Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].Br[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([F:9])[C:7]=1[O:8][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cc(F)c(OCc2ccc3ccccc3c2)c(F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
Ethyl 3,5-difluoro-4-hydroxybenzenepropanoate (200 mg, 0.87 mmol) was dissolved in DMF (10 mL). 2-(Bromomethyl)naphthalene (212 mg, 0.96 mmol) and potassium carbonate (132 mg, 0.96 mmol) were added thereto, and then the mixture was stirred at 80° C. for 4 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 80:20) to give the title compound (298 mg, yield 93%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[I:10]N1C(=O)CCC1=O.FC(F)(F)C(O)=O.N>C(O)(=O)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([I:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(N)ncc1Br
Agent: N
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)cnc(N)c1I
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.5 %

Procedure:
5-Bromo-4-methylpyridine-2-amine (3.1 g) was dissolved in acetic acid (20 ml). N-Iodosuccinimide (3.8 g) and trifluoroacetic acid (0.2 ml) were added and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was poured into ice water and neutralized with 28% aqueous ammonia. Then, the precipitated solid was collected by filtration, washed with water and dried to give the title compound (4.9 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)C(OC)=O.[OH-].[Li+]>CO.C1COCC1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: COC(=O)C(c1ccc([N+](=O)[O-])cc1)c1cccn1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cccc1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Methyl 2-(1-methylpyrrol-2-yl)-2-(4-nitrophenyl)acetate (3.8 g, 14.0 mmol) [prepared as in Example 7, Step (a)] was dissolved in a 1:1 mixture of MeOH-THF (100 ml) and cooled in an ice bath under argon. A solution of 0.4 M lithium hydroxide (69 ml) was added and the reaction mixture was stirred at room temperature. After 2 h, the reaction mixture was poured into 1 M HCl/ice and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The solid residue was redissolved in DMF (40 ml) and heated at reflux. After 20 min the reaction mixture was poured into ice/water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated to dryness. Purification on a Florisil® column (hexane-ethyl acetate, 9:1) gave 4-(1-methylpyrrol-2-yl-methyl)nitrobenzene (2.53 g, 82%) as a solid. ##STR39##
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[F:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]=[O:18].[Cl-].[NH4+]>O1CCCC1>[F:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]([OH:18])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1
Reactant: Cc1ccc(Br)nc1
Reactant: O=Cc1cc(F)ccc1F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2cc(F)ccc2F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol) of isopropylmagnesium chloride was added dropwise to tetrahydrofuran (2 ml) solution of 2-bromo-5-methylpyridine (510 mg, 3 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 60 minutes. To the resulting brown solution was added dropwise 2,5-difluorobenzaldehyde (328 μl, 3 mmol) under ice cooling and then, the temperature of the reaction mixture was raised to room temperature gradually. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and then, the mixture was extracted with ethyl acetate. After drying the solvent, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (130 mg, 18%) as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(#N)C>[OH:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][N:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)[O:4][CH:5]=1
Reactant: O=c1cc(CBr)occ1O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(=O)c(O)co2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
2-(Bromomethyl)-5-hydroxy-4H-pyran-4-one (8.9 g, 43.4 mmol), tert-butyloxycarbonylpiperazine (8.5 g, 45.6 mmol), triethylamine (7 mL, 49.9 mmol) and acetonitrile (200 mL) were charged in a 500 ml round-bottomed flask equipped with a magnetic stirrer. The reaction mixture was stirred for 2 h at 90° C. Acetonitrile was evaporated and EtOAc (50 mL) was added. The precipitate of (C2H5)3N, HCl was filtered off and ethyl acetate was evaporated at 40° C. to dryness. The crude compound was purified by column chromatography (deactivated SiO2:CH2Cl2:triethylamine 98:2 to CH2Cl2:MeOH 95:5, purification: CH2Cl2:MeOH 99.5:0:5 to 96:4) to give after evaporation tert-butyl 4-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)piperazine-1-carboxylate 24 (10.5 g, 78% yield) as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:14])[N:5]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:6]=[CH:7][C:8]=1Cl)[CH3:2].C(N)C1C=CC=CC=1.[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[CH2:1]([C:3]1[C:4](=[O:14])[N:5]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:6]=[CH:7][C:8]=1[NH:29][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([CH3:23])=[CH:25][CH:26]=1)[CH3:2]
Reactant: Cc1ccc(CN)cc1
Reactant: CCc1c(Cl)cnn(C(C)(C)C)c1=O
Solvent: NCc1ccccc1
Product: CCc1c(NCc2ccc(C)cc2)cnn(C(C)(C)C)c1=O

Procedure:
The compound as identified in Table 14 was prepared in the synthetic manner and after-treatment similar to those in Example 7 except that the 4-alkyl-5-chloro-2-alkyl-3(2H)pyridazinone with R1 and R2 as identified in Table 14 was used instead of the starting 4-ethyl-5-chloro-2-t-butyl-3(2H)pyridazinone used in Example 7, and the benzylamine derivative with R3, Y1, Y2 and Y3 as identified in Table 14 was used instead of the starting 4-methylbenzylamine. In the NMR data, only the characteristic absorptions were given in Table 14.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:15])[NH:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1.I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:15])[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1c[nH]c(=O)c(-c2ccc(Cl)cc2)c1
Reactant: Ic1ccccc1
Product: Cc1cc(-c2ccc(Cl)cc2)c(=O)n(-c2ccccc2)c1
Yield: 82 %

Procedure:
3-(4'Chlorophenyl)-5-methyl-1-phenyl-2-(1H)-pyridone is prepared in 82% yield by the reaction of 3-(p-chlorophenyl) -5-methyl-2-(1H)-pyridone (B. E. Witzel et al. Brit. Pat. No. 1,238,959) with iodobenzene as described in Example 1.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:19]([N:21]1[CH2:35][CH2:34][CH2:33][C@@H:22]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:36](OC(=O)C)(=[O:38])[CH3:37].[OH-].[Na+]>O>[NH:2]([C:36]([CH3:37])=[O:38])[C@@H:3]([C:19]([N:21]1[CH2:35][CH2:34][CH2:33][C@@H:22]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1

Procedure:
The previously obtained chloromethylene solution of HCl, H-D-Lys(Z)-D-Pro-OBzl is cooled down to 5° C., added with 135 ml of water, followed by 32.3 ml of acetic anhydride (1.5 eq). At Qsp pH 10 is then added within 30 minutes to 1 hour an aqueous 5N NaOH (90 to 130 ml are required).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[SH:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:25]>CN(C=O)C.C(OCC)(=O)C>[CH2:33]([CH:28]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][O:26][C:24](=[O:25])[CH2:23][CH2:22][S:21][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:34]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCCCC(CC)COC(=O)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC(CC)COC(=O)CCSc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a suspension of methyl 4-fluoro-3-nitrobenzoate (10.0 g, 50.2 mmol) and potassium carbonate (13.9 g, 100 mmol) in DMF (120 mL) was added dropwise under ice-cooling 2-ethylhexyl 3-sulfanylpropanoate (12.1 g, 55.2 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. This solution was applied to basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 3:1) to give the title compound (20.0 g, quantitative).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[C:6]([C:15]#[N:16])=[C:5]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl[CH2:24][C:25]([NH2:27])=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:15]([C:6]1[C:7]([CH2:12][CH2:13][CH3:14])=[N:8][C:9]2[C:4]([C:5]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:3][C:2]([O:1][CH2:24][C:25]([NH2:27])=[O:26])=[CH:11][CH:10]=2)#[N:16]
Reactant: CCCc1nc2ccc(O)cc2c(-c2ccccc2)c1C#N
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc2ccc(OCC(N)=O)cc2c(-c2ccccc2)c1C#N
Temperature: 60 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
A suspension of 6-hydroxy-4-phenyl-2-propylquinoline-3-carbonitrile (0.98 g, 3.4 mmol), chloroacetamide (0.36 g, 3.8 mmol) and potassium carbonate (0.55 g, 4.0 mmol) in N,N-dimethylformamide (10 ml) was stirred at 60° C. for 18 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 2-[(3-cyano-4-phenyl-2-propylquinolin-6-yl)oxy]acetamide (1.0 g, yield 88%) as pale-yellow crystals.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].CN(C)C=O.[CH3:12][C:13]1[N:17]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:29]=[C:30]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:31]=[C:32]([C:33]#[N:34])[C:15]=2[N:14]=1>O>[CH3:12][C:13]1[N:17]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:29]=[C:30]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:31]=[C:32]([C:33]3[NH:34][N:3]=[N:2][N:1]=3)[C:15]=2[N:14]=1
Reactant: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(-c3nnn[nH]3)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Yield: 13 %

Procedure:
In a two 5 mL MW vial was added in 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carbonitrile, prepared as described in Example 24 (80 mg, 0.209 mmol), sodium azide (109 mg, 1.673 mmol) and ammonium chloride (90 mg, 1.673 mmol) and N,N-Dimethylformamide (DMF) (2 mL). The reaction mixture was subjected to MW irradiation for 15 min at 180° C., then 80 min at 185° C. LC-MS analysis only showed 30% conversion; however, heating for longer time caused the decomposition of the product. The two reaction mixtures were combined. The combined mixture was added in water (10 mL) and extracted with DCM (30 mL×4). The combined organic phases were washed with saturated NH4Cl solution, dried, and concentrated. The reaction was subjected to purification on a silica column (20˜60% EtOAc/Hexane) and then (1˜5% MeOH/DCM) to give the product (24 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.53 (s, 3H) 3.08-3.15 (m, 4H) 3.68-3.75 (m, 4H) 6.10 (s, 2H) 6.40 (d, J=7.33 Hz, 1H) 7.26-7.39 (m, 2H) 7.56-7.74 (m, 3H) 7.88 (d, J=8.34 Hz, 1H) 8.03 (d, J=8.08 Hz, 1H) 8.26 (d, 1H). MS(ES+) m/e 426.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][N:27]2[C:23](=[O:33])[C:24]3=[CH:32][CH:31]=[CH:30][CH:29]=[C:25]3[C:26]2=[O:28])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 41.3 %

Procedure:
1-(tert-Butoxycarbonyl)-4-[(2-hydroxymethylphenyl)amino]piperidine (716 mg) was dissolved in tetrahydrofuran (7 ml), added with phthalimide (349 mg), triphenylphosphine (736 mg) and diethyl azodicarboxylate (0.43 ml) and stirred at room temperature for 21 hours. The reaction mixture was added with water (10 ml) and extracted twice with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=4:1) to obtain crude 1-(tert-butoxycarbonyl)-4-[(2-phthalimidylmethylphenyl)amino]piperidine (420 mg).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[N:5]=[CH:4]1.C([O-])(O)=O.[Na+].[CH2:17]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOC(C)=O.CO>[NH:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])[CH2:7][C:6]=2[N:5]=[CH:4]1
Reactant: c1nc2c([nH]1)CCNC2
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCc2[nH]cnc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
A mixture of 2.0 g of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine dihydrochloride, 2.36 g of NaHCO3 and 2.45 g of N-(benzyloxycarbonyloxy)succinimide in 80 ml of dioxane/water mixture (50/50; v/v) is stirred for 16 hours at RT. The reaction mixture is extracted with EtOAc, the organic phase is washed with a saturated solution of NaHCO3, with 0.1M HCl solution, with saturated NaCl solution, it is dried and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM/MeOH mixture. 1.9 g of the expected compound is obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]2[N:13]=[C:12]([CH:29]2[CH2:34][NH:33][CH:32]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH2:30]2)[CH:11]=1>C(#N)C.CO>[NH2:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]2[N:13]=[C:12]([CH:29]2[CH2:34][NH:33][CH:32]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH2:30]2)[C:11]=1[Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1CCC(c2cc(N)n3ncc(-c4cnc5ccccc5c4)c3n2)CN1
Solvent: CC#N
Solvent: CO
Product: COC(=O)C1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
N-bromosuccinimide (44 mg, 0.249 mmol) was added into a solution of methyl 5-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-2-carboxylate (100 mg, 0.249 mmol) in acetonitrile (1.5 mL) and methanol (0.5 ml). The resulting solution is stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and purified by prep-LC to afford the title compound (22.32 mg): LC/MS RT=2.56 min. Mass calculated for, M+H 481.09, observed 481.09.
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][O:4][CH2:3][C:2]1=[O:8].[Br:9][CH2:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:9][CH2:10][CH2:11][CH2:12][N:1]1[C:6](=[O:7])[CH2:5][O:4][CH2:3][C:2]1=[O:8]
Reactant: O=C1COCC(=O)N1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1COCC(=O)N1CCCBr

Procedure:
A pale yellow suspension of morpholine-3,5-dione (1.2 g, 10 mmol), of 1,3-dibromopropane (3.4 ml, 33 mmol), and potassium carbonate (2.7 g, 19 mmol) in 23 ml of 2-butanone is refluxed under an argon atmosphere for 22 hours. After cooling, the suspension is concentrated on a rotary evaporator, poured into ice/water, and extracted twice with ethyl acetate. The combined organic phases are washed with brine, dried over anhydrous sodium sulphate, and evaporated. The residual yellow oil (2.06 g) is purified by chromatography (Biotage 40 Mi, I=15 cm, cyclohexane/ethyl acetate 3:1).
Reaction SMILES: [Br-].C[O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:8][C:7]=1[CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O.[CH3:41][C:42](=O)[CH3:43]>>[CH2:21]([C:7]1[O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)=[CH:10][C:6]=1[CH2:4][OH:3])[CH:42]([CH3:43])[CH3:41]
Reactant: CC(C)=O
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC(C)Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1CO

Procedure:
Prepared from intermediate 62 and propanone
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]4[CH3:40])[C:25]4[CH2:31][CH2:30][N:29]([CH:32]=[O:33])[CH2:28][C:26]=4[N:27]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.CO.C(O)(=O)C>[Pd]>[CH3:40][C@@H:35]1[N:34]([C:24]2[C:25]3[CH2:31][CH2:30][N:29]([CH:32]=[O:33])[CH2:28][C:26]=3[N:27]=[C:22]([C:19]3[CH:18]=[CH:17][C:16]([NH:15][C:13]4[NH:14][C:9](=[O:8])[CH:10]=[CH:11][CH:12]=4)=[CH:21][CH:20]=3)[N:23]=2)[CH2:39][CH2:38][O:37][CH2:36]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(OCc4ccccc4)n3)cc2)nc2c1CCN(C=O)C2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(=O)[nH]3)cc2)nc2c1CCN(C=O)C2
Temperature: 40 °C
Reaction time: 8 h

Procedure:
(S)-2-(4-(6-(benzyloxy)pyridin-2-ylamino)phenyl)-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carbaldehyde (0.066 g, 0.00012 mol), Palladium on Carbon 10% (0.1:0.9, Palladium:carbon black, 0.094 g), dry Methanol (3.30 mL, 0.0815 mol) and Acetic acid (0.21 mL, 0.0037 mol) were combined under nitrogen then purged with hydrogen, heated at 40° C., and stirred overnight. The reaction mixture was purged with nitrogen, added celite, filtered through celite, concentrated, and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 10.23 (s, 1H), 9.14 (s, 1H), 8.31-8.16 (m, 3H), 7.76 (s, 2H), 7.42 (t, J=7.8, 1H), 6.31 (s, 1H), 6.00 (d, J=8.1, 1H), 4.69-4.39 (m, 2H), 4.07 (d, J=5.4, 2H), 3.89 (d, J=11.1, 1H), 3.75-3.38 (m, 4H), 3.18 (d, J=4.4, 2H), 2.74 (s, 1H), 2.66 (d, J=12.1, 1H), 1.27 (t, J=6.4, 3H). LC/MS-m/z+447.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:4]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:16]([OH:19])(=[O:18])=[O:17])=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:4]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1cccc(N2CCOCC2)c1
Product: COc1ccc(S(=O)(=O)O)c(N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 20.3 %

Procedure:
To a cooled (0° C.), stirred portion of 1-methoxy-3-morpholin-4-yl-benzene (1.08 g; 5.6 mmol) was added neat to chlorosulfonic acid (1.8 mL; 28 mmol) via pipette over 2 minutes under calcium sulfate-dried atmosphere. The resulting thick, red solution was allowed to warm to room temperature and stirred for 5 hours. The resulting solution was poured onto ice, then extracted with CH2Cl2 (3×50 mL). Combined organic layers then were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give the acid as a light green solid (0.31 g; 20%).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[C:39]([CH3:40])=[CH:38][CH:37]=[C:36]([F:41])[C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[C:36]([F:41])=[CH:37][CH:38]=[C:39]([CH3:40])[C:32]=3[Cl:31])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(F)c(CBr)c1Cl
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1ccc(F)c(Cn2ccc3c(-c4ccc5c(c4)CCCO5)c(C(OC(C)(C)C)C(=O)O)c(C)nc32)c1Cl

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-chloro-6-fluoro-3-methylbenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.40 (m, 1 H), 7.26-7.17 (m, 2 H), 7.02-6.88 (m, 3 H), 6.20-6.12 (m, 1 H), 5.73-5.66 (m, 1 H), 5.66-5.55 (m, 2 H), 4.30-4.24 (m, 2 H), 2.92-2.78 (m, 2 H), 2.74 (s, 3 H), 2.38 (s, 3 H), 2.12-2.06 (m, 2 H), 1.01-0.92 (s, 9 H); LC/MS (m/z) ES+=551.36 (M+1).