Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:15]=3)[N:12]=2)[N:7]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.Br[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]>CN(C)C=O>[C:50]([O:49][C:47](=[O:48])[CH2:46][N:23]1[CH2:24][CH2:25][N:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:11]3[N:12]=[C:13]4[C:5]([C:3](=[O:4])[C:2]([CH3:35])([CH3:34])[CH3:1])=[CH:6][N:7]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:8]4=[N:9][CH:10]=3)[CH:15]=2)[CH2:21][CH2:22]1)([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(N4CCNCC4)c3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCN(c2cccc(-c3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of 2,2-Dimethyl-1-[2-(3-piperazin-1-yl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one (0.233 g, 0.473 mmol) in 2 mL of dimethyl formamide was added 0.074 mL of diisopropylethylamine (0.055 g, 0.425 mmol) and 0.629 mL of tert-butyl bromoacetate (0.083 g, 0.425 mmol). The reaction was stirred at room temperature overnight before quenching with water and extracting with dichloromethane. The combined organics were washed with water, dried over MgSO4, filtered and concentrated in vacuo. Silica gel chromatography (10→60% EtOAc/hexanes over 30 minutes) afforded 0.1582 g (61% yield) of (4-{3-[7-(2,2-Dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazin-1-yl)-acetic acid tert-butyl ester as a yellow oil. MS (E/I): 608 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>ClCCl>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=2)[O:10]1
Reactant: COc1ccc2c(c1)OC(C)(C)CC2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CCc2ccc(O)cc2O1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.7 %

Procedure:
To a stirred solution of 7-Methoxy-2,2-dimethyl-chroman (4.55 g, 23.7 mmol, from step 1) in anhydrous dichloromethane (50 mL) was added 1M BBr3 (72.86 mL, 47.4 mmol, 2.0 eq ) via cannula over 10 min. The resulting dark brown solution was stirred at rt for 17 h. Saturated solution of NaHCO3 (50 mL) was added and extracted with CH2Cl2 (3×50 mL. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified on silica gel (flash column chromatography) eluting with 5% ethyl acetate-hexane followed by 20% ethyl acetate-hexane to provide the desired product as white solid (1.76 g, 42%). 1H-NMR (CD3CN) δ 6.89 (d, J=8.5 Hz, 1H), 6.68 (broad, s, 1H, OH), 6.31 (dd, J=2.4, 8.5 Hz, 1H), 6.15 (d, J=2.4Hz, 1H ), 2.69 (t, 2H ), 1.79 (t, 2H), 1.31 (s, 6H). MS LC-MS (MH+=179).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[O:12])[C:6](=[O:9])[C:7]=1[Br:8].[C:21]12([CH2:31][CH2:32][OH:33])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.[OH-].[Na+].[Cl-].[Na+]>O1CCOCC1>[Br:8][C:7]1[C:6](=[O:9])[N:5]([CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[O:12])[N:4]=[CH:3][C:2]=1[O:33][CH2:32][CH2:31][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cn1ncc(Br)c(Br)c1=O)NCc1ccncc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(Cn1ncc(OCCC23CC4CC(CC(C4)C2)C3)c(Br)c1=O)NCc1ccncc1
Yield: 9 %

Procedure:
2-{4,5-Dibromo-6-oxopyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (48 mg, 0.119 mmol) and 1-adamantanethanol (92 mg, 0.510 mmol) in 1,4-dioxane (2 mL) were stirred with 6 M aqueous sodium hydroxide (50 μL, 0.300 mmol) at 100° C. for 6 hours. After completion of the reaction, the reaction solution was mixed with saturated aqueous sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 0/1) to give the desired product (9% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:21])[CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCN(C)CC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(N(C)C2CCN(C)CC2)c1C
Temperature: 80 °C
Yield: 80 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((1-methylpiperidin-4-yl)amino)benzoate (0.6 g, 1.76 mmol) in acetonitrile (15 mL), cesium carbonate (1.14 g, 3.52 mmol) and methyl iodide (1.2 g, 8.8 mmol) were added; resulting reaction mass was heated at 80° C. for 7 h. On completion, reaction mass was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated and then purified by column chromatography to afford the desired compound (0.5 g, 80%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1.[OH-].[Na+]>ClCCl>[CH2:5]([O:4][C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:3])[CH3:6]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccccc1-c1ccccc1

Procedure:
A solution of 21.7 g (0.2 mol) of ethyl chloroformate in 20 ml of dichloromethane is slowly added dropwise to a mixture of 25 g of 2-aminobiphenyl (0.148 mol) and 79 g of pyridine (1 mol) in 150 ml of dichloromethane while stirring. After stirring for 12 hours, 100 ml of 10% strength NaOH are added. The aqueous phase is separated off and shaken with dichloromethane. After the dichloromethane extract has been dried over sodium sulfate, the solvent is removed under reduced pressure and the red oil which remains is worked up by column chromatography (silica gel 60, 0.043 . . . 0.060 mm, eluant: hexane/ethyl acetate=9:1). Yield: 31.7 g=89%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][NH:11][C:12]([NH:14][CH2:15][CH:16]=[CH2:17])=[O:13])=O)=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:14]([CH2:15][CH:16]=[CH2:17])[C:12](=[O:13])[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: C=CCNC(=O)NNC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O

Procedure:
26.8 g (106 mmol) of 2-[(4-chlorophenyl)carbonyl]-N-(prop-2-en-1-yl)hydrazinecarboxamide from Example 11A were suspended in 210 ml of 3 M aqueous sodium hydroxide solution, and the mixture was heated under reflux for 20 h. After cooling, the pH was adjusted to 10 using semiconcentrated hydrochloric acid. The precipitated colorless solid was filtered off with suction, washed with water until neutral and then stirred with methanol. By filtration, the mixture was freed from insoluble components, the filtrate was concentrated under reduced pressure on a rotary evaporator and the residue was dried under high vacuum. This gave 21.5 g (86.4% of theory) of the title compound as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.[Pd]>[N:12]1([CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:18][CH:17]=2)[CH:16]=[CH:15][N:14]=[N:13]1
Reactant: O=[N+]([O-])c1ccc(OCCCn2ccnn2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(OCCCn2ccnn2)cc1

Procedure:
1-[3-(4-Nitro-phenoxy)-propyl]-1H-[1,2,3]triazole (2.87 g, 11.6 mmol) is dissolved in THF (40 ml) and hydrogenated for 2.5 h in the presence of palladium on charcoal (10%, 500 mg). After filtration and concentration in vacuo 4-(3-[1,2,3]Triazol-1-yl-propoxy)-phenylamine can be isolated as orange oil which is precipitated with diethyl ether. Yield 2.48 g (98%)
Reaction SMILES: COC1C=CC=C[C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1.C([BH3-])#N.[Na+].C[Si](Cl)(C)C>C(#N)C.ClCCl>[CH2:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:10]=1)[CH3:13]
Reactant: COc1ccccc1Oc1ccc(C(C)=O)cc1
Agent: C[Si](C)(C)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CCc1ccc(OCOc2ccccc2)cc1
Reaction time: 1 h
Yield: 157 %

Procedure:
960 mg of 1-[4-(2-methoxyphenoxy)phenyl]ethanone 69 are dissolved in 20 ml of acetonitrile and cooled in an ice bath, and 1.05 g of sodium cyanoborohydride and 2.01 ml of trimethylsilyl chloride are added. After 1 h, the mixture is diluted with dichloromethane and filtered through Celite, and the organic phase is extracted with sodium chloride solution, dried over sodium sulfate and concentrated. The residue is purified by chromatography (heptane:ethyl acetate 7:1). 710 mg of the desired product are obtained. C15H16O2 (228.29) MS (ESI): 246.20 (M+NH4+).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:16]=[CH:17]/[C:18](OCC)=[O:19]>C1(C)C=CC=CC=1>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:16]=[CH:17]/[CH2:18][OH:19]
Reactant: CCOC(=O)/C=C/c1ccccn1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OC/C=C/c1ccccn1

Procedure:
As in Example 3, Step 2, but using a 1.5M solution of DIBAL in toluene, the ester from Step 1 of the present example was converted to the title compound. The alcohol was chromatographed on silica using EtOAc/toluene (9:1) as eluent.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([N:23]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:24])[CH:17]=[N:16]3)[CH:10]=[N:9]1)=O)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[CH2:25]([N:23]([CH3:24])[C:18]1[CH:17]=[N:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:11]3[CH:10]=[N:9][NH:8][CH:12]=3)[CH:14]=2)[N:19]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(Cc1ccccc1)c1cnc2cc(-c3cnn(C(=O)OC(C)(C)C)c3)ccc2n1
Agent: Cl
Solvent: C1COCCO1
Product: CN(Cc1ccccc1)c1cnc2cc(-c3cn[nH]c3)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice cold solution of 4-[2-(Benzyl-methyl-amino)-quinoxalin-6-yl]-pyrazole-1-carboxylic acid tert-butyl ester (250 mg) in 1,4-dioxane (3 mL), HCl (in 1,4-dioxane) was added. The resulting mixture was allowed to warm to RT and was stirred further for 2 hours. After completion of the reaction the volatiles were evaporated under vacuum and the HCl salt of the final compound was triturated with DCM. The product was further purified by preparative HPLC (0.009 g, 3%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:13][C:14]1[N:15]=[C:16]2[N:20]([C:21]=1[S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:18][S:17]2.CC(C)([O-])C.[K+]>C1COCC1>[Br:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:22]([C:21]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[Cl:13])(=[O:23])=[O:24])[CH:5]=1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(c1c(Cl)nc2sccn12)n1cc(CCBr)c2ccccc21
Reaction time: 16 h
Yield: 58 %

Procedure:
A mixture of 3-(2-bromoethyl)indole (1.0 g, 4.46 mmol) and 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (0.96 g, 1.1 eq.) in THF is treated with potassium t-butoxide (0.48 g, 1.1 equiv.) at room temperature, stirred for 16 h, quenched with saturated NaHCO3 and extracted with EtOAc. The extracts are combined, dried over MgSO4 and concentrated in vacuo to give the title product as a brown oil, 1.2 g (58% yield), identified by HPLC and mass spectral analyses.
Reaction SMILES: [C:1]1(=[O:8])[NH:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2]1.[CH2:9]=[O:10]>O>[CH2:9]([N:6]1[C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:1]1=[O:8])[OH:10]
Reactant: C=O
Reactant: O=C1CCCC(=O)N1
Solvent: O
Product: O=C1CCCC(=O)N1CO
Temperature: 100 °C

Procedure:
Glutarimide (27 g) and a 35% formaldehyde solution (20 ml) were added to water (40 ml), and heated at about 100° C. for 1 hour over an oil bath. The water was completely distilled away from the reaction mixture using a rotary evaporator. Thus, a crude product of N-methylolglutarimide was obtained. This product was added to 200 ml of benzene without purification, and the resulting solution was heated together with phosphorus tribromide (7.5 ml) under reflux for 1 hour. Thereto, water was added and thereby the benzene layer was separated. The crude product obtained by distilling the benzene away from the benzene layer was recrystallized from an ethyl acetate/n-hexane mixture to yield about 25 g of the desired compound. Melting Point: 165° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.F[B-](F)(F)F.[CH3:19][O+](C)C>CC(C)=O>[CH3:19][N:3]1[C:2]([CH3:1])=[C:10]2[C:5]([CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:9]2)=[N:4]1
Reactant: C[O+](C)C
Reactant: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Agent: F[B-](F)(F)F
Solvent: CC(C)=O
Product: Cc1c2ccc([N+](=O)[O-])cc2nn1C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro-1H-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetrafluoroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHCO3 (600 ml) and a 4:1 mixture of chloroform-isopropanol (200 ml), and the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4×200 ml) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 ml) to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73%). 1H NMR (300 MHz, d6DMSO) δ 8.51 (s, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[CH:28][C:20]=2[C:21]([O:23]C(C)(C)C)=[O:22])[CH:15]=[CH:16][CH:17]=1)(=[O:10])[CH3:9]>>[C:8]([NH:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[CH:28][C:20]=2[C:21]([OH:23])=[O:22])[CH:15]=[CH:16][CH:17]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1cccc(Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cccc(Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 7.5 mL was added to the obtained tert-butyl 2-((3-(acetamido)phenyl)amino)-4-phenylbenzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 2-((3-(acetamido)phenyl)amino)-4-phenylbenzoic acid 0.13 g of a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: ClCCCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCCCl)c(OC)c1
Temperature: 82.5 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
In a 100 mL volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 10.2 g (54.9 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 12.6 g (71.4 mmol) of 4-bromo-1-chlorobutane (purity: 99 wt. %), 8.5 g (60.4 mmol) of potassium carbonate (purity: 98 wt. %), and 300 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85° C. for 8 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (gel: Wako gel C-200, eluent: n-hexane), to give 13.6 g (isolated yield: 90.0%, purity: 99% in terms of area percentage by high performance liquid chromatography) of methyl 4-(4-chlorobutoxy)-3-methoxybenzoate as a colorless liquid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].CO>C1COCC1>[C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2F)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1onc(-c2ccc(Br)cc2F)c1C(=O)O
Yield: 100.6 %

Procedure:
In a fashion similar to that described for preparation 16 (120 mg), 4-ethoxycarbonyl-5-methyl-3-(2-fluoro-4-bromophenyl)isoxazole (350 mg, 1.06 mmol), 5N NaOH (1 ml, 5 mmol), methanol (5 ml), and THF (1 ml) gave 4-carboxy-5-methyl-3-(2-fluoro-4-bromophenyl)isoxazole (320 mg, 100%) that was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[NH2:43][C:44]1[CH:49]=[N:48][C:47](Br)=[CH:46][N:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:43][C:44]1[N:45]=[CH:46][C:47]([C:31]2[CH:32]=[CH:33][C:28]([C:9]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:13](=[O:14])[C:12]4[CH:15]=[N:16][N:17]([C:18]5[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=5)[C:11]=4[N:10]=3)=[CH:29][CH:30]=2)=[N:48][CH:49]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4cccc(S(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cnc(N)cn5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of 5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]-pyrimidin-4-one (prepared as described in example 51, 0.50 g, 0.83 mmol) in N,N-dimethylformamide (20 mL) is degassed with argon for 0.5 h. Then 2-amino-5-bromopyrazine (0.216 g, 1.24 mmol), cesium carbonate (0.540 g, 1.66 mmol), Pd(dppf)2Cl2 (0.060 g, 0.082 mmol)) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 24 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography over silica gel (60-120 mesh) to afford 6-[4-(5-amino-pyrazin-2-yl)-phenyl]-5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one. 1H NMR (CDCl3, 400 MHz) δ 8.93 (s, 1H), 8.60 (m, 1H), 8.42 (s, 1H), 8.37 (s, 1H), 8.12 (s, 1H), 7.93 (d, 1H), 7.82 (d, 2H), 7.73 (m, 1H), 7.47 (d, 2H), 7.36 (d, 2H), 7.15 (d, 2H), 5.05 (br, 2H), 3.13 (s, 3H), 3.01 (s, 3H); LC-MS calculated for C28H20ClN7O3S 570.1 (M+H+), found 570.1.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13](=[O:28])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22]COC)=[C:18]([O:26][CH3:27])[CH:17]=2)=[CH:7][C:6]=1[O:29][CH3:30]>CO.Cl>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:14][C:13](=[O:28])[CH:12]=[CH:11][C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[C:6]([O:29][CH3:30])[CH:7]=2)=[CH:17][C:18]=1[O:26][CH3:27]
Reactant: COCOc1ccc(C=CC(=O)C=Cc2ccc(OCOC)c(OC)c2)cc1OC
Agent: Cl
Solvent: CO
Product: COc1cc(C=CC(=O)C=Cc2ccc(O)c(OC)c2)ccc1O
Temperature: 50 °C
Reaction time: 3 h
Yield: 9.5 %

Procedure:
1,5-Bis(4-methoxymethoxy-3-methoxyphenyl)-1,4-pentadien-3-one (20j, 0.41 g, 10.0 mmol) was stirred in methanol (50 ml) for 15 min at 50° C. Concentrated hydrochloric acid (1 drop) was added and the solution stirred for 3 hr at 50° C. The methanol was evaporated and the resulting residue extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a semi-solid. The crude semi-solid was purified by preparative thin layer chromatography with ethyl acetate/hexane to give 0.31 g (96%) of a yellow solid: mp 84-86° C. [expected mp 82-83° C.]; 1H NMR: δ 3.89 (s, 6H), 6.87 (d, 2H, J=8.4 Hz), 6.88 (d, 2H, J=15.9 Hz), 7.10 (m, 4H), 7.62 (d, 2H, J=15.9 Hz); 13C NMR: δ 56.1, 109.8, 114.8, 123.3, 123.4, 127.5, 143.0, 146.8, 148.1, 188.6.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[O:28][CH2:29][CH2:30][O:31][C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[CH:35]=O)=[CH:4][CH:3]=1.C(O)(=O)C.Cl.[CH3:47][NH:48][CH3:49].C([BH3-])#N.[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[O:28][CH2:29][CH2:30][O:31][C:32]2[CH:39]=[CH:38][CH:37]=[C:34]([CH2:35][N:48]([CH3:49])[CH3:47])[CH:33]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(=O)n(CCOC2CCCCO2)c(=O)c2c1nc(OCCOc1cccc(C=O)c1)n2Cc1ccc(Cl)cc1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(OCCOc2nc3c(c(=O)n(CCOC4CCCCO4)c(=O)n3C)n2Cc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To a solution of 3-(2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-2,3,6,7-tetrahydro-1H-purin-8-yloxy)ethoxy)benzaldehyde (100 mg, 0.171 mmol) in methanol (3 mL) and THF (3 mL) was added acetic acid (0.2 ml, 3.49 mmol) and dimethylamine hydrochloride (90 mg, 1.10 mmol). The mixture was stirred at room temperature for 1 h. Then the mixture was cooled to 0° C., sodium cyanoborohydride (16.1 mg, 0.256 mmol) was added under a nitrogen atmosphere. The resulting mixture was stirred and allowed to warm to room temperature overnight. The mixture was concentrated and purified via silica gel chromatography eluting with DCM/methanol (60:1) to give 7-(4-chlorobenzyl)-8-(2-(3-((dimethylamino)methyl)phenoxy)ethoxy)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-purine-2,6(3H,7H)-dione (26.1 mg, 24.9%) as white solid. LCMS MH+ 613.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10]1.[CH:15]1[N:19]=[CH:18][N:17]([C:20](N2C=NC=C2)=[O:21])[CH:16]=1>C(Cl)Cl>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][C@H:11]([NH:14][C:20]([N:17]2[CH:16]=[CH:15][N:19]=[CH:18]2)=[O:21])[CH2:10]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N[C@H]1CCN(c2ccccn2)C1
Agent: Cl
Solvent: ClCCl
Product: O=C(N[C@H]1CCN(c2ccccn2)C1)n1ccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture comprising ((S)-1-Pyridin-2-yl-pyrrolidin-3-ylamine dihydrochloride (0.242 g, 1.02 mmol), TEA (0.2 ml) in DCM (10.2 ml) is treated with CDI (0.364 g, 2.26 mmol). The reaction mixture is stirred at room temperature for 2 hours to yield the titled compound as 0.1 M solution in DCM. This solution consists of the imidazole-urea intermediate together with variable amounts of the corresponding isocyanate and imidazole. This solution is used in the subsequent steps since the imidazole-urea intermediate and isocyanate intermediate are equally suitable as precursors to ureas.