc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2
Reactant: COC(=O)c1ccc(OC)nc1-c1c(C)noc1CO
Agent: Cc1onc(CO)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: [N-]=[N+]=[N-]
Solvent: CO
Product: COc1ccc2c(n1)-c1c(C)noc1CNC2=O

Procedure:
A reaction sequence similar to that used to prepare Compound 191 was followed, except that methyl 2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-6-methoxynicotinate was used as starting material instead of (4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanone and methanol was used as the co-solvent for the conversion of the azide to the lactam. LC/MS m/z 246 [M+H]+.
Reaction SMILES: C(S)C.[CH2:4]([N:6]([CH2:37][CH3:38])[CH2:7][CH2:8][N:9]1[C:25](=[O:26])[C:24]2[C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:27]CC5C=CC=CC=5)[CH:21]=4)[NH:16][C:15]=3[C:14]([O:35][CH3:36])=[CH:13][C:12]=2[C:10]1=[O:11])[CH3:5].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:37]([N:6]([CH2:4][CH3:5])[CH2:7][CH2:8][N:9]1[C:25](=[O:26])[C:24]2[C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([OH:27])[CH:21]=4)[NH:16][C:15]=3[C:14]([O:35][CH3:36])=[CH:13][C:12]=2[C:10]1=[O:11])[CH3:38]
Reactant: CCN(CC)CCN1C(=O)c2cc(OC)c3[nH]c4ccc(OCc5ccccc5)cc4c3c2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCS
Product: CCN(CC)CCN1C(=O)c2cc(OC)c3[nH]c4ccc(O)cc4c3c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
1.8 ml of ethanethiol and 0.47 ml of boron trifluoride-diethyl ether complex were added to 180 mg of N-(2-diethylaminoethyl)-6-benzyloxy-1-methoxycarbazole-3,4-dicarboximide. The mixture was stirred at room temperature overnight. Thereto were added 100 ml of ethyl acetate and 50 ml of an aqueous saturated sodium hydrogencarbonate solution. The mixture was stirred at room temperature for 10 minutes. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/methanol=40/1 to 10/1), followed by recrystallization from ethanol to obtain 26 mg (yield: 18%) of N-(2-diethylaminoethyl)-6-hydroxy- 1-methoxycarbazole-3,4-dicarboximide as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](/[CH:10]=[CH:11]/[B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[F:1][C:2]1[CH:9]=[C:8](/[CH:10]=[CH:11]/[B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC1(C)OB(/C=C/c2ccc(C=O)c(F)c2)OC1(C)C
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC1(C)OB(/C=C/c2ccc(CN3CCOCC3)c(F)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a mixture of (E)-2-fluoro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzaldehyde (0.61 g, 2.2 mmol) and morpholine (0.3 mL) in DCE (20 mL) was added NaBH(OAc)3 (636 mg, 3 mmol), followed by AcOH (0.5 mL). The resulting mixture was stirred for 2 h at rt. The reaction was quenched with sat. NaHCO3 (10 mL), H2O (10 mL), and extracted with EtOAc (2×30 mL). The solvents were removed in vacuo to afford the title compound as a white solid (0.72 g, 94%). 1H NMR (400 MHz, CDCl3) δ 7.20-7.12 (m, 2H), 7.04 (d, J=7.6 Hz, 1H), 6.99 (d, J=10.8 Hz, 1H), 5.98 (d, J=18.4 Hz, 1H), 3.55-3.45 (m, 4H), 3.36 (s, 2H), 2.33-2.23 (m, 4H), 1.14 (s, 12H); MS ESI 348.2 [M+H]+, calcd for [C19H27BFNO3+H]+ 348.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:21][C:22](C)([O-])[CH3:23].[K+].IC(C)C>C1COCC1>[CH3:21][CH:22]([O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:23]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2O)CC1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)I
Product: CC(C)Oc1ccccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of 1-(tert-Butyloxycarbonyl)-4-(2-hydroxyphenyl)piperidine 5a (5 g) in dry THF (100 ml) was added potassium tert-butoxide (2.2 g). After stirring for 5 minutes 2-iodopropane (9 g) was added and the mixture was refluxed for 3 hours. Additionally 1.1 g of potassium tert-butoxide was added and reflux was continued overnight. After cooling to room temperature inorganic salts were filtered off and the solvents evaporated in vacuo. The remaining oil was purified by filtering through silica gel (eluted with a 7:3 mixture of heptane and ethyl acetate). Yield: 4.5 g of 1-(tert-butyloxycarbonyl)-4-[2-(2-propyloxy)phenyl]piperidine all of which was dissolved in a mixture of dichloromethane (90 ml) and trifluoroacetic acid (40 ml). After stirring for one hour at room temperature all volatile material was evaporated in vacuo. To the remaining oil was added ethyl acetate (200 ml) and water (200 ml). pH was adjusted to >10 by addition of diluted aqueous NH4OH. The organic phase was separated and washed with brine (2×50 ml). Work-up of the organic phase as above yielded 2.6 g of 4-[2-(2-propyloxy)phenyl]piperidine. A mixture of the thus isolated 1-unsubstituted piperidine (2.5 g), 1-(4-chloro-1-butyl)-3-(4-fluorophenyl)-2-imidazolidinone 2a (3.0 g), potassium carbonate (1.6 g), and potassium iodide (0.5 g) in MIBK (50 ml) was refluxed overnight. Inorganic salts were filtered off and MIBK evaporated in vacuo. The remaining crude product was purified by column chromatography on silica gel (eluted with 4% triethylamine in ethyl acetate). Pure title compound 6a crystallized from ethyl acetate. Yield: 2.6 g, mp: 130-131° C. 1H NMR (CDCl3) δ 1.45 (d, 6H); 1.60 (t, 4H); 1.70-1.90 (m, 4H); 2.00-2.15 (m, 2H); 2.40 (t, 2H); 2.90-3.05 (m, 3H); 3.35 (t, 2H); 3.45 (t, 2H); 3.75 (t, 2H); 4.55 (h, 2H); 6.80-6.90 (m, 2H); 7.00 (t, 2H); 7.10 (dt, 1H); 7.15 (dd, 1H); 7.50 (dd, 2H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:12]2N=CC=[CH:16][C:11]=2[N:10]=N1.[NH2:25][C:26]1[N:27]=[C:28]([C:38]2[CH:43]=[C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:41]([Cl:52])=[CH:40][C:39]=2[Cl:53])[C:29]2[CH:34]=[C:33]([C:35]([OH:37])=O)[S:32][C:30]=2[N:31]=1.C(N)(C)C>CN(C=O)C>[CH:11]([NH:10][C:35]([C:33]1[S:32][C:30]2[N:31]=[C:26]([NH2:25])[N:27]=[C:28]([C:38]3[CH:43]=[C:42]([O:44][CH2:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:41]([Cl:52])=[CH:40][C:39]=3[Cl:53])[C:29]=2[CH:34]=1)=[O:37])([CH3:16])[CH3:12]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1nc(-c2cc(OCc3ccccc3)c(Cl)cc2Cl)c2cc(C(=O)O)sc2n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CC(C)NC(=O)c1cc2c(-c3cc(OCc4ccccc4)c(Cl)cc3Cl)nc(N)nc2s1
Temperature: 60 °C

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.176 g; 3.07 mmol) was added to 2-Amino-4-(5-benzyloxy-2,4-dichloro-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid. 2NaCl (1.33 g; 2.38 mmol) then DMF (25 ml) was added to afford a turbid brown solution. Isopropylamine (1.01 ml; 11.9 mmol) was added and reaction mixture was heated at 60° C. (oil bath temperature) for 18 hours. Reaction mixture was allowed to cool to room temperature and DMF was removed in vacuo. The residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The phases were separated and the organic phase was washed with saturated aqueous sodium chloride solution (200 ml) the dried over anhydrous sodium sulphate, filtered and the filtrate solvents removed in vacuo to afford a yellow solid. The crude product was purified by flash chromatography on silica gel (50 g IST Flash Si cartridge) eluting with a solvent gradient of 20 to 50% ethyl acetate in hexane. This affords product as a colourless solid (0.612 g; 53%)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].[CH3:11][CH:12]([CH3:15])[C:13]#[CH:14]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[CH:14]=[C:13]([CH:12]([CH3:15])[CH3:11])[O:10][C:3]=2[CH:4]=1
Reactant: C#CC(C)C
Reactant: COc1ccc(I)c(O)c1
Product: COc1ccc2cc(C(C)C)oc2c1
Yield: 38 %

Procedure:
Example 15(a) was prepared from 2-iodo-5-methoxyphenol (896 mg, 3.6 mmole) and 3-methyl-1-butyne in a manner as previously described for example 12a to give 265 mg (38%) of an amber oil. 1H NMR (CDCl3) δ 7.33 (1H, d, J=8.6 Hz), 6.97 (1H, d, J=2.2 Hz), 6.80 (1H, dd, J=2.2, 8.6 Hz), 6.26 (1H, s), 3.83 (3H, s), 3.07–3.01 (1H, m), 1.31 (6H, d, J=7.1 Hz).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[N:17]=[C:18]([CH3:21])[NH:19][CH:20]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[NH:17][C:18]([CH3:21])=[N:19][CH:20]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Cc1nc(I)c[nH]1
Product: Cc1ncc(C#Cc2c(-c3ccccc3)noc2C)[nH]1
Yield: 13 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (73 mg, 0.40 mmol) was converted using (4-iodo-2-methyl-1H-imidazole instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 14 mg, 13%) which was obtained as a light brown solid. MS: m/e=264.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.Br.Br[CH2:12][CH2:13][CH2:14][NH2:15].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:12][CH2:13][CH2:14][NH2:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: NCCCBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cl)ccc1NCCCN
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-2-methylaniline (8 g) and 3-bromopropylamine hydrobromide (5 g) was heated at 100° C. for fifteen minutes. After cooling to room temperature, the resulting crystalline solid was dissolved in water (50 mL) and one equivalent of sodium hydroxide was added. This solution was then washed with ethyl ether and basified with excess sodium hydroxide. It was then extracted with dichloromethane, the combined extracts were dried over anhydrous potassium carbonate and evaporated to dryness.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=1[CH3:21])[CH:8]=2)([O-])=O>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=1[CH3:21])[CH:8]=2
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc([N+](=O)[O-])cnc2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(N)cnc2c1
Reaction time: 8 h
Yield: 40.2 %

Procedure:
In a mixture of ethanol (20 mL) and ethyl acetate (10 mL) was suspended 3-nitro-7-(5-methyl-2-phenyl-4-oxazolylmethoxy)quinoline (740 mg, 2.1 mmol.), and to the suspension was added 10% palladium/carbon (50 mg). Then, catalytic reduction was performed overnight. After the completion of reaction was confirmed, the reaction mixture was filtered over Celite®, and the filtrate was placed under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/7 to ethyl acetate), to give 280 mg of the desired compound as brown oil (yield 42%).
Reaction SMILES: [N:1]1([CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O-:35][N+:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[N:1]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH:2]=[N:3][C:4]=2[CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCOCCn1cnc2cnc3ccccc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOCCn1cnc2c[n+]([O-])c3ccccc3c21
Reaction time: 8 h
Yield: 84 %

Procedure:
A solution of tert-butyl 2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (5.25 g, 14.7 mmol) in 200 mL of CH2Cl2 was treated with MCPBA (77% , 3.63 g, 16.3 mmol). After stirring overnight, the reaction mixture was treated with saturated NaHCO3 solution and the layers were separated. The organic portion was washed with H2O and brine then dried over Na2SO4 and concentrated to give 4.60 g of tert-butyl 2-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:27]=[CH:28][CH:29]=[C:2]([N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)[CH:3]=3)=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide (200 μmol, 1 eq.), cesium carbonate (300 μmol, 1.5 eq), and piperidine (300 μmol, 1.5 eq.) is suspended in anhydrous dioxane (2 ml) in a 2-dram vial. To the heterogeneous mixture is added bis(tri-t-butylphosphine)palladium(0) (5 mg, 5 mol %). The mixture is heated and agitated for 12 hours. The mixture is cooled to room temperature, filtered and concentrated. The residue is purified using reverse phase conditions (5:95; AcCN:H2O) to give N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-3-piperidin-1-yl-benzamide. Mp: 147-148° C. 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.22 (m, 1H), 7.87 (m, 1H), 7.60 (s, 1H), 7.55 (m, 2H), 7.47 (m, 3H), 7.17 (d, 1H), 7.04 (d, 1H, J=8.7), 4.33 (t, 2H, J=5.7), 3.62 (t, 4H, J=4.5), 3.32 (m, 4H), 2.90 (t, 2H, J=5.7), 2.58 (m, 4H), 1.65 (m, 4H), 1.57 (m, 2H). MS: 460.2 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN.[C:18]([BH3-])#[N:19].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC1CCN(Cc2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
A mixture of 1-benzyl-4-piperidone (XXV, Chart G, 24.5 mL, 0.1295 mol), N-methylamine hydrochloride (44.75 g, 0.6628 mol) and methanol (50 ml) is stirred for 35 minutes at 20°-25°, at which time additional methanol (10 ml) is added. The mixture is then cooled in an ice bath and a solution of sodium cyanoborohydride (9.1749 g, 0.1460 mol) in methanol (68 ml) is added to the mixture. The mixture is stirred for 5 min and then is allowed to warm to 20°-25°. After 1.25 hr the mixture is concentrated under reduced pressure and saturated aqueous sodium bicarbonate is added. After stirring for 1 hr, the mixture is extracted with dichloromethane and the organic phases are combined, backwashed with saline, dried with magnesium sulfate and concentrated under reduced pressure to give (XXVII). The material is upgraded by forming the dihydrochloride salt and collecting the resulting solids. The dihydrochloride salt is further upgraded by trituration with dichloromethane. The free base (XXVII) is recovered by slurrying the dihydrochloride salt (7.5204 g, 0.02713 mol) in dichloromethane and adding enough saturated sodium bicarbonate to dissolve all the solids and then extracting the aqueous layer exhaustively with dichloromethane to obtain N-(1-benzylpiperidin-4-yl)-N-methylamine (XXVII), MS (m/z) 204; IR (neat) 2942, 2796, 2775, 743 and 2749 cm-1.
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[N:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=1[O:18][CH3:19])[C:6](=O)[CH3:7])C.Cl.[CH3:22][C:23]1[CH:24]=[C:25]([NH:30][NH2:31])[CH:26]=[CH:27][C:28]=1[CH3:29].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[C:4](=[O:20])[C:5](=[N:9][NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=3[O:18][CH3:19])[C:6]([CH3:7])=[N:31]2)[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: CCOC(=O)C(=NNc1cccc(Br)c1OC)C(C)=O
Reactant: Cc1ccc(NN)cc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(Br)cccc1NN=C1C(=O)N(c2ccc(C)c(C)c2)N=C1C

Procedure:
A solution of ethyl-2-[(3-bromo-2-methoxyphenyl)hydrazono]-3-oxobutanoate (10 g) prepared as in Example 15, and 3,4-dimethylphenylhydrazine hydrochloride (6.05 g) and sodium acetate (2.63 g) in acetic acid (150 mL) was stirred and heated to about 80° C. to about 90° C. for about 3 hours. The reaction mixture was cooled to about room temperature and stirred for about 1 hour. The reaction mixture was filtered to give a solid, which was washed with acetic acid. The solid obtained was stirred in water for about 30 minutes at about room temperature, which was then filtered, washed with water and dried at about 55° C. to about 60° C. Yield: 11 g
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[C:8](=[O:19])[O:9][C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][CH:13]=[C:12]([OH:18])[CH:11]=3)=[CH:4][CH:3]=1.[I-].[N:23]1([C:33](N2C=C[N+](C)=C2)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8](=[O:19])[O:9][C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][CH:13]=[C:12]([O:18][C:33]([N:23]2[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]2)=[O:34])[CH:11]=3)=[CH:20][CH:21]=1
Reactant: Cc1c(Cc2ccc(F)cc2)c(=O)oc2cc(O)ccc12
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Agent: [I-]
Product: Cc1c(Cc2ccc(F)cc2)c(=O)oc2cc(OC(=O)N3CCCc4ccccc43)ccc12

Procedure:
The title compound was prepared from 3-(4-fluoro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[Cl:24])[CH:17]=[C:16]([C@@H:25]([NH:27][C:28]2[N:36]=[CH:35][N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][NH:32]3)[CH3:26])[N:15]=1.O>C1COCC1>[Cl:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[C:14]([O:10][CH:7]1[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)=[N:15][C:16]([C@@H:25]([NH:27][C:28]1[N:36]=[CH:35][N:34]=[C:33]3[C:29]=1[N:30]=[CH:31][NH:32]3)[CH3:26])=[CH:17]2
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(Cl)n1
Reactant: CC(C)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2nc([C@H](C)Nc3ncnc4[nH]cnc34)cc3cccc(Cl)c23)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 1-isopropylpiperidin-4-ol (120 mg, 0.83 mmol, 1.2 eq) in THF (10 mL) at 0° C., NaH (60% in mineral oil, 33.2 mg, 0.83 mmol, 1.2 eq) was added and the resulting mixture was stirred for 10 min. To this mixture, (S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9H-purin-6-amine 38 (250 mg, 0.70 mmol, 1.0 eq) was added. The resulting mixture was stirred at reflux overnight, cooled to RT and then poured into water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (5% MeOH-DCM) to afford the product, (S)—N-(1-(8-chloro-1-(1-isopropylpiperidin-4-yloxy)isoquinolin-3-yl)ethyl)-9H-purin-6-amine 47. ESI-MS m/z: 466.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Br:16])[CH:15]=1)[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.O.NN>C(O)CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Br:16])[CH:15]=1)[CH2:5][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(c1cccnc1)c1cc(Br)cc(Br)c1
Agent: NN
Solvent: OCCO
Solvent: O
Product: Brc1cc(Br)cc(Cc2cccnc2)c1
Temperature: 80 °C

Procedure:
A solution of 3-(3,5-dibromobenzoyl)pyridine (Preparation 1; 19.0 g) and hydrazine hydrate (13.9 ml) in ethylene glycol (140 ml) was heated under reflux for 45 minutes. The volatile material was distilled off until the internal temperature reached 180° C., and then the reaction mixture was cooled to 80° C. Potassium hydroxide (7.80 g) was added and the resulting solution was heated under reflux for 30 minutes, cooled and then poured into water. The mixture was extracted several times with ethyl acetate, and the combined extracts were washed with water and dried (MgSO4). Evaporation under vacuum gave the title compound (16.38 g), m.p. 70°-72° C. (after crystallisation from ethyl acetate-hexane). Found: C,44.29; H,2.66; N,4.29. C12H9Br2N requires C,44.07; H,2.77; N,4.28%.