Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1([CH3:18])[CH:12]2[C:13]3([CH3:17])[O:16][CH:14]3[CH2:15][CH:10]1[CH2:11]2.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(O)(=O)C>[CH3:11][C:12]1[C:9]([CH3:8])([CH3:18])[CH:10]([CH2:15][CH:14]=[O:16])[CH2:17][CH:13]=1
Reactant: CC1(C)C2CC3OC3(C)C1C2
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC1=CCC(CC=O)C1(C)C
Reaction time: 2 h

Procedure:
The reaction mass is then transferred to a 5 liter flask and 2145 grams of toluene are added. Alpha-pinene epoxide (1086 grams, 7.1 moles) is then added over a period of 1 hour while maintaining the reaction mass temperature below 53° C. using dry-ice/isopropanol bath in order to control exotherm. The reaction mass is then stirred for an additional 2 hours after addition is complete. The reaction mass is then intimately admixed with a 10% acetic acid solution to a pH of 4.3 followed by neutralization with sodium bicarbonate and sodium chloride solutions. The toluene is then recovered and the reaction mass crude material is "rush over" distilled whereby 785.3 grams of product is collected. (Chemical yield=74%). The rush over distillation fractions are collected using a 2 inch rush over column packed with saddle stones yielding the following fractions:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Cl)[CH:3]=1.[H-].[Na+].[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@@H:21]([O:24][CH2:8][C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: ClCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2cccnc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
A suspension of 3-picolylchloride hydrochloride (1.84 g, 11.2 mmol) in DMF (50 ml) was added to a stirred slurry of sodium hydride (60% dispersion in oil, 0.45 g, 11.2 mmol) in DMF at 0° C. under nitrogen. The mixture was stirred at 0° C. for 0.25 h and then added to a mixture of (3R)-N-tert-butyloxycarbonylpyrrolidin-3-ol (2.0 g, 10.7 mmol) and sodium hydride (60% dispersion in oil, 0.45 g, 11.2 mmol) in DMF at 0° C. under nitrogen (mixture stirred for 0.2 h at 0° C. prior to the addition). The reaction mixture was stirred at room temperature for 2.5 h. Water (200 ml) was added and the mixture extracted with ethyl acetate (1×200 ml), dried (Na2SO4) and evaporated in vacuo. The crude product was chromatographed on silica gel, eluting with Et2 O/MeOH (95:5), to give the desired product (1.63 g, 55%), δ (250 MHz, d4 -MeOH), 1.46 (9H, s, OC(Me)3), 1.95-2.18 (2H, m, CH2), 3.34-3.51 (4H, m, 2 of CH2), 4.22 (1H, m, CHOCH2Ar), 4.59 (2H, s, OCH2Ar), 7.43 (1H, dd, J=4.7 and 7.8 Hz, Ar--H), 7.48 (1H, d, J=7.9 Hz, Ar--H), 8.45-8.51 (2H, m, 2 of Ar--H).
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:24])([CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH2:4]1.[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[S-:34].[Na+]>>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[S:34][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:24])([CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH2:4]1
Reactant: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1
Reactant: [S-]c1nc2ccccc2s1
Agent: [Na+]
Product: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CSc2nc3ccccc3s2)OC(C)(C)O1

Procedure:
The procedure was carried out in the same manner as in Example 11, except that 3.5 g of 2-methyl-1-phenylpropan-2-yl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate was used in place of 30 g thereof, and sodium benzo[d]thiazole-2-thiolate (3.8 g) prepared in Example 10 was used in place of sodium 1-phenyl-1H-tetrazole-5-thiolate. The title compound was obtained (4.6 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[NH:37][CH:36]=[C:35]2[CH3:43]>>[CH3:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[N:37]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]3[CH2:14][CH2:13][N:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10]3)=[CH:5][CH:4]=1)[CH:36]=[C:35]2[CH3:43]
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)[nH]cc(C)c3c2)c1
Reactant: O=C(N1CCC(c2ccc(CCl)cc2)CC1)C(F)(F)F
Product: COC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccc(C5CCN(C(=O)C(F)(F)F)CC5)cc4)cc(C)c3c2)c1

Procedure:
The sub-title compound was prepared by the method of Intermediate 4 using the product of step ii) and the product of Example 93 step ii).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[C:12](=O)[NH:11][N:10]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:10][N:11]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c3cc(C)ccc23)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nnc(Cl)c3cc(C)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(4-methoxyphenyl)-7-methyl-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[C:12]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[N:13][N:14]4[C:19]=3[CH2:18][CH2:17][CH2:16][NH:15]4)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.O>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[C:12]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:13][N:14]4[C:19]=3[CH2:18][CH2:17][CH2:16][N:15]4[C:27](=[O:29])[CH3:28])[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: Fc1ccc(-c2nn3c(c2-c2ccnc(NC4CC4)n2)CCCN3)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CCCc2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nn21

Procedure:
A catalytic amount of 4-dimethylaminopyridine (ca. 5 mg) was added to a solution of N-cyclopropyl-4-[2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine (i.e. the product of Step E) (42.1 mg, 0.12 mmol) and acetic anhydride (0.023 mL, 0.24 mmol) in 2 mL of pyridine at room temperature. After 3 h the reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by medium pressure liquid chromatography using 20-100% ethyl acetate in hexanes as eluent to give 25 mg of the title product, a compound of the present invention, as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28]Cl)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:28][CH2:27][CH2:26][CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCc3ccccc3)CC2)c1
Yield: 25.1 %

Procedure:
A mixture of 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.100 mmol), 4-phenyl-1-chlorobutane (21.1 mg, 0.125 mmol), diisopropylethylamine (0.50 mL), catalytic amount of tetrabutylammonium iodide and dioxane (2.0 mL) was heated at reflux temperature for 3 days. The reaction mixture was concentrated and chromatographed using preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] afforded the product, 2-methyl-N-{3-[1-(4-phenylbutyl)-4-piperidinyl]phenyl}propanamide (9.50 mg, 25.1% yield) as a thick oil: 1H NMR δ 7.37 (s, 1H), 7.29 (apparent d, 1H, J=7.9 Hz), 7.18 (m, 3H), 7.11 (m, 3H), 6.90 (apparent d, 1H, J=7.9 Hz), 3.02 (d, 2H, J=6.8 Hz), 2.41 (m, 4H, partially hidden), 2.01 (m, 2H), 1.78 (m, 4H), 1.57 (m, 4H), 1.18 (d, 6H, J=7.7 Hz); ESMS m/e: 379.4 (M+H)+.
Reaction SMILES: [CH:1]1([CH:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7](=O)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.S(C)C>C1COCC1>[CH:1]1([CH:4]2[CH2:5][CH2:6][CH2:7][N:8]2[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCC(C2CC2)N1Cc1ccccc1
Solvent: C1CCOC1
Solvent: CSC
Product: c1ccc(CN2CCCC2C2CC2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
To 5-cyclopropyl-1-(phenylmethyl)-2-pyrrolidinone (240 mg, 1.12 mmol) in THF (5 mL) was added BH3.SMe2 2M in THF (5.6 mL, 11.2 mmol), and the reaction mixture was stirred over the weekend at room temperature. The reaction was quenched with the dropwise addition of CH3OH (˜2 mL, caution: vigorous H2 evolution occurs). The solution was poured onto water (˜50 mL) and EtOAc (˜50 mL), and the mixture was stirred at 60° C. for 3 hours. A saturated aqueous solution of NaHCO3 (˜25 mL) and EtOAc (˜50 mL) were added, and the organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% hexanes to 75% EtOAc/hexanes) afforded the title compound (100 mg, 45%) as a yellow oil. LC-MS (ES) m/z=202 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[C:21](=[O:24])[NH:22][N:23]=[C:4]2[C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44].O>CN(C=O)C>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([N:12]2[C:8]([C:7]3[C:2]([CH3:1])=[C:3]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)[C:4]4[N:5]([C:21](=[O:24])[N:22]([CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[N:23]=4)[CH:6]=3)=[CH:9][CH:10]=[N:11]2)=[CH:14][CH:15]=1)#[N:18]
Reactant: CN(C)C(=O)CCl
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2c(=O)[nH]nc2c1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2c(=O)n(CC(=O)N(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.6 %

Procedure:
To a solution of 4-{5-[7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 9, 55 mg. 0.12 mmol) in DMF (3 mL) was added cesium carbonate (58 mg, 0.18 mmol) followed by 2-chloro-N,N-dimethylacetamide (19 μL, 0.18 mmol). The reaction mixture was stirred at RT for 18 hrs then water was added and the reaction mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by preparative HPLC, eluting with a gradient of 20-70% MeCN in water (+0.1% formic acid) to give the title compound as a yellow solid (22 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH:8]2[CH2:13][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][C:10](=[O:20])[O:9]2)=[CH:4][CH:3]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>O1CCOCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH:8]([OH:9])[CH2:13][N:12]([CH2:11][C:10]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: O=C1CN(c2ccccc2)CC(COc2ccc(Cl)cc2)O1
Solvent: C1COCCO1
Product: CC(C)NC(=O)CN(CC(O)COc1ccc(Cl)cc1)c1ccccc1
Reaction time: 8 h
Yield: 10.5 %

Procedure:
After 7.0 g (0.22 moles) of 6-(p-chlorophenoxymethyl)-4-phenyl-2-morpholinone and 20 g of isopropylamine were dissolved in 50 ml of dioxane and the resulting Solution was left to stand overnight at room temperature, the reaction mixture was concentrated in vacuo. The residue was solidified by addition of a small amount of ether. The solid was filtered, washed with ether and dried to give 8.7 g of the product. Recrystallization from ethanol afforded 5.5 g (66.3%) of crystals, with a melting point of 140.5° to 142.5°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:15]1([O:21][C:22](=[O:23])[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccncc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4 aminopyridine (0.6 g, 6.37 mmol) in dichloromethane (15 ml) is treated with triethylamine (0.89 ml, 6.37 mmol) followed by phenylchloroformate (0.80 ml, 6.37 mmol) and then stirred at room temperature for 3 days. The reaction mixture is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase is dried over magnesium sulphate and evaporated to afford pyridin-4-yl-carbamic acid phenyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=1[CH2:14][C:15]([OH:17])=[O:16].S(=O)(=O)(O)O.[N+:23]([O-])([OH:25])=[O:24]>ClCCl>[CH3:1][C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]([N+:23]([O-:25])=[O:24])=[CH:5][C:4]=3[C:3]=1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: Cc1c(CC(=O)O)c2cccc3c2n1CCC3
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1c(CC(=O)O)c2cc([N+](=O)[O-])cc3c2n1CCC3
Temperature: 0 °C

Procedure:
20 g of 5,6-dihydro-2-methyl-4H-pyrrolo[3,2,1-ij]-quinoline-1-acetic acid (prepared by hydrolysis of its ethyl ester obtained by Example 1C)) were cautiously added to 50 ml of sulfuric acid cooled to 0° C. The nitrating acid (=mixture of 5.56 ml of concentrated sulfuric acid and 4.04 ml of concentrated nitric acid) was then added cautiously. The reaction mixture was allowed to react at a temperature of 0° C. for 1 hour and at room temperature for 2 hours. To work up the reaction mixture, it was added to 200 g of ice, and a precipitate formed. The reaction mixture was extracted with dichloromethane, and a part of the precipitate which formed dissolved in the dichloromethane phase. The dichloromethane phase was separated, and the residual precipitate which remained in the aqueous phase was filtered out, washed with water and dried. 7.54 g of 5,6-dihydro-2-methyl-8-nitro-4H-pyrrolo-[3,2,1-ij]quinoline-1-acetic acid were obtained as a greenish-yellow powder. The dichloromethane phase was washed with water, dried and concentrated. The residue which remained, which further contained acid in addition to oily impurities, was treated with about 25 ml of ethanol to remove the oily impurities and filtered. A further 3.23 g of the acid were thus obtained, so that the total yield was 10.8 g.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15]C(OC(C)(C)C)=O)[CH:6]=1.OS(O)(=O)=O>CO.O1CCOCC1>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1
Reactant: Cc1cn(CCc2ccccc2NC(=O)OC(C)(C)C)cn1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cn(CCc2ccccc2N)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
2-(4-Methyl-1H-imidazol-1-yl)-1-[2-[(tert-butoxycarbonyl)amino]-phenyl]ethane (2.555 g) from Step B above was dissolved in methanol (20 mL) and 10% conc. H2SO4 in dioxane (v/v) (40 mL) was added. The solution was stirred at 25° C. for 4 h. The solution was diluted with methanol and BioRad AG® 1-X8 (OH−) resin was added until the pH was basic. The resin was filtered off and washed with methanol. The combined filtrates were evaporated to dryness and the residue was chromatographed on silica gel using 4% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (1.605 g, 94%): ESMS: m/z 202.0 (MH+); δH (CDCl3) 2.20 (3H, s, 4-CH3), 2.90 (2H, dd, 1-CH2), 3.33 (2H, bs, NH2), 4.09 (2H, dd, 2-CH2), 6.60 (1H, s, Im-H5), 6.68 (1H, d, Ar—H6), 6.74 (1H, dd, Ar—H4), 6.92 (1H, d, Ar—H3), 7.08 (1H, dd, Ar—H5) and 7.22 ppm (1H, s, Im-H2); δC (CDCl3) CH3: 13.8; CH2: 33.7, 46.7; CH: 115.2, 116.3, 119.4, 128.2, 130.1, 136.3; C, 122.3, 138.7, 144.5.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13]Cl>O1CCCC1>[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
A suspension of sodium hydride (3.08 g of 60% in oil, 1.85 g, 77 mmol) in dry tetrahydrofuran (80 mL) at 0° C. was treated dropwise with a solution of imidazole (5.00 g, 73.4 mmol) in dry tetrahydrofuran (20 mL) over 15 minutes. The mixture was stirred at ambient temperature for 30 minutes, cooled to 0° C. and treated dropwise with 2-trimethylsilylethyoxymethyl chloride (13.7 mL, 12.86 g, 77 mmol). The mixture was stirred at ambient temperature for 18 hours and quenched by the addition of saturated ammonium chloride solution. The mixture was diluted with water and concentrated in vacuo to remove tetrahydrofuran. The residue was diluted with ethyl acetate and the organic layer was washed with saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to afford an orange oil. Distillation (93-94° C./0.2 mm Hg) afforded the title compound as a colorless liquid (12.97 g, 89%). MS (ESI+) m/z 199 (M+H)+.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=O)[S:14][CH:15]=1)([O-:10])=[O:9].Cl.[NH2:19]O>N1C=CC=CC=1>[N+:8]([C:11]1[CH:12]=[C:13]([C:16]#[N:19])[S:14][CH:15]=1)([O-:10])=[O:9]
Reactant: NO
Reactant: O=Cc1cc([N+](=O)[O-])cs1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc([N+](=O)[O-])cs1
Temperature: 95 °C
Yield: 68 %

Procedure:
Acetic anhydride (1.2 mL) was added to a mixture of aldehyde 1 (314.3 mg, 2.00 mmol) and hydroxylamine hydrochloride (277.6 mg, 4.00 mmol) in pyridine (1.5 mL) pre-heated at 95° C. according to the procedure of M. Bobosikova et al. (J. Chem. Soc., Perkin Trans. I, 2001, 680-689). After 2 h at 95° C. the mixture was cooled and poured over ice and the precipitate was filtered out and allowed to air dry. Nitrile 2 was obtained in 68% yield as beige solid 1H NMR (CDCl3) δ(ppm): 8.51 (s, 1H), 8.14 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1.C(COC)OC.[C:31]1(OB(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+]>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>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:9]3[N:10]=[C:5]4[CH:4]=[CH:3][C:2]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:7][N:6]4[CH:8]=3)[CH2:13][CH2:14]2)=[CH:19][CH:20]=1
Reactant: OB(O)Oc1ccccc1
Reactant: Clc1ccc(N2CCN(Cc3cn4cc(Br)ccc4n3)CC2)cc1
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: COCCOC
Product: Clc1ccc(N2CCN(Cc3cn4cc(-c5ccccc5)ccc4n3)CC2)cc1

Procedure:
A mixture of 6-bromo-2-[[4-(4-chlorophenyl)-1-piperazinyl]methyl]imidazo[1,2-a]pyridine. (Example 23; 0.091 g), tetrakis(triphenylphosphine)palladium (0) (Aldrich; 0.0078 g), and dimethoxyethane (2 mL) is stirred at room temperature for 10 min, at which time phenylboric acid (Aldrich; 0.0306 g) is added, followed by sodium bicarbonate (0.0565 g) in water (1 mL). The mixture is stirred at reflux for 3 h and then allowed to cool. Dimethoxyethane is removed under reduced pressure and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel using acetone/dichloromethane/methanol (50/200/1) to give 0.027 g of the title compound. MS m/z 402; 1H NMR (CDCl3) δ2.76, 3.21, 3.80, 6.84, 7.19, 7.37-7.58, 7.61, 7.64, 8.26.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:17][C:18]4[CH:24]=[C:23](B5OC(C)(C)C(C)(C)O5)[CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)S(O[C:40]1[CH:41]2[CH:43]([C:44](=[O:56])[N:45]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=3)[N:46]=1)[CH2:42]2)(=O)=O>>[CH3:55][O:54][C:51]1[CH:50]=[CH:49][C:48]([CH2:47][N:45]2[N:46]=[C:40]([C:23]3[CH:22]=[CH:21][C:19]4[N:20]=[C:16]([C:13]5[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]6[CH2:6][CH2:5][O:4][CH2:3][CH2:2]6)=[CH:11][CH:12]=5)[O:17][C:18]=4[CH:24]=3)[CH:41]3[CH:43]([CH2:42]3)[C:44]2=[O:56])=[CH:53][CH:52]=1
Reactant: COc1ccc(CN2N=C(OS(=O)(=O)C(F)(F)F)C3CC3C2=O)cc1
Reactant: CC1(C)OB(c2ccc3nc(-c4ccc(OCCN5CCOCC5)cc4)oc3c2)OC1(C)C
Product: COc1ccc(CN2N=C(c3ccc4nc(-c5ccc(OCCN6CCOCC6)cc5)oc4c3)C3CC3C2=O)cc1

Procedure:
The preparation is carried out analogously to Example 136c from 2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoxazole and 4-(4-methoxy-benzyl)-5-oxo-3,4-diaza-bicyclo[4.1.0]hept-2-en-2-yl trifluoromethanesulphonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:23]([N:15]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([NH2:22])=[C:21]2[C:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:14]1)([CH3:25])[CH3:24]
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: CCO
Solvent: COCCOC
Product: COc1cccc(-c2nn(C(C)C)c3ncnc(N)c23)c1
Temperature: 80 °C

Procedure:
A solution of 3-Methoxyphenylboronic acid (17 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA49. ESI-MS (M+H)+ m/z calcd 284.1, found 284.0.