Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+].Cl>O1CCOCC1>[F:25][C:23]1[CH:24]=[C:19]([CH:20]=[C:21]([F:27])[C:22]=1[F:26])[O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:28])=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(OCCCCCCOc2cc(F)c(F)c(F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(OCCCCCCOc2cc(F)c(F)c(F)c2)cc1
Reaction time: 24 h
Yield: 62 %

Procedure:
2.75 g of 4-[6-(3,4,5-Trifluoro-phenoxy)-hexyloxy]-benzoic acid ethyl ester was dissolved in 100 ml of 1,4-dioxane, and then 100 ml of a 1.0M NaOH solution was added thereto. After stirring for one day, the reaction solution was acidified with a 10% HCl solution and filtered to obtain a solid. The solid was recrystallized from ethanol to afford 4-[6-(3,4,5-trifluoro-phenoxy)-hexyloxy]-benzoic acid (yield: 62%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.[ClH:27]>CO.C(OCC)(=O)C>[ClH:27].[ClH:27].[CH:21]1([NH:20][C:17]2[CH:18]=[CH:19][C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:15][CH:16]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(NC3CCCCC3)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: c1cc(C2CCCNC2)ccc1NC1CCCCC1
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 3-(4-cyclohexylaminophenyl)-piperidine-1-carboxylic acid tert-butyl ester (6.74 g, 18.8 mmol) in methanol (50 mL) was added 4N hydrochloric acid in ethyl acetate (40 mL) at room temperature. After stirring for 1 h, the resulting suspension was concentrated in vacuo. The residue was washed with ethyl acetate to furnish 3-(4-cyclohexylaminophenyl)-piperidine dihydrochloride (5.84 g, 17.6 mmol, 94%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH3:11][N:12]([CH3:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:20][Sb-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[Na+]>CO>[F:20][Sb-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N+:12]([CH3:19])([CH3:11])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccccc1
Reactant: COc1ccc(CCl)cc1
Agent: F[Sb-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C[N+](C)(C)c2ccccc2)cc1

Procedure:
4,698 g (0.03 mol) of p-methoxybenzyl chloride and 3,638 g (0.03 mol) of N,N-dimethylaniline were reacted in 40 ml of methanol at 40° C. for 3 days. After the reaction, the solvent was evaporated in vacuo and ether/water was added to the residue to extract unreacted reactans in the etherial layer. To the aquous layer containing the ammonium chloride was added 7.77 g (0.03 mol) of sodium hexafluoroantimonate. The resulting crystals were suction filtered, washed and dried to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH2:11]([Mg]Br)[CH2:12][CH:13]=[CH2:14]>C1COCC1.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH2:14][CH2:13][CH:12]=[CH2:11])[CH:8]=[CH:9][CH:10]=1
Reactant: C=CCC[Mg]Br
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CCCC(=O)c1cccc(Cl)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of 3-chlorobenzoyl chloride (7 ml, 54.7 mmol) in THF (60 mL) was added copper (I) iodide (0.521 g, 2.73 mmol). The slurry was cooled to −10° C. and 3-butenylmagnesium bromide (0.5M in THF) (112 ml, 55.8 mmol) was added dropwise via cannula over 30 min. The reaction mixture was stirred at −10° C. for 1 h and then warmed to room temperature. The reaction mixture was concentrated to 25 mL and diluted with 100 mL DCM and 100 mL 1M HCl. The layers were separated and the organic layer was filtered. The filtrate was washed with sat. NaHCO3, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 50% DCM in hexanes) to give the title compound.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[CH2:2][CH2:3][CH3:4].C(OC(C)C)(C)C.[CH3:21][N:22]=[C:23]=[O:24]>C(N(CC)CC)C>[CH3:21][NH:22][C:23]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:24]
Reactant: CCCCNc1ccc(Cl)c(Cl)c1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Product: CCCCN(C(=O)NC)c1ccc(Cl)c(Cl)c1
Yield: 46.8 %

Procedure:
A mixture of 100 g of N-n-butyl-3,4-dichloroaniline (described in West German Pat. No. 1,902,419), 250 ml of isopropyl ether, 10 ml of triethylamine and 60 g of methyl isocyanate was stirred for 18 hours at room temperature and the solvent was distilled off under reduced pressure. The residue was added to petroleum ether (b.p.=65°-75° C.) and after cooling, the precipitate formed was recovered by vacuum filtration to obtain 59 g of N-methyl-N'-n-butyl-N'-(3,4-dichlorophenyl)-urea melting at 58° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:11][C:12]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:13]([CH3:15])[N:14]=1.Cl.C(N(CC)CC)C.[NH2:31][CH2:32][C@H:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[OH:34]>C(O)(=O)C>[Cl:41][C:37]1[CH:36]=[C:35]([C@H:33]([OH:34])[CH2:32][NH:31][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:10]2[NH:11][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:13]([CH3:15])[N:14]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Reactant: COc1nccc(I)c1-c1nc(C)c(CN2CCOCC2)[nH]1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2c(NC[C@@H](O)c3cccc(Cl)c3)cc[nH]c2=O)[nH]c1CN1CCOCC1
Temperature: 90 °C
Yield: 11.9 %

Procedure:
4-((2-(4-Iodo-2-methoxypyridin-3-yl)-4-methyl-1H-imidazol-5-yl)methyl)morpholine (0.008 g, 0.019 mmol) was dissolved in acetic acid (2 mL) and concentrated hydrochloric acid (2 mL) and this mixture was stirred at 90° C. for 2 hours. The mixture was then evaporated and the residue was dissolved in 1-methyl-2-pyrrolidone (4 mL) and treated with triethylamine (100 μL, 0.72 mmol) and the hydrochloric acid salt of (S)-2-amino-1-[3-chlorophenyl]ethanol (0.010 g, 0.048 mmol). The mixture was heated at 90° C. for 4 hours, then the solvent was evaporated and the residue was purified by Prep HPLC (ammonium acetate/acetonitrile/water) to give the title compound (0.001 g, 11%) as a white solid. HPLC<95% (220 nm), LCMS (+ESI, M+H+) m/z 444; 1H NMR (400 MHz, methanol-d4) δ (ppm): 2.21 (3H, br s), 2.56 (˜4H, br s), 3.46 (2H, br s), 3.49 (1H, dd, J=6.8 and 13.6 Hz), 3.55 (1H, dd, J=5.3 and 13.6 Hz), 3.61 (4H, br s), 4.79-4.84 (1H, m overlapped by D2O), 6.08 (1H, d, J=7.3 Hz), 7.06 (1H, d, J=7.6 Hz), 7.16 (1H, dt, J=8.4 and 1.8 Hz), 7.20 (1J, t, J=7.7 Hz), 7.27 (1H, br d, J=8.3 Hz), 7.39 (1H, br s).
Reaction SMILES: C(O[C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:22])[C:13]3[C:14](=[C:16]([CH2:20][CH3:21])[N:17]([CH3:19])[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:6][N:5]=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:44][C@@H:45]([OH:48])[CH2:46][CH3:47]>>[CH2:20]([C:16]1[N:17]([CH3:19])[N:18]=[C:13]2[C:12](=[O:22])[NH:11][C:10]([C:9]3[C:4]([O:48][C@H:45]([CH3:44])[CH2:46][CH3:47])=[N:5][CH:6]=[C:7]([S:23]([N:26]4[CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH2:31]4)(=[O:25])=[O:24])[CH:8]=3)=[N:15][C:14]=12)[CH3:21]
Reactant: CC[C@@H](C)O
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(C)nc2c(=O)[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3O[C@H](C)CC)[nH]c(=O)c2nn1C
Temperature: 110 °C
Reaction time: 18 h
Yield: 17 %

Procedure:
The title compound of Example 78 (400 mg, 0.84 mmol) was added to a mixture of potassium bis(trimethylsilyl)amide (840 mg, 4.2 mmol) in (R)-2-butanol (4 ml) and the mixture stirred at 110° C. for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue suspended in water (10 ml) and neutralised using 2N hydrochloric acid. This aqueous suspension was extracted with ethyl acetate (3×30 ml), the combined organic extracts washed with sodium hydroxide solution (20 ml), brine (2×30 ml), dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using an elution gradient of dichloromethane:methanol (100:0 to 97.5:2.5) and the product suspended in ether and evaporated under reduced pressure. This solid was recrystallised from hexane/ethyl acetate to afford the title compound (72 mg, 17%) as a white solid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1C
Reactant: NCCc1ccccc1
Product: Cc1sc2nc(-c3cccnc3)nc(NCCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-3-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-phenethylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[N+:16]([O-])=O>C(O)C>[NH2:16][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH2:1])[N:8]([CH2:11][CH3:12])[C:7](=[O:13])[C:6]2([CH3:14])[CH3:15]
Reactant: CCN1C(=O)C(C)(C)c2cc([N+](=O)[O-])c(N)cc21
Solvent: CCO
Product: CCN1C(=O)C(C)(C)c2cc(N)c(N)cc21
Reaction time: 3.5 h

Procedure:
To a solution of 6-amino-1-ethyl-3,3-dimethyl-5-nitro-1,3-dihydro-indol-2-one (4.15 g, 16.65 mmol) in ethanol (80 ml) PtO2 (0.4 g) was added and the mixture hydrogenated at room temperature for 3.5 h. After filtration and evaporation of the solvents 3.25 g (89%) 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one was isolated as orange solid.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:25][C@@H:26]5[CH2:28][O:27]5)=[C:19]([CH2:29][CH3:30])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:35][C:36](=[O:41])[CH2:37][CH2:38][NH:39][CH3:40])C>>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:25][C@@H:26]([OH:27])[CH2:28][N:39]([CH3:40])[CH2:38][CH2:37][C:36]([OH:41])=[O:35])=[C:19]([CH2:29][CH3:30])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OC[C@@H]1CO1
Reactant: CCOC(=O)CCNC
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OC[C@@H](O)CN(C)CCC(=O)O

Procedure:
The title compound is prepared starting from (S)-5-(2-cyclopentyl-6-methoxypyridin-4-yl)-3-(3-ethyl-5-methyl-4-(oxiran-2-ylmethoxy)phenyl)-1,2,4-oxadiazole and ethyl-3-(methylamino)-propanoate in analogy to Example 9; LC-MS: tR=0.95 min, [M+H]+=539.53; 1H NMR (CDCl3): δ 7.84 (s, 1H), 7.82 (s, 1H), 7.48 (s, 1H), 7.27 (s, 1H), 6.49 (s br, 2H), 4.52-4.60 (m, 1H), 4.00 (s, 3H), 3.90-3.96 (m, 1H), 3.84-3.90 (m, 1H), 3.41-3.51 (m, 2H), 3.18-3.39 (m, 3H), 2.97 (s, 3H), 2.68-2.80 (m, 4H), 2.36 (s, 3H), 2.04-2.14 (m, 2H), 1.82-1.94 (m, 4H), 1.68-1.78 (m, 2H), 1.30 (t, J=7.5 Hz, 3H).
Reaction SMILES: C(O[C:4](=O)[CH2:5][CH2:6][CH:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10]1)C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:32][CH2:31]C1>[NH4+].[Cl-]>[CH2:15]([CH:11]1[CH2:12][CH2:13][CH2:14][N:9]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:31][OH:32])[CH2:10]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)CCC(C)N1CCCC(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: OCCCCCN1CCCC(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 4-[(3-benzyl)-1-piperidinyl]valeric acid ethyl ester (0.96 g, 3.31 mmol) in THF dry (20 mL) were added portionwise LiAlH4 (0.38 g, 9.95 mmol). The resulting mixture was stirred at 25° C. for 2 hrs then diluted with NH4Cl (sat. solution, 50 mL) and extracted with ethyl acetate (3×30 mL). The collected organic phases were washed with brine (50 mL), dried and concentrated in vacuum. The crude compound was purified by filtration on silica gel (260-400 mesh) using CH2Cl2/MeOH 8/2 as solvent to give the title compound as an oil (0.70 g, 81%). 1H-NMR (CDCl3): 0.8-1.0 (m, 1H); 1.3-1.45 (m, 2H); 1.45-1.75 (m, 9H); 1.8-2.0 (m, 2H); 2.25-2.4 (m, 2H); 2.4-2.6 (m, 2H); 2.78-2.93 (m, 2H); 3.607 (t, J=6.3, 2H); 7.136 (d, J=7.2, 2H); 7.186 (d, J=6.9, 1H); 7.264 (t, J=7.2, 2H).
Reaction SMILES: [CH3:1][C:2]1([O:15][CH2:16][CH2:17][CH:18]=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:27][C:28](=[O:30])[CH3:29])C=CC=CC=1.O>C(Cl)Cl>[CH3:1][C:2]1([O:15][CH2:16][CH2:17]/[CH:18]=[CH:27]/[C:28](=[O:30])[CH3:29])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(OCCC=O)CC1
Solvent: O
Solvent: ClCCl
Product: CC(=O)/C=C/CCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a solution of tert-butyl 4-methyl-4-(3-oxopropoxy)piperidine-1-carboxylate (5.7 g, 21.01 mmol) in CH2Cl2 (150 mL) was added 1-(triphenylphosphoranylidene)propan-2-one (8.69 g, 27.3 mmol) and the resulting mixture was stirred at room temp for 16 h. Water was then added and the mixture was extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-40% EtOAc/hexane) to afford (E)-tert-butyl 4-methyl-4-((5-oxohex-3-en-1-yl)oxy)piperidine-1-carboxylate (5.25 g, 16.86 mmol, 80% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 6.85 (dt, J=16.1, 6.9 Hz, 1H), 6.15 (dt, J=16.0, 1.4 Hz, 1H), 3.79-3.66 (m, 2H), 3.47 (t, J=6.4 Hz, 2H), 3.12 (t, J=11.6 Hz, 2H), 2.49 (qd, J=6.5, 1.5 Hz, 2H), 2.29-2.26 (m, 3H), 1.73 (d, J=13.2 Hz, 2H), 1.47 (s, 9H), 1.46-1.39 (m, 2H), 1.18 (s, 3H). LCMS (M+Na)=334.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[CH3:15])[CH3:2].Cl[CH2:18][C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[N:21][C:20]=1[CH3:34].[Na+].[I-].[H-].[Na+]>CN(C=O)C.CCOCC>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:14])[CH2:18][C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:34])=[CH:9][C:8]=1[CH3:15])[CH3:2]
Reactant: CCOC(=O)COc1ccc(NC)cc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)COc1ccc(N(C)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Yield: 113.6 %

Procedure:
To an ice-cooled and stirred solution of (2-methyl-4-methylamino-phenoxy)-acetic acid ethyl ester (0.357 g, 1.6 mmol), 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (0.513 g, 1.76 mmol, WO02/28433) and NaI (0.24 g, 1.6 mmol) in DMF (4.8 ml) was added NaH (55% in oil, 0.105 g, 2.4 mmol). The reaction was stirred at RT for 2¾h, diluted with Et2O and extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated to give 0.87 g (quantitative) of crude (2-methyl-4-{methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester as a yellow solid, MS: 479 (MH+).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH:31][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Reactant: NCc1ccccc1Cl
Product: CN1CCN(c2nccn3c(-c4ccnc(NCc5ccccc5Cl)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (150 mg, 0.402 mmol) and 2-chlorobenzylamine (228 mg, 1.608 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200˜300 mesh, eluting with dichloromethane:methanol, 30:1˜10:1) to afford the crude product (90 mg). The crude product was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford (2-chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine; hydrochloride. (Yield 25 mg, 14.3%). 1H NMR (300 MHz, CD3OD): δ 8.62 (s, 1H), 8.58 (s, 1H), 8.25 (s, 1H), 7.52-7.38 (m, 4H), 7.23 (brs, 2H), 5.49-5.45 (m, 2H), 4.87 (brs, 2H), 3.56 (brs, 4H), 3.24 (brs, 2H), 2.87 (s, 3H). LC-MS: [M+H]+ 435.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]1[C:11](=[O:21])[N:12](CC(O)=O)[C:13]([CH3:16])=[CH:14][N:15]=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:24]=1[CH2:25]N>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]1[C:11](=[O:21])[N:12]([NH:12][C:11](=[O:21])[CH2:10][CH2:25][C:24]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:23]=2[Cl:22])[C:13]([CH3:16])=[CH:14][N:15]=1
Reactant: NCc1cc(Cl)ccc1Cl
Reactant: Cc1cnc(NCCc2ccccn2)c(=O)n1CC(=O)O
Product: Cc1cnc(NCCc2ccccn2)c(=O)n1NC(=O)CCc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared from 3-[2-(2-pyridyl)ethylamino]-6-methyl-1-carboxymethylpyrazinone and 2,5-dichlorobenzylamine using the procedure of EXAMPLE V, Step F, mp 188°-191° C.: MS (FAB) 446 (M+1)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:28])=[N:8][N:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+].CO>C1COCC1.O>[Cl:26][C:24]1[CH:25]=[C:20]([C:14]2([C:16]([F:18])([F:17])[F:19])[O:13][N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[C:7]([CH3:28])=[N:8]3)[CH2:15]2)[CH:21]=[C:22]([Cl:27])[CH:23]=1
Reactant: CCOC(=O)c1cn(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl ester of example 17.3 (493 mg) in 10 ml THF:water (4:1) was added sodium hydroxide (68 mg). The reaction mixture was stirred at room temperature for 3 hours before adding 2 ml of methanol. The reaction was stirred overnight before evaporation of the solvent in vacuo. The aqueous layer was extracted with ethyl acetate before being acidified. It was then extracted several times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford a mixture of regioisomeric acids (224 mg, 3-methyl major and 5-methyl minor). 1H-NMR (CDCl3, 400 MHz): 8.5 (s, 1H), 7.5 (m, 2H), 7.45 (m, 1H), 4.35 (d, 1H), 3.85 (d, 1H), 2.50 (s, 3H).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:23]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CO.C(Cl)Cl>CS(C)=O>[CH:23]1([NH:30][C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: NC1CCCCCC1
Solvent: ClCCl
Solvent: CO
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCCCCC1
Temperature: 100 °C
Yield: 84.6 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 38.7 mg, 0.091 mmol) and cycloheptanamine (TCI America, Portland, Oreg.; 0.035 mL, 0.274 mmol) in DMSO (0.8 mL), heating at 100° C. for 40 min. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(3-(cycloheptylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (29.8 mg, 0.077 mmol, 84% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (1H, br. s.), 7.86 (1H, d, J=7.6 Hz), 7.55 (1H, d, J=7.8 Hz), 7.30 (1H, t, J=7.8 Hz), 7.11 (1H, d, J=2.0 Hz), 6.92 (1H, br. s.), 6.79 (1H, d, J=7.4 Hz), 4.14-4.29 (1H, m), 3.44 (2H, td, J=6.8, 2.2 Hz), 2.88 (2H, t, J=6.7 Hz), 2.53 (3H, br. s.), 1.97-2.10 (2H, m), 1.62-1.79 (6H, m), 1.49-1.61 (4H, m). m/z (ESI, +ve) 390.2 (M+H)+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[CH:24]=[CH:23][N:22]=[CH:21][C:16]=3[C:17](=O)[NH:18][N:19]=2)=[CH:10][CH:9]=1>O>[Cl:3][C:17]1[N:18]=[N:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[C:15]2[CH:24]=[CH:23][N:22]=[CH:21][C:16]=12
Reactant: COc1ccc(-c2n[nH]c(=O)c3cnccc23)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(-c2nnc(Cl)c3cnccc23)cc1
Yield: 92 %

Procedure:
With cooling with ice, 2.5 ml of phosphorus oxychloride was added to 2.53 g (10.0 mmol) of 1-(4-methoxyphenyl)-3H-pyrido[3,4-d]pyridazin-4-on, and the reaction liquid was stirred under reflux for 6 hours. Water was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium chloride, and concentrated under reduced pressure to obtain 2.50 g (yield: 92%) of 4-chloro-1-(4-methoxyphenyl)-pyrido[3,4-d]pyridazine as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C(OCC3C=CC=CC=3)=O)[CH2:12][CH2:11]2)=[N:6][CH:7]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2ncc(F)cn2)CC1
Agent: [Pd]
Solvent: CO
Product: Fc1cnc(NCC2CCNCC2)nc1

Procedure:
A mixture of benzyl 4-{[(5-fluoropyrimidin-2-yl)amino]methyl}piperidine-1-carboxylate (EXAMPLE 142, STEP 3) (9.0 g, 0.026 mol) and Pd/C (10%, 0.9 g) in anhydrous methanol (250 mL) was vigorously stirred under hydrogen atmosphere provided by a hydrogen balloon for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give the title compound. M.S. (M+1): 211.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:5]=[CH:6][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].CI.[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:8]([C:7]1[C:2](=[O:1])[C:3]2[C:4](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:5]([CH3:22])[CH:6]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cn1cc2c(O)c(C(=O)c3ccccc3)cnc2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc2c(=O)c(C(=O)c3ccccc3)cn(C)c2n1

Procedure:
25.3 g. of (4-hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenylmethanone (0.1 mol.), 15.5 g. of methyl iodide (0.11 mol.) and 21 g. of potassium carbonate (0.15 mol.) are heated in 150 ml. of dimethylformamide with stirring at 80° for 10 hours. After this time, the inorganic precipitate is filtered off and the filtrate evaporated to dryness. The remaining 5-benzoyl-2,7-dihydro-2,7-dimethyl-4H-pyrazolo[3,4-b]pyridin-4-one is recrystallized from butanol, yield 18 g. (67%); m.p. 272°-274°.