Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[O:1]1[C:2]([C:10]([Cl:16])=[O:12])=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2ccccc2o1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2ccccc2o1
Reaction time: 15 h

Procedure:
A suspension of 2-benzofurancarboxylic acid (0.746 g, 4.6 mmol) in dichloromethane (3 mL) was treated with oxalyl chloride (0.700 g, 5.52 mmol) and one drop of dimethylformamide. The reaction mixture was shaken for 15 h. The solvent was removed under reduced pressure and dried under high vacuum to afford a quantitative amount of benzo[b]furan-2-carbonyl chloride. The oil was directly used in the following reaction.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(O[C:26](C)([CH3:28])[CH3:27])=O.ICCC.C(O)(C(F)(F)F)=O>>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:27][CH2:26][CH3:28])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Solvent: CCCI
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ccc(C[C@@H]2CNCCO2)cc1Cl

Procedure:
Example 58 was prepared using the same procedure as described for example 20, starting from N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a), and 1-iodopropane. The resulting intermediate was deprotected with TFA as described for example 20 to yield the desired morpholine example 58 as a colorless oil (16 mg) after purification by HPLC.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[C:10]=1[NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[O:5])C.[OH-].[Na+]>C(O)C>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([N:9]2[C:10]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1NS(=O)(=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)S(=O)(=O)Nc1c(C(=O)O)cnn1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Dissolve 1-(4-Bromo-phenyl)5-(propane-2-sulfonylamino)-1H-pyrazole-4-carboxylic acid ethyl ester (2.549 g, 6.12 mmol) in ethanol (10 mL)(denatured with methanol) and then add an aqueous solution of sodium hydroxide (12.5 mL, 2.0M). Immerse the resulting mixture into a pre-heated oil bath (65° C.) and stir overnight. Upon completion, concentrate to remove ethanol/methanol, wash the resulting aqueous mixture with dichloromethane, and concentrate to remove any trace of dichloromethane. Cool the aqueous mixture to 0° C., add 1.0 HCl until pH 4 is achieved (extensive precipitation of acid may be observed), and stir for 15 min. Filter the mixture under reduced pressure. Allow the reduced pressure to cool the filtrate, and filter a second crop of product. Combine the two crops to yield 1-(4-Bromo-phenyl)-5-(propane-2-sulfonylamino)-1H-pyrazole-4-carboxylic acid (2.031 g, 85%).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8]O>S(Cl)(Cl)=O>[ClH:1].[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][Cl:1]
Reactant: Cc1nc[nH]c1CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: Cc1nc[nH]c1CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10 g of 4-methyl-5-hydroxymethylimidazole hydrochloride in 25 ml of thionyl chloride was allowed to stir at room temperature overnight. The crystalline product was filtered, washed with chloroform and dried, 11 g.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][O:13][CH3:14])[CH:6]=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na].Cl.CO.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][O:13][CH3:14])[CH2:6][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: COCOc1ccc(C=O)cc1N(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCOc1ccc(CNc2ccccc2)cc1N(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 120.5 %

Procedure:
To a solution of Compound A (1.71 g, 8.17 mmol) in methanol (80 ml) was added dropwise aniline (1.49 ml, 16.3 mmol), and the mixture was stirred at room temperature for 15 minutes. Thereto was added sodium cianoborohydride (1.62 g, 24.5 mmol) by portions. The pH of the reaction mixture was adjusted to 7 by the addition of hydrochloric acid-methanol. After being stirred for 1 hour, the reaction mixture was poured into water and basified with sodium hydrogencarbonate. The mixture was extracted with ethyl acetate, washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated to give the title compound (1) (2.82 g) in quantative yield.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:22])[C:5]2=[N:4][C:3]=1[CH3:23].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[NH2:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:22])[C:13]=1[CH2:12][O:11][C:10]1[C:5]2[N:6]([C:2]([Br:1])=[C:3]([CH3:23])[N:4]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1nc2c(OCc3c(Cl)cccc3[N+](=O)[O-])cccn2c1Br
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc2c(OCc3c(N)cccc3Cl)cccn2c1Br
Reaction time: 0.5 h
Yield: 14.4 %

Procedure:
To a mixture of 3-bromo-8-(2-chloro-6-nitrobenzyloxy)-2-methylimidazo[1,2-a]pyridine (300 mg), nickel(II) chloride hexahydrate (360 mg) and methanol (9 ml) was added sodium borohydride (114 mg) portionwise under an ice-water bath cooling for 20 minutes. After stirring for 30 minutes, the mixture was concentrated in vacuo and diluted with water. The pH value of the mixture was adjusted to 3 and the separated crystals were collected by filtration. The crystals were dissolved in dichloromethane, and the solution was washed with saturated aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (3% solution of methanol in dichloromethane) and preparative thin-layer chromatography (3% solution of methanol in dichloromethane) followed by crystallization from diethyl ether to give 8-(2-amino-6-chlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine (40 mg).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].CN(C=O)C.I[CH2:19][C:20]1([CH3:32])[CH2:24][C:23]2[C:25]([CH3:31])=[CH:26][C:27]([CH3:30])=[C:28]([CH3:29])[C:22]=2[O:21]1.O>C(OCC)(=O)C>[CH3:19][C:20]1([CH2:32][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH2:24][C:23]2[C:25]([CH3:31])=[CH:26][C:27]([CH3:30])=[C:28]([CH3:29])[C:22]=2[O:21]1
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CI)C2
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(c1C)OC(C)(CN1C(=O)c3ccccc3C1=O)C2
Temperature: 140 °C
Reaction time: 15 h
Yield: 68.9 %

Procedure:
Potassium phthalimide (702 mg, 3.79 mmol) was added to a solution of DMF (10 mL) containing 2-(iodomethyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (1.00 g, 3.16 mmol) synthesized in Reference Example 126, and the mixture was stirred at 140° C. for 15 hours. After that, the reaction solution was cooled to room temperature, and water and ethyl acetate were added thereto to separate an organic layer. The organic layer was washed with water and saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5-75:25) to give 730 mg of the title compound (yield: 69%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:15][C:4]1[N:3]=[C:2]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1nc(Cl)c2cccc([N+](=O)[O-])c2n1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(N2CCOCC2)c2cccc([N+](=O)[O-])c2n1
Yield: 78.1 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-15, step-1 using 4-chloro-2-methyl-8-nitroquinazoline (Intermediate-27, step-2, 280 mg, 1.26 mmol), morpholine (219 mg, 2.52 mmol), and K2CO3 (521 mg, 3.78 mmol) in CH3CN (5 mL) to afford 270 mg of the title product. MS [M+H]+: 275.22.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]([CH:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:23][CH:22]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCOCC1.[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:23][CH:22]=1)[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCN(Cc3ccccc3)c3nc4ccccc4s3)cc2)S1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C1NC(=O)C(Cc2ccc(OCCN(Cc3ccccc3)c3nc4ccccc4s3)cc2)S1

Procedure:
5-(4-(2-(N-(2-Benzothiazolyl)-N-benzylamino)ethoxy) benzylidene)-2,4-thiazolidinedione (2.4 g) in dioxan (150 ml) was hydrogenated in the presence of 10% palladium-charcoal (4.8 g) for 3h. at room temperature and atmospheric pressure. A further portion of catalyst (2.4 g) was added and the hydrogenation continued for a total of 20h. The mixture was filtered through diatomaceous earth and the solvent was evaporated. The residue was chromatographed on silica gel with 3% methanol-dichloromethane as eluant to afford the title compound as a foam, which collapsed at 78° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[CH3:34][C:35]1[C:39](B2OC(C)(C)C(C)(C)O2)=[C:38]([CH3:49])[O:37][N:36]=1.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CO>[CH3:34][C:35]1[C:39]([C:2]2[N:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]3[C:10]([C:11](=[O:31])[C:12]([N:14]4[CH2:19][CH2:18][N:17]([C:20]5[N:24]([C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=6)[N:23]=[N:22][N:21]=5)[CH2:16][CH2:15]4)=[O:13])=[CH:9][NH:8][C:7]=23)=[C:38]([CH3:49])[O:37][N:36]=1
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1cnc(-c2c(C)noc2C)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Temperature: 115 °C
Yield: 54.3 %

Procedure:
Compounds 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (100 mg, 0.195 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole, 1,1′-Bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (16.06 mg, 0.020 mmol) and Cesium carbonate (127 mg, 0.390 mmol) were combined in Dioxane (2 mL) and Water (0.5 mL). The mixture was heated at 115° C. for 2 hours. After cooling to rt, the mixture was diluted with 10 ml of MeOH and filtered. The filtration was concentrated and purified by HPLC to give 1-(7-(3,5-dimethylisoxazol-4-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (56 mg, 0.106 mmol, 54.3% yield). LCMS: m/e 529.3 (M+H)+, ret time 1.03 min. 1H NMR (500 MHz, MeOD) δ ppm 8.65 (s, 1H) 8.62-8.64 (m, J=4.88 Hz, 1H) 8.23 (s, 1H) 8.08-8.13 (m, 1H) 7.84 (d, J=8.24 Hz, 1H) 7.55-7.60 (m, J=6.71, 4.88 Hz, 1H) 4.15 (s, 3H) 3.87-3.90 (m, 2H) 3.66-3.69 (m, 2H) 3.44-3.54 (m, 4H) 2.41 (s, 3H) 2.22 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])=[CH:6][CH:5]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(/C=C/C(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCC(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A 500 mL round-bottomed flask equipped with a stirrer was charged with 4-[(E)-3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propenyl]-benzoic acid methyl ester (5.5 g, 14.0 mmol) and ethyl acetate (100 mL). The resulting mixture was stirred under a hydrogen atmosphere for 1 h. At this time, the catalyst was removed by filtration and washed with ethyl acetate. The filtrates were concentrated in vacuo to afford 4-[3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propyl]-benzoic acid methyl ester (5.5 g, 99.5%) as a gummy solid. This material was used without further purification.
Reaction SMILES: Br.[O:2]1[CH2:7][CH2:6][N:5]([C:8]([NH2:10])=[NH:9])[CH2:4][CH2:3]1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:10]=[C:8]([N:5]2[CH2:6][CH2:7][O:2][CH2:3][CH2:4]2)[N:9]=1
Reactant: N=C(N)N1CCOCC1
Reactant: SC(Cl)(Cl)Cl
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(N2CCOCC2)ns1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
To a solution of morpholinoformamidine hydrobromide (2.00 g, 9.52 mmol) and perchloromethyl mercaptan (1.02 ml, 9.52 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.52 g, 38.1 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give 1.07 g (54.6%) of the desired product as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccc(Cl)cc2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (1 g, 5 mmol) and triethylamine (1.05 mL, 7.5 mmol) in THF (30 mL) at 0° C. was slowly added 4-chloro-benzoyl chloride (0.77 mL, 6 mmol). The reaction mixture was stirred from 0° C. to room temperature for 2 hours. The reaction mixture was diluted with CH2Cl2 and washed with water (3 times) and brine. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the titled compound. MS (DCI) m/z 339 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[CH2:29]([NH2:38])[CH2:30][N:31]([CH2:35][CH2:36][NH2:37])[CH2:32][CH2:33][NH2:34].[CH3:39][P:40]([NH2:43])(=[O:42])[O-:41].[N:44]1([C:49]([NH2:51])=[NH:50])C=CC=N1.Cl.C(N(C(C)C)CC)(C)C>CN(C=O)C.ClCCl>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1].[CH2:29]([NH2:38])[CH2:30][N:31]([CH2:35][CH2:36][NH2:37])[CH2:32][CH2:33][NH2:34].[CH3:39][P:40]([NH2:43])(=[O:41])[O-:42].[NH2:50][C:49]([NH2:51])=[NH2+:44].[NH2:50][C:49]([NH2:51])=[NH2+:44]
Reactant: N=C(N)n1cccn1
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CP(N)(=O)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(N)=[NH2+]
Reaction time: 8 h

Procedure:
Compound (18) (0.148 g, 0.25 mmol) was dissolved in anhydrous DMF (1.0 ml) and anhydrous dichoromethane (5.0 ml). 1-H-pyrazole-1carboxarnidine.HCl (73 mg, 0.50 mmol) was added to the reaction mixture followed by diisopropylethylamine (87 ml, 0.50 mmol). Dichloromethane was stripped off of the reaction mixture on a rotovap then rotation continued overnight without vacuum at room temperature. After removing DMF in vacuo the reaction residue was dissolved in dichloromethane and applied to a flash silica gel column. A gradient of 5 to 20% MeOH/dichloromethane with 0.5 to 2% NH4OH followed by treatment with Dowex OH− (300 mg) in MeOH gave pure (19): 0.11 g, 65%, 31P NMR (d, 33.83 ppm), mass spec. calcd=676.97. Found=677.54.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].Br[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[Cu]=O>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([OH:12])=[O:11])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CC(C)c1ccc(Br)cc1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(-n2c(C(=O)O)cc3ccccc32)cc1

Procedure:
A suspension of 128.8 g (0.8 mol) of 1H-indole-2-carboxylic acid, of 159.2 g (0.8 mol) of 4-bromocumene, of 111.6 g (0.808 mol) of potassium carbonate and of 8 g (0.1 mol) of copper oxide in 200 ml of dimethylformamide is stirred at reflux for 24 hours. After cooling, 6 l of water are added to the beige suspension obtained. The suspension is filtered and then the insoluble material is taken up in 1 l of a 5N hydrochloric acid solution. This mixture is extracted with 500 ml of dichloromethane. The organic phase is washed with water, dried over sodium sulfate and then concentrated under reduced pressure. After drying under reduced pressure, 204.4 g of a white solid are obtained, which solid is used as is in the following stage.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:11]1([S:14](Cl)(=[O:16])=[O:15])[CH2:13][CH2:12]1.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][S:14]([CH:11]2[CH2:13][CH2:12]2)(=[O:16])=[O:15])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1N
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ncc(Br)cc1NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
5-Bromo-2-(methyloxy)-3-pyridinamine (1.05 g, 5.17 mmol, available from Asymchem) was dissolved in pyridine (10 ml) and cyclopropanesulfonyl chloride (1.818 g, 12.93 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight, then acidified to ca. pH 2 with 2M HCl (aq) and extracted into DCM. The DCM was passed through a hydrophobic frit and the filtrate was evaporated to dryness to afford the title compound (1.48 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16](Br)=[N:15][C:14]2[C:9]1=[N:10][C:11]([Cl:19])=[N:12][C:13]=2[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:24])CCC>Cl>[NH2:18][C:13]1[N:12]=[C:11]([Cl:19])[N:10]=[C:9]2[C:14]=1[NH:15][C:16](=[O:24])[N:8]2[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCO
Reactant: Nc1nc(Cl)nc2c1nc(Br)n2Cc1ccccc1
Agent: Cl
Product: Nc1nc(Cl)nc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 25 °C
Yield: 94 %

Procedure:
The product from Step 3 (2 g, 5.9 mmol) was suspended in 12 N HCl (35 mL) and n-butanol (35 mL) and the mixture heated at 100° C. for 7 h and then allowed to cool to room temperature. The reaction mixture was evaporated to dryness in vacuo, and then partitioned between 2 N NaOH (50 mL) and dichloromethane (50 mL). The organic layer was separated and found to contain some unreacted starting material only and was discarded, while the aqueous layer was neutralized with concentrated HCl and the resulting precipitate collected by filtration and washed with ethyl acetate to give 6-amino-9-benzyl-2-chloro-7,9-dihydro-purin-8-one as an off-white solid (1.5 g, 94%) which was found to be >90% pure and was used with no further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][NH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][CH2:16][CH2:17][CH2:18]I.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[CH2:18][CH2:17][CH2:16][Cl:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCI
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CC1CN2CCCCl
Temperature: 50 °C
Yield: 69.1 %

Procedure:
To a solution of 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.10 g, 0.50 mmol) in acetone (2 mL) was added 1-chloro-3-iodo-propane (0.10 g, 0.50 mmol, 1 eq) and K2CO3 (0.084 g, 0.60 mmol, 1.2 eq). The mixture was heated at 50° C. for 3 h and then cooled to r.t. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. Chromatography on silica gel by eluting with 5% MeOH/CH2Cl2 gave 0.095 g (69%) of 5-(3-chloro-propyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a yellowish oil. 1H NMR (300 MHz, CDCl3): δ 4.20 (m, 1H), 3.58 (m, 2H), 3.46 (m, 2H), 3.12 (m, 1H), 2.86 (m, 1H), 2.62 (m, 3H), 1.82 (m, 3H), 1.66 (m, 1H), 1.41 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:6][C@@H:5]([C@H:7]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:8]([O:10]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[C:4](=[O:26])[O:3]1.ONC(=O)[C@@H](O)[C@@H](C(N1CCN(C2C=CC=CN=2)CC1)=O)CC(C)C.C(N(CC)CC)C.[CH3:60][C@H:61]1[NH:66][CH2:65][CH2:64][N:63]([C:67]2[CH:72]=[C:71]([C:73]([F:76])([F:75])[F:74])[CH:70]=[CH:69][N:68]=2)[CH2:62]1>CN(C=O)C>[CH3:27][C:2]1([CH3:1])[O:3][C:4](=[O:26])[C@H:5]([C@@H:7]([C:8]([N:66]2[CH2:65][CH2:64][N:63]([C:67]3[CH:72]=[C:71]([C:73]([F:76])([F:74])[F:75])[CH:70]=[CH:69][N:68]=3)[CH2:62][C@H:61]2[CH3:60])=[O:10])[CH2:22][CH:23]([CH3:24])[CH3:25])[O:6]1
Reactant: C[C@@H]1CN(c2cc(C(F)(F)F)ccn2)CCN1
Reactant: CC(C)C[C@H](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)[C@@H]1OC(C)(C)OC1=O
Agent: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@H](O)C(=O)NO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](C(=O)N1CCN(c2cc(C(F)(F)F)ccn2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O

Procedure:
To a 55/45 diastereoisomeric mixture of pentafluorophenyl (2S)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate and pentafluorophenyl (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate (Intermediate 1, 484.8 mg; 1.22 mmol; 1.0 eq.) and triethylamine (339.13 μl; 2.45 mmol; 2.0 eq.) in DMF (10.0 mL) was added (3R)-3-methyl-1-[4-(trifluoromethyl)pyridin-2-yl]piperazine (Intermediate 9, 300 mg; 1.22 mmol; 1.0 eq.). After 14 h of reaction at RT, the solvent was evaporated and the residue dissolved in ether and extracted with water (3×). The combined organic layers were dried and evaporated to give an oil. This residue was purified by chromatography to give the title product (170 mg; 30.4% as a mixture of 2 diastereoisomers). M+(ESI): 458.4. HPLC (Condition A): Rt: 4.1 min (HPLC purity: 91.8%).