Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12](=[O:21])[NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1)([CH3:10])([CH3:9])[CH3:8].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>CO>[C:7]([O:11][C:12](=[O:21])[NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[CH2:16]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCCN(Cc2ccc(C(F)(F)F)cc2)C1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
To a mixture of 830 mg of potassium carbonate in 50 ml of methanol was added tert-butyl(piperidin-3-ylmethyl)carbamate (643 mg), followed by 1-(bromomethyl)-4-(trifluoromethyl)benzene (717 mg). The mixture was heated to 70° C. and stirred for 0.5 h. The sample was filtered through a small plug of silica gel and concentrated in vacuo to provide tert-butyl({1-[4-(trifluoromethyl)benzyl]piperidin-3-yl}methyl)carbamate (640 mg). To a solution of this protected amine in 10 ml of dichloromethane was added trifluoroacetic acid (5 ml). The mixture was stirred at 70° C. for 1.5 h, and then concentrated in vacuo. The residue was diluted with 30 ml of ethyl acetate and basified by slow and cautious addition of 30 ml of a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and extracted once with 30 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound (418 mg, 89%). Mass spectrum (ESI) 273.2 (M+1).
Reaction SMILES: Br[C:2]1[N:6]=[C:5](/[CH:7]=[CH:8]/[C:9]2[N:17]=[C:16]3[N:11]([C:12]([CH3:19])=[N:13][CH:14]=[C:15]3[CH3:18])[N:10]=2)[N:4]([CH3:20])[N:3]=1.[F:21][C:22]([F:29])([F:28])[C@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1>>[CH3:19][C:12]1[N:11]2[N:10]=[C:9](/[CH:8]=[CH:7]/[C:5]3[N:4]([CH3:20])[N:3]=[C:2]([N:24]4[CH2:25][CH2:26][CH2:27][C@@H:23]4[C:22]([F:29])([F:28])[F:21])[N:6]=3)[N:17]=[C:16]2[C:15]([CH3:18])=[CH:14][N:13]=1
Reactant: Cc1cnc(C)n2nc(/C=C/c3nc(Br)nn3C)nc12
Reactant: FC(F)(F)[C@H]1CCCN1
Product: Cc1cnc(C)n2nc(/C=C/c3nc(N4CCC[C@@H]4C(F)(F)F)nn3C)nc12
Yield: 14.5 %

Procedure:
Was prepared in the same manner as described in Example 87a) using (E)-2-(2-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)vinyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine (100 mg, 299 μmol, Eq: 1.00) instead of 2-[(E)-2-(5-Bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine and (R)-2-(trifluoromethyl)-pyrrolidine (83.3 mg, 598 μmol, Eq: 2) instead of pyrrolidin-2-one affording 5,8-dimethyl-2-{(E)-2-[2-methyl-5-((R)-2-trifluoromethyl-pyrrolidin-1-yl)-2H-[1,2,4]triazol-3-yl]-vinyl}-[1,2,4]triazolo[1,5-c]pyrimidine (17 mg, 14.5%) as a light yellow solid. MS: m/z=393.4 (M+H+)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]1[O:10][C:9](/[CH:15]=[CH:16]/[CH:17]2[CH2:19][CH2:18]2)([C:11]([F:14])([F:13])[F:12])[C:8]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:7]=2[N:6](CC2C=CC(OC)=CC=2)[C:5]1=[O:34].O>C(#N)C>[Br:1][CH2:2][CH2:3][C@@H:4]1[O:10][C@:9](/[CH:15]=[CH:16]/[CH:17]2[CH2:18][CH2:19]2)([C:11]([F:13])([F:14])[F:12])[C:8]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:7]=2[NH:6][C:5]1=[O:34]
Reactant: COc1ccc(CN2C(=O)C(CCBr)OC(/C=C/C3CC3)(C(F)(F)F)c3cc(Cl)ccc32)cc1
Solvent: CC#N
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2[C@@](/C=C/C2CC2)(C(F)(F)F)O[C@H]1CCBr
Reaction time: 0.33 h

Procedure:
To a room temperature solution of 750 mg of trans-3-(2bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-l-(4-methoxybenzyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 35 mL of acetonitrile was added 18 mL of water and 3.78 g of ceric ammonium nitrate. After 20 min, the reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. This produced two diastereomeric products which were separated by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes). The first diastereomer eluted (162 mg) was the title compound.
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][C:18]([NH:29]C(=O)C)(C(OCC)=O)[C:19]([O:21]CC)=[O:20])([O:6]CC)=[O:5])C>Cl>[P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][CH:18]([NH2:29])[C:19]([OH:21])=[O:20])([OH:6])([OH:5])=[O:3]
Reactant: CCOC(=O)C(CCc1ccccc1CP(=O)(OCC)OCC)(NC(C)=O)C(=O)OCC
Agent: Cl
Product: NC(CCc1ccccc1CP(=O)(O)O)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 2.5 g (5.3 mmol) of ethyl 4-[2-(diethylphosphonomethyl)-phenyl]-2-acetamido-2-carboethoxybutanoate in 50 mL of 6N HCl was stirred at vigorous reflux for 12 h. After cooling to room temperature the reaction mixture was concentrated at reduced pressure yielding an oil. This oil was washed with three 50 mL portions of water then dissolved in 95% ethanol and a slight excess of propylene oxide added. The precipitated acid was collected by filtration and recrystallized from dilute ethanol yielding 1.26 g (77%) of the product as a white solid: mp 247°-249° C. IR(KBr): 1725, 1620 cm-1 ; 1H NMR (D2O) δ 2.0-3.4 (6H unresolved), 3.9-4.3 (m, 1H), 7.4 (s, 4H); Anal. Calcd. for C11H16NO5P0.5H2O: Calcd: C, 46.62; H, 6.05; N, 4.94. Found: C, 46.73; H, 6.04; N, 4.79.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=O)[C:20]12OCCC[O:27]1)(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:33][C:34]1([C:38]#[N:39])[CH2:37][CH2:36][CH2:35]1>>[O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:25]=[CH:24][C:23]2[N:22]3[CH2:33][C:34]4([CH2:37][CH2:36][CH2:35]4)[CH2:38][N:39]=[C:21]3[C:20](=[O:27])[C:19]=2[CH:18]=1)(=[O:15])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1(CCl)CCC1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C12OCCCO2
Product: O=C1C2=NCC3(CCC3)CN2c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc21

Procedure:
The title compound was prepared as a yellow foam from 5′-{[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one and 1-chloromethyl-cyclobutanecarbonitrile (Syn. Comm. 20(12) 1757, 1990) using a procedure similar to that of steps 3-5 of Example 12. NMR (400 Mz, DMSO-d6): consistent. MS: (ES−) m/z 464 [M−H].
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[O:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=3[F:37])=[O:28])=[C:22]([F:38])[CH:21]=2)[CH:11]=1)=[O:9])C.Cl.O.[OH-].[Na+]>O1CCCC1>[F:38][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[NH:26][C:27]([NH:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[F:37])=[O:28])[O:19][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:11]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][CH:4]=[O:3])=[O:9])[S:18][C:17]=12
Reactant: CCOC(CCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCC=O)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of N-(3,3-diethoxypropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide (1.23 g, 2.11 mmol) in 20 ml of tetrahydrofuran was added 2 ml of 2M HCl (4.0 mmol). The mixture was stirred at room temperature for 5 hours and poured into 100 ml of water. 1M NaOH solution was added slowly until pH=7˜8. The precipitates were filtered, washed with water and dried in vacuo to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide as brown solid. Yield: 1.07 g, 100%.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1N)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]>CN(C)C=O.C(OCC)C>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc2c(Oc3ccc(F)cc3N)cccc2[nH]1
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cc2c(Oc3ccc(F)cc3)cccc2[nH]1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl nitrite (0.46 ml, 4.45 mmol) is dissolved in 5 ml of dimethylformamide and heated to 65° C. A solution of 147 (1.4 g, 4.45 mmol) in 5 ml of dimethylformamide is added dropwise and the mixture is stirred of additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether and washed with 2N HCl and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (1.0 g of a brown oil) is further purified by flash-chromatography (hexane/ethyl acetate 7:3).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([NH2:30])=[CH:25][CH:24]=2.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.ClC(Cl)C>C(O)(C)(C)C>[CH3:20][C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([NH:30][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[S:12][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:14][N:15]=4)[S:10][C:3]=13)=[CH:25][CH:24]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CC(C)(O)c1cnc(-c2cc3nccc(Cl)c3s2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ncc(C(C)(C)O)s5)sc34)ccc2[nH]1
Yield: 94 %

Procedure:
2-[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-thiazol-5-yl]-propan-2-ol (129 mg, 0.42 mmol), 2-methyl-5-aminoindole (72 mg, 0.50 mmol), potassium carbonate (138 mg. 8.84 mmol), and triethylamine (0.12 mL, 0.84 mmol) were dissolved in 2 mL of t-butyl alcohol and 2 mL of dichloroethane and the solution was heated to 85° C. After allowing the reaction to go dry overnight solvent was added along with an additional 36 mg of the indole an the solution was heated an additional 18 hours. Chromatography of the residue with 20% methanol:methylene chloride afforded 166 mg (40%) of 2-{2-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-propan-2-ol. 1H NMR (400 MHz, CD3OD) δ8.13 (d, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 6.99 (d, 1H), 6.64 (d, 1H), 6.13 (s, 1H), 2.43 (s, 3H), 1.65 (s, 6H). LC-MS: 421 (MH+); HPLC RT: 4.75 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[I-].[Na+].Cl[Si](Cl)(C)C.C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(O)c2ccc(C#N)cc2)cc1
Agent: C[Si](C)(Cl)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: COc1ccc(Cc2ccc(C#N)cc2)cc1
Reaction time: 1 h

Procedure:
To a mixture of 26-2 (0.622 g, 2.6 mmol) and sodium iodide (1.56 g, 10.4 mmol) in acetonitrile (7 ml) at ambient temperature in a 3-necked round bottom flask equipped with a nitrogen inlet and rubber septum was added dichlorodimethylsilane (0.63 ml, 5.2 mmol) via syringe. The resulting mixture was stirred 60 min. Saturated sodium bicarbonate solution (30 ml) was added and the mixture was extracted with ethyl acetate (2×90 ml). The combined organic fractions were washed with 10% sodium thiosulfate solution (30 ml), brine (30 ml), dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1:6 increasing to 1:5), to give product 26-3 as a white solid, mp: 41.5°-43.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[N:8]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[N:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1nc(OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1nc(OC)ccc1N
Reaction time: 2 h

Procedure:
A 2.2 g (8.7 mmol) solution of 3-(6-methoxy-3-nitro-pyridin-2-yl)-acrylic acid ethyl ester (M. Makosza, A. Tryula Synthesis, 1987, 1142–1144) in 50 ml of ethanol containing a catalytic amount of 10% Pd/C was hydrogenated at 50 PSI for 2 hours. The reaction was filtered and the solvent evaporated to afford crude intermediate 3-(3-amino-6-methoxy-pyridin-2-yl)-propionic acid ethyl ester. This material was disolved in 5 ml of acetic acid and heated on a steam bath for 30 minutes. The solution was cooled to room temperature and the solvent evaporated. The residue was dissolved in 25 ml of ethyl acetate and washed with saturated NaHCO3. The ethyl acetate solution was dried (Na2SO4) and evaporated to yield a brown solid residue. This material was chromatographed on silica using 5:1 chloroform/ethyl acetate as the elutant. Appropriate fractions were combined and evaporated to yield 1.2 g of 6-methoxy-3,4-dihydro-1H-[1,5]naphthyridin-2-one. TLC: Rf=0.55 (5:1 ethyl acetate:hexane). 1H NMR (CDCl3) δ 8.6 (s, 1H), 7.1 (d, 1H), 6.6 (d, 1H), 3.9 (s, 3H), 3.05 (m, 2H), 2.7 (m, 2H). Mass Spectrum: m/e=179.2 (p+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:31]([O:32][CH3:33])=[O:34])=[CH:20][CH:21]=1)(=[O:4])=[O:3]
Reactant: COC(=O)C1CCNC(Cc2ccc(S(C)(=O)=O)cc2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(S(C)(=O)=O)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Methyl 2-(4-(methylsulfonyl)benzyl)piperidine-4-carboxylate (5.88 g, 18.88 mmol) was dissolved in DIPEA (4.93 mL, 28.32 mmol) and dichloromethane (150 mL). Methyl carbonochloridate (2.141 g, 22.66 mmol) was added dropwise and the reaction mixture stirred at room temperature overnight. The solvent was evaporated and the residue partitioned between 1 M KHSO4 and diethyl ether. The organic layer was dried over Na2SO4, filtered through celite and evaporated to yield dimethyl 2-(4-(methylsulfonyl)benzyl)piperidine-1,4-dicarboxylate (5.5 g, 79%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].N([O-])=O.[Na+].[Cu](C#N)[C:18]#[N:19].[C-]#N.[Na+]>Cl.O>[C:18]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12])#[N:19]
Reactant: Nc1ccc2nc[nH]c(=O)c2c1
Reactant: N#C[Cu]C#N
Agent: Cl
Agent: O=N[O-]
Agent: [C-]#N
Solvent: O
Product: N#Cc1ccc2nc[nH]c(=O)c2c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
6-Aminoquinazolin-4(3H)-one was slurried in 300 ml of 5% hydrochloric acid and the reaction mixture was cooled to 5° C. A solution of 6.72 g (0.097 mol) of sodium nitrite in 30 ml of water was added dropwise over 2.5 hours while maintaining the reaction temperature below 10° C. The resulting diazonium salt was then added portionwise to a hot (86° C.) solution of 7.84 g (0.0876 mol) of copper cyanide and 11.0 g (0.224 mol) sodium cyanide in 60 ml of water. Evolution of nitrogen was evident throughout the addition. After stirring for 30 minutes, the reaction mixture was filtered, washed with water, and air-dired. The crude product (9.1 g) was purified by silica gel chromatography to afford 3.89 g (26%) of the title compound; m.p. 294°-300° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][CH2:9][CH2:10][CH2:11]Cl.BrCCCBr.ClCCCI.[H-].[Na+].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][NH:35][CH3:36])[CH:26]=1.CN>CN(C)C=O.CO.O1CCCC1>[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][NH:35][CH3:36])[CH:26]=1.[Cl:8][CH2:9][CH2:10][CH2:11][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: ClCCCCl
Agent: BrCCCBr
Agent: CN
Agent: CNCCCOc1cccnc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: ClCCCOc1cccnc1

Procedure:
The manner by which pyridyloxyalkylamine compounds of the present invention are provided can vary. Certain pyridyloxyalkylamine compounds can be prepared by the alkylation of 3-hydoxypyridine with a 1,3-dihalopropane, such as 1,3-dichloropropane, 1,3-dibromopropane, 1,3-diodopropane or 1-chloro-3-iodopropane, which are commercially available from Aldrich Chemical Company, in the presence of a base (e.g., sodium hydride) in dry N,N-dimethylformamide. The resulting 3-halo-1-(3-pyridyloxy)propane can be converted to a pyridyloxyalkylamine, such as (3-(3-pyridyloxy)propyl)methylamine, by treatment with methylamine in a solvent, such as tetrahydrofuran or aqueous methanol. One representative compound, (3-(3-pyridyloxy)propyl)methylamine is prepared by the reaction of 3-hydroxypyridine with 1.2 molar equivalents of 1-chloro-3-iodopropane and 1.6 molar equivalents of sodium hydride in dry N,N-dimethylformamide at ambient temperature. The resulting intermediate, 3-chloro-1-(3-pyridyloxy)propane, obtained in about 54% yield, is converted to (3-(3-pyridyloxy)propyl)methylamine in about 40% yield, by treatment with an excess (25 molar equivalents) of aqueous methylamine in methanol, assisted by heating. Certain pyridyloxyalkylamine compounds, such as (4-(3-pyridyloxy)-butyl)methylamine, can be prepared by alkylating 3-hydoxypyridine with a 1,4-dihalobutane, such as 1,4-diiodobutane, 1,4-dibromobutane, 1,4-dichlorobutane or 1-chloro-4-iodobutane, which are commercially available from Aldrich Chemical Company, in the presence of a base (e.g., sodium hydride) in N,N-dimethylformamide. The resulting 4-halo-1-(3-pyridyloxy)butane can be converted to a pyridyloxyalkylamine, such as (4-(3-pyridyloxy)butyl)methylamine, by treatment with methylamine in a solvent, such as tetrahydrofuran or aqueous methanol.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]>[C].[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]
Reactant: O=Cc1cccc(C=Cc2ccc3ccccc3n2)c1
Agent: [Pd]
Product: O=Cc1cccc(CCc2ccc3ccccc3n2)c1
Yield: 50.5 %

Procedure:
5.5 g (21.2 mmol) of 3-[2-(2-quinolyl)ethenyl]benzaldehyde was dissolved in 500 ml and hydrogenated in the presence of 1.1 g of 10% palladium carbon at atmospheric pressure at room temperature for 10 hours under stirring. The 10% palladium carbon was filtered out through celite, and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:1) to give 2.8 g (10.7 mmol) of the title compound in a yield of 51%.
Reaction SMILES: [CH3:1][C:2]1([C@H:8]2[C:35](=[O:36])[N:34]3[CH2:37][C@@H:31]([CH2:32][C@H:33]3[C:38]([O:40][CH3:41])=[O:39])[O:30][C:20]3=[N:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:28]([OH:29])=[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[CH2:42][C@H:12]3[O:11][C:10](=[O:43])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:64]1[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][C:2]1([C@H:8]2[C:35](=[O:36])[N:34]3[CH2:37][C@@H:31]([CH2:32][C@H:33]3[C:38]([O:40][CH3:41])=[O:39])[O:30][C:20]3=[N:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:28]([O:29][CH:64]4[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]4)=[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[CH2:42][C@H:12]3[O:11][C:10](=[O:43])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1(C)CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Reactant: CN1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1(C)CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CCN(C)CC1)O2
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 96.6 %

Procedure:
A reaction tube was charged with the product of step 5 (400 mg, 0.674 mmol) and triphenylphosphine (1414 mg, 5.39 mmol). The tube was sealed and THF (6737 μl) was added via syringe at 0° C. 4-hydroxy-1-methylpiperidine (633 μl, 5.39 mmol) was added followed by slow addition of diisopropyl azodicarboxylate (1044 μl, 5.39 mmol). After 5 min, the cooling bath was removed and the mixture was allowed to reach room temperature and stirred for 10 minutes. The reaction tube was heated at 40° C. LCMS showed complete reaction after 2 hours. The reaction mixture was concentrated to dryness in rotavap and the residue was purified on a gold cap silica gel (120 g) column (gradient: 0 to 50% solvent B in dichloromethane (solvent B: 20% methanol in ethyl acetate)) to give the title compound (450 mg, 0.651 mmol, 97% yield) as a white powder.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[O:21]C)([CH3:4])([CH3:3])[CH3:2].Br>>[C:1]([C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[OH:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc2c(-c3ccccc3)c(C(C)(C)C)n(C)c(=O)c12
Agent: Br
Product: Cn1c(C(C)(C)C)c(-c2ccccc2)c2cccc(O)c2c1=O

Procedure:
A mixture of 3-tert-butyl-8-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (0.500 g) and 48% HBr (15 mL) was heated at reflux overnight. The reaction was concentrated and purified by flash chromatography (10% EtOAc in hexanes) to give the titled compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C
Reactant: Cc1ncc[nH]1
Product: Cc1sc2nc(-n3ccnc3C)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:14][C:15]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:16]=1[NH2:17].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][CH2:9][C:10]([NH:17][C:16]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=1[Cl:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: O=C(Cl)COCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)c(NC(=O)COCc2ccccc2)c1
Temperature: 25 °C
Yield: 103 %

Procedure:
Benzyloxy acetyl chloride (1) (11.0 g, 60.0 mmol) and 2-chloro-5-methoxyaniline hydrochloride (11.7 g, 60.2 mmol) in dichloromethane (100 mL) at 0° C., was stirred and triethylamine (13.0 g 126.0 mmol, 18.0 mL) added slowly over 15 min. The stirred reaction was allowed to warm to RT over 18 h. There was a heavy precipitation of triethylamine hydrochloride. The dichloromethane solution was washed with 10% aqueous potassium carbonate (50 mL), dried over magnesium sulfate and concentrated in vacuo to afford 18.9 g (quantitative) of 2-Benzyloxy-N-(2-chloro-5-methoxy-phenyl)acetamide (2) as a gum. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 55.6, 69.6, 73.6, 106.2, 111.1, 114.1, 127.7, 128.3, 128.6, 129.2, 134.6, 136.5, 158.9, and 167.7.