Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)=[CH:4][C:3]=1[N:20]=[C:21]=[O:22].[NH2:23][C@@H:24]([C:29]([OH:31])=[O:30])[CH2:25]C(O)=O.C(N(CC)CC)C.C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)=[CH:4][C:3]=1[NH:20][C:21](=[O:22])[NH:23][CH:24]([CH3:25])[C:29]([OH:31])=[O:30]
Reactant: O=C=Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: N[C@H](CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(NC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)C(=O)O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of 4-(3-isocyanato-benzyl)-2H-phthalazin-1-one (2)(1.4 g, 4.7 mmol) in dry DCM (40 ml) was added D-aspartic acid (0.455 g, 5.0 mmol), followed by triethylamine (1.4 ml, 10.0 mmol). The reaction was stirred at room temperature for 4 days. The reaction mixture was then filtered. The filtrate was then diluted with water (20 ml) and washed twice with DCM (2×20 ml). The combined DCM layers were dried over sodium sulfate and then concentrated in vacuo to afford a crude oil which was subjected to flash chromatography eluent neat ethyl acetate to remove impurity and the then 1:1 ethyl acetate/methanol to remove the desired component. (Rf of 0.2 in 1:1 ethyl acetate methanol). Single peak in LC-MS analysis, (0.79 g) requiring no further purification; m/z (LC-MS, ESP), RT=2.70 (M+H) 384;
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[NH:17][C:18]1[C:19]([C:26](O)=[O:27])=[CH:20][N:21]([CH3:25])[C:22](=[O:24])[CH:23]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>O.CO>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[NH:17][C:18]1[C:19]([C:26]([NH:1][O:2][CH2:3][CH2:4][OH:5])=[O:27])=[CH:20][N:21]([CH3:25])[C:22](=[O:24])[CH:23]=1
Reactant: NOCCO
Reactant: Cn1cc(C(=O)O)c(Nc2ccc3ccccc3c2Cl)cc1=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Cn1cc(C(=O)NOCCO)c(Nc2ccc3ccccc3c2Cl)cc1=O
Yield: 24 %

Procedure:
2-(Aminooxy)ethanol, 4-[(1-chloro-2-naphthyl)amino]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid, DMT-MM and N-MM (2 eq) were reacted in 20% water/MeOH for 15 h according to the procedure outlined in example 33, step D. Further purification by flash chromatography on silica gel (EtOAc followed by 10% MeOH/CH2Cl2—100% MeOH gradient elution) gave 4-[(1-chloro-2-naphthyl)amino]-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (24%). 1H NMR [400 MHz, (CD3)2SO] δ 11.72 (br s, 1H), 9.89 (br s, 1H), 8.20-8.14 (m, 1H), 7.98 (t, J=9.6 Hz, 2H), 7.74-7.67 (m, 2H), 7.61-7.56 (m, 2H), 5.69 (s, 1H), 4.78 (br s, 1H), 3.94 (t, J=4.8 Hz, 2H), 3.67-3.61 (m, 2H), 3.38 (s, 3H). LCMS (ACPI−) 386 (100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[C:11](=[O:20])[N:10]([CH2:21][C:22]([N:24]([CH3:35])[C:25]3[CH:34]=[CH:33][C:28]4[N:29]=[C:30]([CH3:32])[O:31][C:27]=4[CH:26]=3)=[O:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:20])[N:10]([CH2:21][C:22]([N:24]([CH3:35])[C:25]3[CH:34]=[CH:33][C:28]4[N:29]=[C:30]([CH3:32])[O:31][C:27]=4[CH:26]=3)=[O:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(-c3cccc(F)c3)nn(CC(=O)N(C)c3ccc4nc(C)oc4c3)c(=O)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1nc2ccc(N(C)C(=O)Cn3nc(-c4cccc(F)c4)c4ccc(O)cc4c3=O)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of 2-(4-(3-fluorophenyl)-7-methoxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (example 70) (4.0 g, 8.469 mmol) in DCM (30 mL) was added BBr3 (4.8 mL, 50.8 mmol) at 0° C. The reaction mixture was stirred at rt overnight then diluted with water (150 mL), neutralized with NaHCO3, then extracted with DCM (3×100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, and concentrated to yield 2-(4-(3-fluorophenyl)-7-hydroxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (2.9 g, 74%) (459.36 [M+H]).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([CH2:10][CH2:11]1)[CH2:8][CH:7]2[OH:22])=[O:5])[CH3:2].C1(C)C=CC=CC=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([CH2:10][CH2:11]1)[CH2:8][CH:7]2[O:22][S:38]([CH3:37])(=[O:40])=[O:39])=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C12CCC(NCc3ccccc3)(CC1)CC2O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C12CCC(NCc3ccccc3)(CC1)CC2OS(C)(=O)=O

Procedure:
To 4-(benzylamino)-2-hydroxybicyclo[2.2.2]octane-1-carboxylic acid ethyl ester (6.0 g, 19.8 mmol), there were added toluene (42.0 g), tetrahydrofuran (10.8 g) and triethylamine (4.0 g, 39.6 mmol) and then the resulting mixture was stirred. Methanesulfonyl chloride (2.9 g, 24.9 mmol) was added dropwise to the mixture, followed by the stirring thereof for one hour and 30 minutes. After quenching the reaction mixture with water, the resulting mixture was subjected to extraction procedures and the organic phase was quantitatively analyzed (according to the LC technique). As a result, the yield of the desired product was found to be 100% (the internal standard substance used was m-xylene).
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>[Pd]>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH2:3]2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Pd]
Product: COC(=O)c1cc2c([nH]1)CCC2c1ccc(Cl)cc1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.3 g, 1.7 mmol) was reacted with (4-chlorophenyl)magnesium bromide (6.7 mL, IM in diethyl ether, 6.7 mmol, 4 equiv) according to General Procedure 3. The resulting endo-olefin (methyl 4-(4-chlorophenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate) was converted to the title compound by hydrogenation according to General Procedure 6 (with 5% Pd/C). The crude product was purified by preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 60% methanol and increasing to 100% over 7 minutes) afforded the title compound. 49.2 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.84 (br. s, 1H), 7.23-7.27 (m, 2H), 7.10-7.16 (m, 2H), 6.62 (d, J=1.61 Hz, 1H), 4.20 (t, J=7.22 Hz, 1H), 3.83 (s, 3H), 2.72-2.99 (m, 3H), 2.20-2.31 (m, J=12.81, 8.65, 6.47, 6.47 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:20])[CH2:14][C:15](=[O:19])[CH:16](Br)[CH3:17].C(N(CC)CC)C>CC(C)=O>[CH3:11][O:12][C:13]([CH2:14][C:15](=[O:19])[CH:16]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1)[CH3:17])=[O:20]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)C(C)OC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-Chloro-nicotinic acid (10 g, 63.5 mmol) and 4-Bromo-3-oxo-pentanoic acid methyl ester (1.51 g, 7.2 mmol) (14.6 g, 70 mmol) in acetone (100 mL) is added triethyl amine (9.76 mL, 70 mmol) at 0-5° C. After addition, the reaction mixture is warmed to room temperature and stirred overnight, solid is filtered off, the filtrate is concentrated and taken into methylene chloride, washed with water and brine, dried. The residue is purified by column giving 6-chloro-nicotinic acid 3-methoxycarbonyl-1-methyl-2-oxo-propyl ester (16.3 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[N:29]=[CH:28][NH:27][C:24]2=[N:25][CH:26]=1)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[N:29]=[CH:28][N:27]([CH2:11][C:9]3[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]4[C:8]=3[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]4)[C:24]2=[N:25][CH:26]=1)=[O:20]
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CO)c21
Reactant: COC(=O)c1cnc2[nH]cnc2c1
Product: COC(=O)c1cnc2c(c1)ncn2Cc1cc(Cl)cc2cnn(CC(C)C)c12
Yield: 30 %

Procedure:
Compound 35 was prepared following general method 3A, using compound 17 as a starting material and 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid methyl ester as the heterocycle. Yield: 30%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:33][C:32]1[CH:31]=[C:30]([CH3:34])[NH:29][C:28](=[O:35])[C:27]=1[CH2:26][NH:25][C:24]([C:4]1[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][CH2:14]2)[CH:7]=[C:2]([C:41]2[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=2)[CH:3]=1)=[O:36]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(C)c3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Temperature: 100 °C

Procedure:
To a stirred solution of tert-butyl 4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)(methyl)amino)piperidin-1-carboxylate (1 equiv.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The reaction was heated at 100° C. for 5 h. After cooling, the reaction mixture was diluted with water, and the product was extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure to afford crude product which was purified by column chromatography over silica gel to afford tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)phenyl)(methyl)amino)piperidine-1-carboxylate. A stirred solution of this compound (1 mmol) in DCM (5 mL) was cooled to 0° C. and TFA (2 mL) was added to it. The reaction was stirred at room temperature for 1 h. On completion, the solution was concentrated to dryness. The residue was purified by solvent washings to afford the title compound (0.07 g, 87%). LCMS: 463.30 (M+1)+; HPLC: 98.02% (@ 254 nm) (Rt; 4.145; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.47 (bs, 1H), 8.12 (s, 2H), 8.05 (s, 1H), 7.83 (s, 1H), 7.32 (s, 1H), 7.14 (s, 1H), 5.86 (s, 1H), 4.28 (m, 2H), 3.84 (s, 3H), 3.24-3.27 (m, 2H), 3.11 (bs, 1H), 2.87-2.89 (m, 2H), 2.59 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H), 2.10 (s, 3H), 1.77-1.80 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([OH:15])=[O:14])=[C:4]([CH3:16])[N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>C(OCC)(=O)C.O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]([OH:15])=[O:14])=[C:4]([CH3:16])[N:3]=2)=[CH:20][CH:19]=1
Reactant: Cc1nc(Cl)c2ccccc2c1CC(=O)O
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(Oc2ccc(Cl)cc2)c2ccccc2c1CC(=O)O

Procedure:
A mixture of 1-chloro-3-methyl-4-isoquinoline acetic acid (237 mg., 1.01 mmol) prepared as in Example 8, 4-chlorophenol (260 mg., 2.02 mmol), and potassium tert-butoxide (226 mg., 2.02 mmol) were heated at 100° for 3 hr. After cooling the mixture was diluted with ethyl acetate and water and acidified to pH 1-2. The separated aqueous phase was extracted with 20 ml. ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and vacuum evaporated to a brown oil. Chromatography of this on silica gel eluted with ethyl acetate gave a pale yellow solid; 80 mg., 24%, mp 192°-195° d.
Reaction SMILES: Cl.C(=[N:15][C:16]1[CH:17]=[C:18]([C@:22]23[CH2:30][CH2:29][O:28][CH2:27][C@H:26]2[S:25][C:24]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[N:23]3)[CH:19]=[CH:20][CH:21]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CCOCC>[NH2:15][C:16]1[CH:17]=[C:18]([C@:22]23[CH2:30][CH2:29][O:28][CH2:27][C@H:26]2[S:25][C:24]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[N:23]3)[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(N=C(c4ccccc4)c4ccccc4)c3)CCOC[C@H]2S1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(N)c3)CCOC[C@H]2S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
1 N hydrochloric acid (1 mL) was added to a solution of tert-butyl(±)-{(3aS*,7aR*)-7a-[3-(benzhydrylidene-amino)phenyl]-3a,6,7,7a-tetrahydro-4H-pyrano[4,3-d]thiazol-2-yl}carbamate (165 mg) in ether (1 mL), and the mixture was stirred at room temperature for one hour. The reaction solution was neutralized with a sodium bicarbonate solution, the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography to obtain the title compound (77 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][O:17][C:11]=2[N:10]=[C:9]1[CH:18]([NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.C([BH3-])#N.[Na+].O1CCCC1>CO.C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][O:17][C:11]=2[N:10]=[C:9]1[CH:18]([N:21]([CH2:32][C:31]1[CH:34]=[CH:35][C:28]([Br:27])=[CH:29][CH:30]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2occc2c(=O)n1Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCC(c1nc2occc2c(=O)n1Cc1ccccc1)N(CCN(C)C)Cc1ccc(Br)cc1
Temperature: 60 °C

Procedure:
A solution of 3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}-propyl)furo[2,3-d]pyrimidin-4(3H)-one (1-6, 1 equiv) and 4-bromobenzaldehyde (2 equiv) in methanol is treated with a solution of sodium cyanoborohydride in tetrahydrofuran (1M, 2 equiv). Acetic acid is added to obtain a pH of 6–7 and the reaction is warmed at 60° C. for 18 h. An additional 2 equivalents of 4-bromobenzaldehyde and sodium cyanoborohydride are added after 18, 42 and 66 hours while maintaining the pH at 6–7 with acetic acid. After warming 90 h at 60° C., the reaction is concentrated and the residue is partitioned between EtOAc and aqueous saturated NaHCO3 solution. The organic layer is washed with brine, dried (MgSO4) and concentrated. The residue is purified by flash chromatography. Elution with EtOAc to 5% NH3-EtOH/EtOAC gives 3-benzyl-2-(1-{(4-bromobenzyl)[2-(dimethylamino)ethyl]amino}propyl)furo[2,3-d]pyrimidin-4(3H)-one (2-1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@@H:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:15]([C:24](O)=[O:25])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@@H:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:15]([CH2:24][OH:25])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CN(C(=O)C2(c3ccc(Cl)cc3)CC2)C[C@H]1c1ccccc1
Agent: COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N1C[C@@H](CO)[C@H](c2ccccc2)C1)C1(c2ccc(Cl)cc2)CC1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
To a solution of (3S,4R)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-4-phenylpyrrolidine-3-carboxylic acid (80 mg, 0.0002 mol, example 355) in tetrahydrofuran (2 mL, 0.02 mol) were added triethylamine (0.0316 mL, 0.000227 mol) and methyl chloroformate (20.0 μL, 0.000260 mol) at −15° C. The mixture was stirred at −15° C. for 20 minutes. To the above mixture was added sodium borohydride (16.4 mg, 0.000433 mol) in THF and the resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched by water and then was extracted with AcOEt. The organic layer was dried over MgSO4, and concentrated to afford the product. The product was purified with Combiflash eluting with 60% AcOEt in hexanes. LCMS: m/z 356.4 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cccnc4)ncnc32)CC1
Temperature: 160 °C
Yield: 33.6 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 3-hydroxypyridine (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 18 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.19 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Dichloromethane and water were added, and the aqueous layer was extracted twice with dichloromethane. The dichloromethane layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated under high vacuum to give 4-[4-(pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (20 mg, 34%) as a white powder. Mass spectrum (ES) MH+=397. HRMS Calcd. for C20H25N6O3 (MH+): 397.1983. Found: 397.1983.
Reaction SMILES: NCC1C[CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:10]=2)[CH2:5][CH2:4]1.[C:32]([N:39]1CCNCC1)(OC(C)(C)C)=O>>[F:15][C:14]1[C:9]([N:6]2[CH2:5][CH2:4][NH:39][CH2:32][CH2:7]2)=[N:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH2:25][N:26]([C:29](=[O:31])[CH3:30])[CH2:27][CH2:28]3)=[CH:19][CH:18]=2)=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(CN)CC4)n3)cc2)CC1
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCNCC4)n3)cc2)CC1

Procedure:
The titled compound was synthesized analogously as compound 1-(4-(4-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone, by using 1-Boc-piperazine. MS 400.3 (M+H); UV 203.8, 268.8 nm.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[Li]CCCC.[CH2:16]([CH:18]([C:21]1[C:22]2[N:23]([C:28](I)=[C:29]([CH3:31])[N:30]=2)[N:24]=[C:25]([CH3:27])[CH:26]=1)[CH2:19][CH3:20])[CH3:17].Cl>[Cl-].[Cl-].[Zn+2].C1COCC1>[CH2:16]([CH:18]([C:21]1[C:22]2[N:23]([C:28]([C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:2]=3[CH3:1])=[C:29]([CH3:31])[N:30]=2)[N:24]=[C:25]([CH3:27])[CH:26]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1coc2ccccc12
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3oc4ccccc4c3C)c(C)nc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
A THF solution (6 mL) of 3-methyl-benzofuran (200 mg, 1.51 mmol) is cooled to −78° C. under N2 then treated with nBuLi (1.6 M in hexane, 1.0 mL, 1.6 mmol). After 5 min at −78° C., the solution is warmed to 0° C. for 10 minutes, then to room temperature for 10 min. The mixture is then cooled to −78° C. and treated with ZnCl2 (Aldrich, 0.5 M in THF, 3.2 mL, 1.6 mmol). The resulting mixture is warmed to room temperature and treated with 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (235.3 mg, 0.69 mmol) and PdCl2(dppf)-CH2Cl2 complex (Aldrich, 64 mg, 0.078 mmol). The mixture is heated to 60° C. for 4 hours, then poured into 1 N HCl (60 mL) and extracted with ethyl acetate (2×60 mL). The organic extract is washed with aq. brine, dried over Na2SO4, filtered, and concentrated. The crude product is purified by chromatography using hexane-ethyl acetate gradient (100% hexane to 20% ethyl acetate in hexane) to elute the product. Obtained is 8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-benzofuran-2-yl)-imidazo[1,2-b]pyridazine as a solid (143.8 mg, 60% yield). ES-MS (m/z): calc'd for C22H25N3O: 347.20. found 348.5 (M+H)+1H NMR (400 mHz, CDCl3): δ 7.65 (d, J=8.4 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.41-7.31 (m, 2H), 6.76 (br s, 1H), 3.38 (br s, 1H), 2.56 (s, 6H), 2.32 (s, 3H), 1.94-1.81 (m, 4H), 0.91 (t, J=7.5 Hz, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccnc(Cl)n2)C1
Temperature: 90 °C
Yield: 68.5 %

Procedure:
A solution of 2,4-dichloropyrimidine (2.0 g, 13.4 mmol), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (2.7 g, 13.5 mmol) and NN-diisopropylethylamine (2.3 mL, 13.4 mmol) in N,N′-dimethylformamide (15 mL) was stirred and heated overnight at 90° C. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (2.87 g, 68%) as a yellow oil.