Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:12][C@@H:13]1[CH2:18][CH2:17][C@H:16](O)[CH2:15][CH2:14]1>>[CH3:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:14]1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: C[C@H]1CC[C@@H](O)CC1
Product: CCOC(=O)/C(=N\O[C@H]1CC[C@H](C)CC1)C(C)=O

Procedure:
Ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (3.0 g) was reacted with cis-4-methylcyclohexanol as described in Example 4a, Method 3, to give the title compound as a colourless liquid (1.2 g, 25%), νmax (film) 2950, 1745, 1695 cm-1, δH (CDCl3) 0.91 (3H, d), 1.02 (2H, m), 1.32 (3H, t), 1.41 (3H, m), 1.78 (2H, m), 2.10 (2H, m), 2.39 (3H, s), 4.20 (1H, m), 4.34 (2H, q); δC (CDCl3) 14.1, 21.7, 25.1, 31.2 (2C), 31.7, 32.9 (2C), 61.8, 85.2, 149.9, 161.5, 193.0.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:16]([NH:18][C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:39])[NH:28][S:29]([CH2:32][CH2:33][CH2:34][O:35]C(=O)C)(=[O:31])=[O:30])=[CH:23][CH:22]=3)[CH3:20])=[O:17])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+].Cl>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:16]([NH:18][C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:39])[NH:28][S:29]([CH2:32][CH2:33][CH2:34][OH:35])(=[O:31])=[O:30])=[CH:23][CH:22]=3)[CH3:20])=[O:17])[CH:9]=[CH:8]2)=[CH:40][CH:41]=1
Reactant: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(Cc4ccc(Cl)cc4)c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)c1cccc2ccn(Cc3ccc(Cl)cc3)c12)c1ccc(C(=O)NS(=O)(=O)CCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a mixture of 1-(4-chlorobenzyl)-N-[(1S)-1-(4-{[(3-acetoxypropyl)sulfonyl]carbamoyl}phenyl)ethyl]-1H-indole-7-carboxamide (200 mg), THF (3 mL), and methanol (3 mL) was added a 1 M aqueous sodium hydroxide solution (1.7 mL), followed by stirring at room temperature overnight. The reaction mixture was adjusted to pH 4 by adding 1 M hydrochloric acid (1.7 mL), and further, water (20 mL) was added thereto, followed by stirring at room temperature for 30 minutes. The precipitated solid was collected by filtration, washed with water (4 mL), and then washed with cold ethanol (3 mL) to obtain 1-(4-chlorobenzyl)-N-[(1S)-1-(4-{[(3-hydroxypropyl)sulfonyl]carbamoyl}phenyl)ethyl]-1H-indole-7-carboxamide (80 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:30][CH2:31][CH3:32])[N:4]=[C:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.C([Li])(C)(C)C.[O:38]1[CH2:43][CH2:42][C:41](=[O:44])[CH2:40][CH2:39]1.[Cl-].[NH4+]>O1CCCC1.CCCCC>[NH2:15][C:6]1[C:5]2=[N:4][N:3]([CH2:30][CH2:31][CH3:32])[C:2]([CH2:1][C:41]3([OH:44])[CH2:42][CH2:43][O:38][CH2:39][CH2:40]3)=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1C
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCOCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
A solution of di(tert-butyl) 1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (1.32 g, 3.00 mmol) in anhydrous tetrahydrofuran (THF) (30 mL) was cooled to −78° C. under an argon atmosphere. tert-Butyllithium (4.4 mL of a 1.7 M solution in pentane) was added over a period of five minutes, and the resulting dark-colored solution was stirred at −78° C. for 30 minutes. Tetrahydro-4H-pyran-4-one (901 mg, 9.0 mmol) was added, and reaction mixture was stirred for 10 minutes. The −78° C. bath was replaced with a 0° C. bath, and then saturated aqueous ammonium chloride (30 mL) was added. The aqueous layer was separated and extracted three times with tert-butyl methyl ether, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (1.3 g) was purified by automated flash chromatography (eluting with ethyl acetate) and heated in refluxing 1 M hydrogen chloride in ethanol (50 mL) for one hour. The solution was allowed to cool to room temperature and then made basic with the addition of 2 M aqueous sodium carbonate. The resulting solution was extracted four times with chloroform, and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (1.2 g) was purified by automated flash chromatography and recrystallized from acetonitrile to provide 430 mg of 4-[(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as a white solid, mp 209-211° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:3]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:38]1[CH2:42]OC[CH2:39]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:3]=1[CH:23]([CH2:39][CH2:38][CH3:42])[C:24]([O:26][CH3:27])=[O:25]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1Cc1ccc(OC)cc1)CCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1Cc1ccc(OC)cc1)CCC3

Procedure:
This compound was prepared according to the procedure C from Methyl [2-methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.245 g; 0.667 mmol), LHMDS 1N in THF (0.733 mL; 0.733 mmol), 1-iodopropane (0.098 mL; 1.000 mmol) in DMF (2.6 mL) for 18 h.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].Br[CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1>CN(C=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1
Reactant: BrCCOC1CCCCO1
Reactant: Oc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccccc1OCCOC1CCCCO1
Reaction time: 1 h
Yield: 79.8 %

Procedure:
Add 2-bromo-phenol (10 g, 57.80 mmol) to a suspension of sodium hydride (60% dispersion in mineral oil, 2.77 g, 69.36 mmol) in DMF (6 mL). Stir the mixture for 1 h. Add 2-(2-bromo-ethoxy)-tetrahydropyran (13.54 g, 64.74 mmol). Stir the solution at RT overnight. Dilute the mixture with ethyl acetate and water. Wash the organic layer with aqueous saturated sodium chloride and water. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (10% ethyl acetate in hexane) to give the title compound (13.9 g, 80%) as a light yellow oil. MS (ES) m/z 323 [M+Na]+.
Reaction SMILES: C1C(C(O)CCCN2CC3C4C=C(F)C=CC=4N(C4C=CC(F)=CC=4)C=3CC2)=CC=C(F)C=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1.[C:43]([N:48]1[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]1)([O:45][CH2:46][CH3:47])=[O:44]>>[F:34][C:35]1[CH:40]=[CH:39][C:38]2[NH:41][C:51]3[CH2:52][CH2:53][N:48]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:49][C:50]=3[C:37]=2[CH:36]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: NNc1ccc(F)cc1
Agent: OC(CCCN1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1)c1ccc(F)cc1
Product: CCOC(=O)N1CCc2[nH]c3ccc(F)cc3c2C1

Procedure:
Plattner et al. and Harbert et al. also describe the earliest synthesis of flutroline: p-Fluorophenylhydrazine is condensed with N-carbethoxy-4-piperidone to form 8-fluoro-2-carbethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. By the Ulmann reaction the latter is arylated to form the 5-(p-fluorophenyl) derivative and then hydrolyzed under vigorous basic conditions to yield 8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. The synthesis of flutroline is completed by 2-alkylation with 3-(p-fluorobenzoyl)propyl chloride and finally reduction of the ketone group to an alcohol group.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:12]C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[OH-].[Na+]>[CH2:1]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(NCc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(NCc1ccccc1)c1ccccc1
Yield: 99.9 %

Procedure:
A solution of methyl 2-(benzylamino)-2-phenylacetate (1.00 g, 3.90 mmol) in THF (90 mL) and 1N NaOH (10 mL) is stirred at room temperature overnight (LC-MS monitoring: complete conversion). The solvent is removed under reduced pressure and the crude is portioned between EtOAc and water. The aqueous phase is acidified with conc. HCl (pH about 3) and then extracted with EtOAc (three times). The organic phase is dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a white solid (940 mg, quantitative yield), which is used in the next step without any further purification.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[N:14]=[C:15]([S:25][CH3:26])[N:16]=[N:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH3:12][C:13]1[N:14]=[C:15]([S:25]([CH3:26])=[O:9])[N:16]=[N:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Solvent: ClC(Cl)Cl
Product: Cc1nc(S(C)=O)nnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
m-Chloroperbenzoic acid (20 g) was added to a stirred solution of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (20 g) in chloroform (600 ml) under ice cooling, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, and then concentrated. The resulting residue was crystallized with diethyl ether, and the crystals were collected by filtration, washed with diethyl ether and dried to give 5-methyl-3-methylsulfinyl-6-phenyl-1,2,4-triazine (19.0 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C=O)C.O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CSc1ccc(NS(C)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(N(CC(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.1 %

Procedure:
N-(4-(methylthio)phenyl)methanesulfonamide (200 mg, 0.920 mmol) was dissolved in DMF (3 ml). K2CO3 (254 mg, 1.841 mmol) and tert-butyl 2-bromoacetate (359 mg, 1.841 mmol) were added, and the reaction was stirred at RT for 4 hours. The reaction mixture was diluted with water and filtered. The precipitate was dissolved in EtOAc and extracted with water and HCl 1M, dried over Na2SO4 and concentrated under vacuum to give tert-butyl 2-(N-(4-(methylthio)phenyl)methylsulfonamido)acetate (220 mg, 72.1% yield).
Reaction SMILES: C[Al](C)C.[NH2:5][CH2:6][CH2:7][CH2:8][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:10]([C:12](OC)=[O:13])[CH3:11]>ClCCl>[CH3:11][C@@H:10]1[C:12](=[O:13])[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: COC(=O)[C@@H](C)N(CCCN)C(=O)OC(C)(C)C
Agent: C[Al](C)C
Solvent: ClCCl
Product: C[C@@H]1C(=O)NCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a 2M solution of trimethylaluminum in dichloromethane (30 mL) was added slowly a solution of methyl N-(3-aminopropyl)-N-(tert-butoxycarbonyl)-D-alaninate (11.5 g) in dichloromethane. The reaction mixture was stirred at room temperature for four days and then poured into a flask containing 30 g of Celite. The mixture was stirred and quenched by the slow addition of ˜10 mL of saturated aqueous ammonium chloride solution. Sodium sulfate (20 g) and methanol (50 mL) were added. The mixture was stirred for 1 h, then filtered. The solids were washed with 5% methanol/dichloromethane. The filtrate was concentrated. The residue was purified by flash chromatography (silica gel, eluting sequentially with 4, 6, 7 and 12% of 10:1 methanol/aqueous concentrated ammonium hydroxide in dichloromethane) to provide the title compound containing less than 3% of the (3S)-isomer.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:3]=1[C:4]#[N:5].CS(O)(=O)=[O:16].ClCCl.Cl>O>[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:3]=1[C:4]([NH2:5])=[O:16]
Reactant: COc1cc(N)c(C#N)c(OC)c1
Reactant: CS(=O)(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(N)c(C(N)=O)c(OC)c1
Temperature: 107.5 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
2-amino-4,6-dimethoxybenzonitrile (50.0 g, 0.2805 mol, 1 eq.) was charged to a 3-L glass vessel under N2 atmosphere and agitation was started. Methanesulfonic acid (537 mL, 8.29 mol, 29.5 eq.) was charged to the vessel and the reaction was heated at 100-115° C. for 1-2 hours. Upon verification of reaction completion by HPLC, the batch was cooled to 20-30° C. Upon cooling, dichloromethane (334 mL) and cool water (807 mL) (5-10° C.) was added to keep the temperature in the range of 10-30° C. 50% caustic (423 mL) was charged to the vessel using an addition funnel while maintaining 0-30° C. Fine pH adjustment to 6.5 to 7.5 was completed using either 32% HCl or 50% caustic, or diluted solutions thereof. Upon equilibration, the first organic phase cut was performed. The aqueous layer was extracted two additional times with DCM (371 mL and 286 mL respectively). Dichloromethane (271 mL) was added to the combined organic layers and the organic layer was washed with water (714 mL) to remove methanesulfonate salts. Dichloromethane (79 mL) was added to the combined organic layers and the organic layer was washed once more with water (714 mL) to remove methanesulfonate salts. The batch was distilled using (5-10 inches Hg) vacuum to a pot volume of 6 volumes DCM (300 mL). Solvent exchange with isopropyl acetate (2 exchanges of 402 mL and 484 mL respectively) was completed when less than 1-2% DCM remained and the pot volume was between 400-450 mL. The contents of the vessel were stirred for 1 hour at 85-90° C. The vessel was cooled to 50° C. over at least 2 hours with slow agitation. The vessel was slowly charged with MtBE (250 mL) and the batch was agitated for 30 min at 50° C. The batch was slowly cooled to 30° C. over at least 1 hour. The batch was cooled to −5° C. and 5° C. over at least 2 hours. The batch was held between −5° C. and 5° C. over at least 1 hour. Precipitation was verified through collection of at least two samples from the liquor to determine the amount of 2-amino-4,6-dimethoxybenzamide remaining in solution. The batch was isolated by filtration and the wet cake washed with cold (0° C.) MtBE (100 mL). The 2-amino-4,6-dimethoxybenzamide wet cake was dried in a vacuum oven (40-45 C, 25 inches Hg) to give 2-amino-4,6-dimethoxybenzamide (42.79 g, 0.218 mol, 77.7% yield; 54.5% yield over 5 steps from 3,5-dimethoxyaniline). Variations of the volumes of solvent used during extraction and the precipitation portions in this example may give improved or reduced yield and/or purity. One skilled in the art may modify these conditions for the desired result.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:23]([O:24]C)=[CH:22][C:10]2[S:11][C:12]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:13][C:9]=2[CH:8]=1.O>ClCCl>[OH:6][C:7]1[C:23]([OH:24])=[CH:22][C:10]2[S:11][C:12]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:13][C:9]=2[CH:8]=1
Reactant: COc1cc2cc(C3=NNC(=O)CC3C)sc2cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC1CC(=O)NN=C1c1cc2cc(O)c(O)cc2s1
Yield: 93.7 %

Procedure:
Boron tribromide (1.55 ml) was added to a stirred solution of 4,5-dihydro-6-(5,6-dimethoxy-benzo[b]thien-2-yl)-5-methyl-3(2H)-pyridazinone (1.14 g) in dichloromethane (200 ml). After 2 hours the orange solution was cooled in ice, and water (40 ml) was added. The dichloromethane was then evaporated off under reduced pressure and the residual suspension was filtered to give 4,5-dihydro-6-(5,6-dihydroxy-benzo[b]thien-2-yl)-5-methyl-3(2H)-pyridazinone (0.97 g) as a yellow solid. Crystallisation from dichloromethane:methanol and diethylether gave 4,5-dihydro-6-(5,6-dihydroxybenzo[b]thien-2-yl)-5-methyl-3(2H)-pyridazinone. m.p. >270° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:8]([CH3:17])=[CH:7][C:6]=1[NH:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[C:27]([CH3:28])[C:22]2=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=1)([CH3:3])[CH3:2].[CH3:42]C(O)=O.C=O.[NH4+].[Cl-]>CO.C1COCC1>[CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:42])[CH2:13][CH2:12]2)[C:8]([CH3:17])=[CH:7][C:6]=1[NH:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[C:27]([CH3:28])[C:22]2=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Agent: C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (39 mg, 0.067 mmol) in 5.0 mL of MeOH and 5.0 mL of THF was added drops of AcOH and HCHO [1N in MeOH and THF (v/v: 1/1), 0.12 mmol, 120 μL] sequentially. The reaction mixture was stirred at room temperature for 30 min, then NaB(CN)H3 (6.6 mg, 0.12 mmol) was added and the reaction mixture was stirred for another 1 h. Saturated aqueous NH4Cl was added to the reaction and the reaction mixture was concentrated in vacuo. The crude was partitioned between EtOAc and brine. The organic extracts were concentrated and purified by RP-HPLC to afford N6-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine. MS (ES+): 592.3 (MH+).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]([NH2:10])=[O:9])=[CH:5][CH:4]=[C:3]([OH:11])[CH:2]=1.C1(C)C=CC(S(O[CH2:22][C@H:23]2[O:25][CH2:24]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:11][CH2:22][CH:23]2[O:25][CH2:24]2)=[CH:2][CH:1]=1)(=[O:9])[NH2:10]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: NC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)Cc1ccc(OCC2CO2)cc1
Reaction time: 30 h

Procedure:
P-Hydroxyphenylacetamide (1 g) and (S)-glycidyl p-toluenesulfonate (1.51 g, 99.3% e.e.) were dissolved in acetone (30 ml). Potassium carbonate (1.19 g) was added to the solution and stirred for 30 hours under refluxing. After the reaction, inorganic materials were filtered off and acetone was removed to give 1.43 g of crude (S)-1-[p-(carbamoylmethyl)phenoxy-2,3-epoxypropane. Then, crude (S)-1-[p-(carbamoylmethyl)phenoxy-2,3-epoxypropane (1.43 g) was dissolved in methanol (8 ml). The solution was dropped in isopropylamine (6.8 g) under cooling to 10° C. over a period of 1 hour and the reaction temperature was raised to room temperature and stirred for 7 hours. After the reaction, the mixture was condensed in vacuo until crystals beginning to separate, cooled, filtrated by suction and dried in vacuo to give crude (S)-atenolol (1.29 g). The optical purity of it was 62.8% e.e. by measurement of Chiral column OD (Daisel Chemical industries Ltd.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:29])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:5]([Cl:29])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a mixture of 50.0 g of product from Example 37 in 700 ml of chloroform and 10 drops of dimethylformamide is added, dropwise, 25.8 g of oxalyl chloride. The reaction is stirred at room temperature for 18 hours and concentrated in vacuo. The residue is dissolved in diethyl ether, filtered and concentrated in vacuo to give 51.1 g of the desired product as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:33][C:34]1([CH3:37])[CH2:36][O:35]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:33][C:34]([OH:35])([CH3:37])[CH3:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC1(C)CO1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CC(C)(C)O)CC4)cn3)nc2n1C1CCCC1
Yield: 29.2 %

Procedure:
Following General Procedure E, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 0.115 mmol) and 2,2-dimethyloxirane (72 mg, 0.805 mmol) gave 7-cyclopentyl-2-{5-[4-(2-hydroxy-2-methyl-propyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (17 mg, 29%). MS (ESI) m/z 507.3 (M+H)+
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10](=[O:17])[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CC(CC)=O>[CH2:25]([N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=1)=[O:17])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: COc1cccc(C(=O)CC2CCCN2)c1
Reactant: CCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCN1CCCC1CC(=O)c1cccc(OC)c1

Procedure:
5.11 g of 1-(3-methoxyphenyl)-2-(2-pyrrolidinyl)-ethanone hydrochloride, 5.6 g of anhydrous potassium carbonate, 3.7 g of 1-bromohexane and 60 ml of ethyl methyl ketone are heated under reflux for 18 hours. The solvent is distilled off, the residue is taken up with 50 ml of water and extraction is effected twice with, in each case, 50 ml of diethyl ether. After drying over sodium sulfate, the united organic phases are concentrated to an oil, which is distilled under a high vacuum to obtain 5.0 g (82% of theory) of the title compound: b.p. 138° to 144° at 0.005 mm Hg.