Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1([O:13][C:14]2[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[C:24]1[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][N:29]=1>O.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:7]1([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:24]3[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][N:29]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Nc1nccnc1Cl
Reactant: OB(O)c1ccc(OC2CCCCC2)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: COCCOC
Solvent: O
Product: Nc1nccnc1-c1ccc(OC2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
A mixture of sodium carbonate (491 mg), tetrakis(triphenylphosphine)palladium(0) (80 mg), 4-(cyclohexyloxy)phenylboronic acid (612 mg) and 3-chloropyrazin-2-amine (300 mg) in water (3 mL) and DME (15 mL) was stirred at 80° C. for 4 hr. Silica gel was added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give 3-[4-(cyclohexyloxy)phenyl]pyrazin-2-amine (485 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH3:37][C:38]([CH3:40])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][N:34]([CH:38]([CH3:40])[CH3:37])[CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCNC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(C3CCN(C(C)C)C3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.3 %

Procedure:
A suspension of N2-[4-(4-amino-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (0.250 g, 0.518 mmol) in dichloroethane (5 mL) was treated with acetone (1.96 g, 33.15 mmol) and sodium triacetoxy borohydride (0.220 g, 1.04 mmol). The reaction mixture was stirred at room temperature for 18 h under a nitrogen atmosphere. Sodium hydroxide (1N, 15 mL) was added to the reaction mixture and was stirred for 1 h. The organic layer was removed under reduced pressure and dichloromethane was added. The layers were partitioned and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane (15 min), 15% methanol in dichloromethane (15 min), 20% methanol in dichloromethane (20 min) and 50% methanol in dichloromethane (5 min) as the eluent. The column afforded 0.123 g (44%) of pure N2-{4-[4-amino-1-(1-isopropyltetrahydro-1H-3-pyrrolyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.449 (s, 1H), 8.265 (s, 1H), 8.127-8.1068 (d, 1H, J=8.08 Hz), 7.7196-7.6999 (d, 1H, J=7.88 Hz), 7.6013-7.5803 (d, 1H, J=8.4 Hz), 7.351-7.299 (m, 4H), 7.173-7.135 (m, 1H), 5.394 (m, 1H), 4.042 (s, 3H), 3.961 (s, 3H), 2.793 (m, 3H), 2.337 (m, 3H), 1.068 (br.s, 6H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) R 2.38 min (100%), MH+ 525.3.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]=1[CH:34]=[O:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:34]=[O:35])=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: O=Cc1c(O)ccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc3ccccc3c2C=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.9 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (11.13 g), 2-hydroxy-1-naphthaldehyde (5.96 g), anhydrous potassium carbonate (5.03 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 2 days. The reaction mixture was poured into water, and the precipitated solid was collected by filtration, and dried with air to give crystals (13.83 g, 89%) of 2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthaldehyde. Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 141-142° C.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][C:6]1([CH3:46])[C:10](=[O:11])[N:9]([C@@H:12]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:13]([NH:15][C@H:16]([CH3:20])[CH2:17][CH2:18][OH:19])=[O:14])[C:8](=[O:25])[N:7]1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH3:43])=[O:35])=[C:29]([O:44]C)[CH:28]=1.O>ClCCl>[CH3:46][C:6]1([CH3:5])[C:10](=[O:11])[N:9]([C@@H:12]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:13]([NH:15][C@H:16]([CH3:20])[CH2:17][CH2:18][OH:19])=[O:14])[C:8](=[O:25])[N:7]1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH3:43])=[O:35])=[C:29]([OH:44])[CH:28]=1
Reactant: COc1cc(CN2C(=O)N([C@@H](CC3CC3)C(=O)N[C@H](C)CCO)C(=O)C2(C)C)ccc1NC(=O)Nc1ccccc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1NC(=O)Nc1ccc(CN2C(=O)N([C@@H](CC3CC3)C(=O)N[C@H](C)CCO)C(=O)C2(C)C)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
488 μL of boron tribromide were added under argon to a solution of 220 mg (0.39 mmol) of the compound of Example 3 in 40 mL of absolute dichloromethane at −78° C. and the reaction mixture was allowed to warm to 0° C. with ice cooling. After 30 minutes at 0° C., water was cautiously added. The phases were separated, and the organic phase was washed four times with water and dried over sodium sulfate. After filtration, removal of the solvent in vacuo, chromatographic purification by preparative HPLC and freeze drying of the product fractions, 81 mg (37%) of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C@@H:11]([CH2:22][CH:23]=[O:24])[CH2:12][O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:36](O)[CH2:37][OH:38]>C(Cl)Cl>[O:24]1[CH2:36][CH2:37][O:38][CH:23]1[CH2:22][C@H:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)[CH2:12][O:13][C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCCO
Reactant: Cn1cc([C@@H](CC=O)COC(=O)c2ccccc2)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Cn1cc([C@H](COC(=O)c2ccccc2)CC2OCCO2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-Benzoic acid 2-(1-methyl-1H-indol-3-yl)-4-oxo-butyl ester (1.65 g, 5.10 mmol) was dissolved in CH2Cl2 (50 mL). This solution was treated with p-TSA (20 mg) and ethylene glycol (1.4 mL, 26 mmol). The reaction was stirred at room temperature overnight, at which time the organics were removed in vacuo. The solution was diluted with H2O (10 mL) and extracted with Et2O (3×20 mL). The collected organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide (R)-benzoic acid 3-[1,3]dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propyl ester. The unpurified product was dissolved in MeOH/THF (18 mL/18 mL) and allowed to stir at room temperature for 10 min. To this was added a 4% NaOH/MeOH (18 mL) solution. The reaction was allowed to stir at room temperature for 1 h. The solution was diluted with H2O (10 mL) and extracted with Et2O (3×20 mL). The collected organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide (R)-3-[1,3]dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propan-1-ol (600 mg, 2.30 mmol) after silica gel chromatography (50:50 Et2O/hexanes). 50% Et2O/hexanes). (R)-3-[1,3]Dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propan-1-ol (69.5 mg, 0.267 mmol) was dissolved in CH2Cl2 (8 mL) and Et3N (56 μl, 0.40 mmol). The reaction was cooled to 0° C. and treated with methanesulfonyl chloride (31 μl, 0.40 mmol). The reaction stirred for 1.5 h at this temperature then was allowed to warm to room temperature and stirred for an additional 10 min. The solution was diluted with H2O (5 mL) and extracted with Et2O (3×10 mL). The collected organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide (R)-methanesulfonic acid 3-[1,3]dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propyl ester. Deoxygenation was performed following the method of Holder and Matturro (1977) J. Org. Chem. 42:2166.
Reaction SMILES: [OH:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([N+:10]([O-])=O)=[C:4]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:3]=1.[H][H]>CO.[OH-].[Na+].[Pd]>[NH2:10][C:5]1[C:6](=[O:9])[N:7]([CH3:8])[C:2]([OH:1])=[N:3][C:4]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: Cn1c(O)nc(-c2ccncc2)c([N+](=O)[O-])c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(O)nc(-c2ccncc2)c(N)c1=O
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxy-3-methyl-5-nitro-6-pyridin-4-yl-3H-pyrimidin-4-one (22.6 mmol) in 200 mL methanol and 75 mL 1N sodium hydroxide was added 50 mg Pd/C and stirred overnight under a balloon filled with hydrogen. The solvents were removed under vacuum. The solids were suspended in water and acidified to pH 5 with SN HCl. The solid was collected by filtration. M+1=219.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([NH2:24])[CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[Na+]>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]([NH:24][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CCCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 69.5 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (100 mg, 0.385 mmol) and pentylamine (336 mg, 3.85 mmol) suspended in 1-butanol (10 ml) were heated at 100° C. for 10 hours in autoclave. The reaction mixture was condensed in vacuo. To the residue was added 1N aqueous sodium hydroxide and the solution was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (83 mg, yield 70%).
Reaction SMILES: [CH3:1][C@H:2]([N:9]=[C:10]=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)[N:16]=[CH:15][N:14]=[C:13]2[NH:12][C:10]([NH:9][C@@H:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:11]
Reactant: COc1cc2c(N)ncnc2cc1OCC1CCN(C)CC1
Reactant: C[C@H](N=C=O)c1ccccc1
Product: COc1cc2c(NC(=O)N[C@@H](C)c3ccccc3)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Using an analogous procedure to that described in Example 14, (S)-(−)-α-methylbenzyl isocyanate was reacted with 4-amino-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline to give the title compound; NMR Spectrum: (CDCl3) 1.4-1.56 (m, 2H), 1.61 (d, 3H), 1.84-2.05 (m, 5H), 2.31 (s, 3H), 2.91 (d, 2H), 3.88 (s, 3H), 4.04 (d, 2H), 5.2 (m, 1H), 7.23 (d, 2H), 7.3-7.41 (m, 5H), 8.66 (s, 1H), 8.7 (s, 1H), 10.58 (s, 1H); Mass Spectrum: M+H+ 450.
Reaction SMILES: N[C@H](C(OCC)=O)CCC(OCC)=O.[NH2:15][C:16]1[NH:21][C:20]2=[N:22][CH:23]=[C:24]([CH2:25][CH2:26][CH2:27][C:28]3[CH:49]=[CH:48][C:31]([C:32]([NH:34][C@H:35]([C:43]([O:45]CC)=[O:44])[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:33])=[CH:30][CH:29]=3)[C:19]2=[C:18]([OH:50])[N:17]=1>>[NH2:15][C:16]1[NH:21][C:20]2=[N:22][CH:23]=[C:24]([CH2:25][CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH:34][C@H:35]([C:43]([OH:45])=[O:44])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:33])=[CH:48][CH:49]=3)[C:19]2=[C:18]([OH:50])[N:17]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCCc2cnc3[nH]c(N)nc(O)c2-3)cc1)C(=O)OCC
Agent: CCOC(=O)CC[C@H](N)C(=O)OCC
Product: Nc1nc(O)c2c(CCCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc-2[nH]1

Procedure:
By substituting 4-(4-carbethoxyphenyl)butanal for 3-(4-carbethoxyphenyl)propanal in the procedure of Example 1 and thereafter substituting an equivalent amount of ethyl cyanoacetate for malononitrile in Example 2, there is obtained ethyl 4-[3-(2-amino-3-carbethoxyfur-4-yl)prop-1-yl]benzoate which thereafter is treated with guanidine in free base as described above to yield ethyl 4-[3-(2-amino-4-hydroxypyrrolo[2,3-d]-pyrimidin-5-yl)prop-1-yl]benzoate. This is subjected to saponification to yield 4-[3-(2-amino-4-hydroxypyrrolo[2,3-d]pyrimidin-5-yl)prop-1-yl]benzoic acid which then is coupled with diethyl L-glutamate, and the resulting diethyl N-[4-{3-(2-amino-4-hydroxypyrrolo[2,3-d]-pyrimidin-5-yl)prop-1-yl}benzoyl]-L-glutamate is saponified to yield N-[4-(3-(2-amino-4-hydroxypyrrolo[2,3-d]pyrimidin-5-yl)prop-1-yl}benzoyl]-L-glutamic acid, m.p. 190°-193° C.
Reaction SMILES: [OH-].[K+].C([O:6][CH2:7][C:8]1[C:13]([Br:14])=[C:12]([Br:15])[C:11]([CH2:16][O:17]C(=O)C)=[C:10]([Br:21])[C:9]=1[Br:22])(=O)C>O.O1CCOCC1>[Br:14][C:13]1[C:12]([Br:15])=[C:11]([CH2:16][OH:17])[C:10]([Br:21])=[C:9]([Br:22])[C:8]=1[CH2:7][OH:6]
Reactant: CC(=O)OCc1c(Br)c(Br)c(COC(C)=O)c(Br)c1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: OCc1c(Br)c(Br)c(CO)c(Br)c1Br
Yield: 96 %

Procedure:
A solution of potassium hydroxide, 20 parts, in water, 50 parts, was added dropwise to a refluxing solution of 20 parts 2,3,5,6-tetrabromo-p-xylene-α,α'-diol diacetate, prepared as in Example III above, in p-dioxane, 200 parts. After 2 hours at reflux the mixture was cooled somewhat and the bulk of the dioxane-water removed by a rotary evaporator. Water was added to the semi-solid residue, the precipitate filtered, washed with water and air dried to give crude diol, 16.7 parts. Recrystalization from dioxane-water gave 12.2 parts 2,3,5,6-tetrabromo-p-xylene-α,α'-diol, melting at 262°-263.5° C. A second crop, 3.95 parts, melted at 260-262° C. A third crop, 0.4 parts, melted at 225°-245° C. Combining the first two crops gives a yield of 96 percent. Analysis showed the following results: Percent bromine calculated -- 70.5; found -- 71.5.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C)C=O>[N:13]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1)=[N+:14]=[N-:15]
Reactant: CC(C)(O)c1cccc(CBr)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(O)c1cccc(CN=[N+]=[N-])n1

Procedure:
2-Bromomethyl-6-(1-hydroxy-1-methylethyl)pyridine (7.61 g, 33 mmol) was dissolved in dimethylformamide (100 mL) and sodium azide (2.6 g, 39.7 mmol) added. After stirring the resultant mixture overnight at ambient temperature, the reaction was poured into dicholoromethane and washed well with water. The organic layer was dried (magnesium sulphate), filtered and concentrated to dryness. The resulting yellow oil (5.88 g, 93%) was used without further purification; NMR δH (400 MHz, CDCl3) 7.70 (1H, t, J 7.8 Hz), 7.30 (1H, d, J 8.0 Hz), 7.19 (1H, d, J 7.8 Hz), 4.82 (1H, br s), 4.42 (2H, s), 1.51 (6H, s); LC-MS Retention time 2.06 min, (M+H)+ 193.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]([OH:12])=O)[CH2:6]1)=[O:4].CN(C=O)C.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1>ClCCl>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[C:10]([C@@H:7]1[CH2:8][CH2:9][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)=[O:12]
Reactant: C[Si](C)(C)c1nccs1
Reactant: COC(=O)[C@H]1CC[C@@H](C(=O)O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@@H](C(=O)c2nccs2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1R,3S)-3-(methoxycarbonyl)cyclopentanecarboxylic acid (130 mg, 0.76 mmol) in dichloromethane (3 mL) was added DMF (5.85 μL, 0.08 mmol). The solution was cooled to 0° C. oxalyl chloride (73.0 μL, 0.83 mmol) was added. The mixture was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature for one hour. The reaction was re-cooled to 0° C., 2-(trimethylsilyl)thiazole (178.0 mL, 1.13 mmol) was added and the mixture was stirred at room temperature for two hours. The mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford (1S,3R)-methyl 3-(thiazole-2-carbonyl)cyclopentanecarboxylate. MS ESI calc'd. for C11H14NO3S [M+H]+ 240. found 240. 1H NMR (500 MHz, DMSO-d6) δ 8.21 (d, J=3.0 Hz, 1H), 8.14 (d, J=3.0 Hz, 1H), 3.58 (s, 3H), 2.96-2.89 (m, 1H), 2.27-2.20 (m, 1H), 1.74-2.04 (m, 6H)
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23](Br)[O:22][C:18]=2[N:19]=[CH:20][N:21]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[O:36][CH3:35])[O:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3OC)c(-c3ccc(OC)cc3)c12
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Add 0.45 ml of a 2 M aqueous sodium carbonate solution to a mixture of 200 mg (0.45 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 16 mg (0.02 mmol) bis(triphenylphosphine)palladium(II) chloride in 10 ml dimethylsulphoxide. Next, add 85 mg (0.56 mmol) (2-methoxyphenyl)boronic acid and stir the mixture for 15 h at 80° C. Filter the reaction mixture and purify directly by preparative RP-HPLC (gradient: water/acetonitrile). 63 mg (42% of theor.) of the desired product is obtained.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([CH:8]([CH2:11][CH2:12][CH3:13])[CH2:9]O)[CH2:6][CH3:7]>>[Br:2][CH2:9][CH:8]([CH2:11][CH2:12][CH3:13])[CH2:5][CH2:6][CH3:7]
Reactant: CCCC(CO)CCC
Reactant: BrP(Br)Br
Product: CCCC(CBr)CCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 168.4 %

Procedure:
Phosphorus tribromide (33.3 g, 0.123 mol) was added dropwise to 2-propyl-1-pentanol (40 g, 0.307 mol) at −10° C. to maintain the temperature below 0° C. and the mixture was stirred overnight at room temperature. The reaction mixture was heated at 100° C. for 1 h, cooled to room temperature, and poured into ice water (250 ml). The organic layer was separated, washed with conc. H2SO4 (25 ml) followed by saturated K2CO3 (25 ml), dried and distilled in vacuo (80° C./15 mm Hg) to furnish 40 g (83%) of 1-bromo-2-propylpentane.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[NH:14][CH:15]=[CH:16][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.[H-].[Na+].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O1CCCC1.C(OC)(C)(C)C>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:14]2[N:13]3[C:3]4[C:2]5[C:7](=[CH:8][CH:9]=[CH:10][CH:1]=5)[N:6]=[CH:5][C:4]=4[N:11]=[C:12]3[CH:16]=[CH:15]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc2c(c1)ncc1nc3cc[nH]n3c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3nc4cnc5ccccc5c4n32)cc1
Reaction time: 0.17 h
Yield: 28.2 %

Procedure:
A solution of 10H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]quinoline (1.00 g, 4.80 mmol) in tetrahydrofuran (24 mL), under a nitrogen atmosphere, was chilled in an ice-water bath. The solution was treated with NaH (0.29 g, 7.20 mmol, 60%) in small portions over 2 min. After 10 min, the mixture was treated with p-toluenesulfonyl chloride (1.01 g, 5.28 mmol), and allowed to come to ambient temperature. After 1.5 h the reaction was quenched with slow addition of water (5 mL). The reaction mixture was concentrated under reduced pressure to yield a brown solid. The solid was purified by prep. HPLC (100 g silica gel eluted with 1-10% CMA in chloroform) to give a tan foam. The foam was dissolved in methyl tert-butyl ether (25 mL) and filtered through filter paper. The filtrate was concentrated under reduced pressure to yield 0.49 g of 10-[(4-methylphenyl)sulfonyl]-10H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: [CH2:1]([S:4][C:5]1[C:6](=[O:13])[O:7][C:8]([CH3:12])=[CH:9][C:10]=1[OH:11])[CH:2]=[CH2:3].[OH:14]O>C(O)(=O)C>[CH2:1]([S:4]([C:5]1[C:6](=[O:13])[O:7][C:8]([CH3:12])=[CH:9][C:10]=1[OH:11])=[O:14])[CH:2]=[CH2:3]
Reactant: OO
Reactant: C=CCSc1c(O)cc(C)oc1=O
Solvent: CC(=O)O
Product: C=CCS(=O)c1c(O)cc(C)oc1=O
Temperature: 25 °C

Procedure:
3-Allylthio-4-hydroxy-6-methyl-2-pyrone (5.95 g., 0.0300 mol), 30% hydrogen peroxide (3.85 g., 0.0330 mol), and 40 ml. glacial acetic acid were combined and stirred over night at room temperature. The clear solution was poured into 250 ml. ice water. The aqueous mixture was extracted with clhoroform. The CHCl3 was dried (Na2SO4) and evaporated in vacuo. The recovered pink solid was recrystallized from cyclohexane-benzene to recover 5.0 g. (78 percent) of the desired compound. One additional recrystallization from cyclohexane-n-hexane gave the pure compound, m.p. 111°-112°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][C:9]=2[C:8]([NH:21][C:22](=[O:35])[CH:23]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH3:24])=[N:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH2:11][NH:12][CH2:13][C:9]=2[C:8]([NH:21][C:22](=[O:35])[CH:23]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH3:24])=[N:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1nc(NC(=O)C(C)c2ccc3ccccc3c2)c2c1CN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)n1nc(NC(=O)C(C)c2ccc3ccccc3c2)c2c1CNC2
Reaction time: 0.5 h
Yield: 101.6 %

Procedure:
2.5 g (5.2 mmol) of 3-(2-naphthalen-2-yl-propionylamino)-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester in 15 ml DCM was treated with 16 ml of (1:1) TFA/DCM. The reaction mixture was stirred for 30 min. and evaporated to dryness. The resulting residue was dissolved in DCM and the solution washed with brine and then treated with NaHCO3 aq. The obtained precipitate was filtered, washed with water and DCM, and then dried under vacuum to give 2.0 g (quantitative yield) of the title compound.