Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][C:25]([CH3:40])([C:27]([O:29]CC2C=CC([N+]([O-])=O)=CC=2)=[O:28])[CH3:26])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15](=[O:17])[NH2:16])[N:13]([S:18]([O-:21])(=[O:20])=[O:19])[C:12]2=[O:22])=[O:9])[N:6]=1.[Na+].[H][H]>O.[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][C:25]([CH3:40])([C:27]([OH:29])=[O:28])[CH3:26])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15](=[O:17])[NH2:16])[N:13]([S:18]([OH:21])(=[O:20])=[O:19])[C:12]2=[O:22])=[O:9])[N:6]=1
Reactant: [H][H]
Reactant: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1C(N)=O)c1csc(N)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1C(N)=O)c1csc(N)n1)C(=O)O
Reaction time: 0.08 h

Procedure:
In 10 ml of water is dissolved 200 mg of sodium cis-3-{2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido}-4-carbamoyl-2-oxoazetidine-1-sulfonate (syn-isomer) as obtained in Example 132C, followed by addition of 200 mg of 10% palladium-on-carbon. The mixture is stirred in a hydrogen atmosphere at room temperature for one hour. The catalyst is filtered off, and under icecooling 27 mg of sodium hydrogen carbonate is added. The mixture is stirred for 5 minutes and washed with ethyl acetate. To the aqueous layer is added 30 ml of Dowex 50W (H-form) resin, and the mixture is stirred for 1.5 hours. The resin is filtered off and the filtrate is concentrated under reduced pressure to about a half volume thereof. The residue is chromatographed on an Amberlite XAD-II (40 g) column, eluting with water and then 15% ethanol. The fractions including the desired product are combined and lyophilized to give cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-carbamoyl-2-oxoazetidine-1-sulfonic acid (syn-isomer).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1Cl)([O-:3])=[O:2].[CH:18]([NH2:22])([CH2:20][CH3:21])[CH3:19].C1(C)C=CC=CC=1>C(O)C>[CH:18]([NH:22][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH2:20][CH3:21])[CH3:19]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CCC(C)N
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
One gram of 2,6-dinitro-4-t-butylchlorobenzene was allowed to react with one gram of sec-butylamine by adding the amine dropwise to a refluxing mixture of 50 ml. dry toluene, and the 2,6-dinitro-4-t-butylchlorobenzene. After complete addition, the mixture was refluxed eight hours, cooled to room temperature, the amine hydrochloride filtered off, and toluene and unreacted amine were removed under reduced pressure. The thick material that resulted was dissolved in hot ethanol and the product was crystallized upon cooling to yield N-sec-butyl-2,6-dinitro-4-t-butylaniline melting at 60°-62° C.
Reaction SMILES: [OH:1][C:2]1([CH3:15])[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7]C(=O)OC(C)(C)C.[ClH:16].O1CCOCC1>ClCCl>[ClH:16].[NH2:7][C@H:3]1[CH2:4][CH2:5][CH2:6][C:2]1([CH3:15])[OH:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC1(C)O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(O)CCC[C@@H]1N

Procedure:
A solution of tert-butyl N-[(1S)-2-hydroxy-2-methyl-cyclopentyl]carbamate (mixture of cis and trans diastereomers) (6.66 g, 30.9 mmol), 4 M HCl in dioxane (46.4 mL, 185.6 mmol), and dichloromethane (62 mL) is stirred at room temperature for 1 h. The reaction is concentrated in vacuo, and then redissolved in MeOH and reconcentrated to give the title compound as a brown oil (5.09 g). LC-ES/MS m/z 116 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.C[O-:12].[Na+].CO>[Pd]>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:2][CH2:1][OH:12])=[CH:9][CH:8]=1
Reactant: C[O-]
Reactant: CC(=O)c1ccc(O)cc1
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Product: OCCc1ccc(O)cc1
Temperature: 45 °C

Procedure:
To a five-gallon stainless steel reactor, a solution of 4-hydroxyacetophenone (2500 g, 18.4 moles) and a 25% solution of sodium methoxide in methanol (39.1 g, 0.26 moles) in methanol (10,000 g, 312.5 moles), and palladium on carbon catalyst (ESCAT 10, 125 g) were charged. The reactor is purged three times with nitrogen (100 psi). Hydrogen is then charged to a pressure of 300 psi and the reactor is heated to 45° C. The temperature is maintained at 45° C. for three hours at a constant hydrogen pressure of 500 psi. The reactor is cooled to 30° C. and then discharged (12,245 g). The analysis of the solution gave a conversion of 97.6% and a selectivity of 96.0% (note Table 2).
Reaction SMILES: [C:1]([CH:4]([CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:5]([NH:7][CH:8]([C:10]1[C:11](=[O:27])[NH:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)=[N:14][N:15]=1)[CH3:9])=O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH:4]([C:5]1[N:15]2[C:10]([C:11](=[O:27])[NH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)=[N:14]2)=[C:8]([CH3:9])[N:7]=1)[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(Cc2nnc(C(C)NC(=O)C(CCCc3ccccc3)C(C)=O)c(=O)[nH]2)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cc2nn3c(C(CCCc4ccccc4)C(C)=O)nc(C)c3c(=O)[nH]2)cc1OC

Procedure:
Analogously to Example 1, 1.30 g (2.64 mmol) of 2-acetyl-N-{1-[3-(3,4-dimethoxy-benzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenylpentanamide and 1.65 mg (10.7 mmol) of phosphorus oxychloride are reacted to give 7-(1-acetyl-4-phenylbutyl)-2-(3,4-dimethoxybenzyl)-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][C:25](OCC)=[O:26])=[CH:17][CH:16]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:19][CH:20]=1
Reactant: CCOC(=O)CCCCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCCCO)cc1
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
A solution of ethyl 5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]valerate (2.55 g) in ether (20 ml) was added dropwise, under ice-cooling, to a suspension of lithium aluminum hydride (LiAlH4) (0.247 g) in ether (40 ml). The mixture was stirred for 15 minutes under ice-cooling, to which was added water (2 ml). Insoluble solid was filtered off, and the filtrate was concentrated to give 5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-1-pentanol (2.15 g, 94%), which was recrystallized from ethyl acetate--hexane to give colorless rods, m.p.78°-79° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1([C:26]2[NH:27][C:28]3[C:33]([C:34]=2[CH3:35])=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH2:17][C:16]([N:23]([CH3:25])[CH3:24])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:14]1.[C:36]1([N:42]=[C:43]=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(#N)C.[OH-].[Na+]>[CH2:19]([C:16]1([N:23]([CH3:25])[CH3:24])[CH2:17][CH2:18][C:13]([C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH2:3][CH2:2][NH:1][C:43]([NH:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:44])=[CH:11][CH:10]=[CH:9][CH:8]=3)([C:26]2[NH:27][C:28]3[C:33]([C:34]=2[CH3:35])=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:14][CH2:15]1)[CH2:20][CH2:21][CH3:22]
Reactant: O=C=Nc1ccccc1
Reactant: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2C)(c2[nH]c3ccccc3c2CCN)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2C)(c2[nH]c3ccccc3c2CCNC(=O)Nc2ccccc2)CC1

Procedure:
4-(3-(2-aminoethyl)-1H-indol-2-yl)-1-butyl-N,N-dimethyl-4-(3-methyl-1H-indol-2-yl)cyclohexylamine (120 mg, 0.255 mmol, mixture of the two possible diastereoisomers in a ratio of approx. 30:70) was mixed in acetonitrile (2.4 ml) with phenyl isocyanate (0.042 ml, 0.386 mmol). After a reaction time of 2 h at 24° C. the reaction mixture was diluted with 1N sodium hydroxide solution (20 ml) and extracted with dichloromethane (4×10 ml). The combined organic phases were dried with Na2SO4 and then filtered. The volatile constituents of the filtrate were completely removed in a vacuum. The residue (yellow solid, 150 mg) was purified by column chromatography [silica gel 60 (25 g); cyclohexane/ethyl acetate 2:1 (300 ml), ethyl acetate/methanol 1:1 (300 ml]. The product was obtained as a white solid with a yield of 115 mg (76%) (melting point 115-120° C., mixture of the two possible diastereoisomers in a ratio of approx. 25:75).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:38])([S:34](F)(=[O:36])=[O:35])[C:24]([F:33])([F:32])[C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27].C(OC)(C)(C)C>O>[F:29][C:26]([F:27])([F:28])[C:25]([F:30])([F:31])[C:24]([F:32])([F:33])[C:23]([F:38])([F:22])[S:34]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][N:13]=2)=[CH:16][CH:17]=1)(=[O:35])=[O:36]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCCCCCc1cnc(-c2ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Temperature: 16 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
A 12 liter flask fitted with a mechanical stirrer, a constant addition funnel, a thermometer, and a reflux condenser was charged with of 5-octyl-2-(4-hydroxyphenyl)pyrimidine (300 g, 1.05 mol), perfluorobutanesulfonyl fluoride (378 g, 1.25 mol), and tert-butylmethylether (3 L) under positive nitrogen pressure and was cooled with an ice bath to 16° C. 1,8-Diazobicyclo[5.4.0]undec-7-ene (180 g, 1.18 mol) was added to the resulting mixture over 25 minutes, while maintaining the temperature of the mixture below 20° C. After the addition was complete, the mixture was stirred at room temperature for 2 hours, and then 3 liters of water was added. The resulting aqueous phase was separated from the resulting organic phase, and the organic phase was washed with a mixture of 2.25 liters of water and 0.75 liters of concentrated HCl. The solvent was removed from the organic phase under reduced pressure to yield 697 g of crude product, which was recrystallized from ethanol to yield 4-(5-octyl pyrimidine-2-yl)phenyl nonafluorobutane sulfonate (499 g, 84% yield).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:8]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:35]([NH:38][NH2:39])(=[O:37])[CH3:36]>CN(C=O)C>[C:35]([NH:38][NH:39][C:13]([C:12]1[C:7]([NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:8]2[CH:18]=[N:17][N:16]([CH2:19][CH3:20])[C:9]2=[N:10][CH:11]=1)=[O:15])(=[O:37])[CH3:36]
Reactant: CC(=O)NN
Reactant: CCn1ncc2c(NC3CCCC3)c(C(=O)O)cnc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC3CCCC3)c(C(=O)NNC(C)=O)cnc21
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
Intermediate 3 (0.066 g), EDC (0.06 g) and HOBT (0.035 g) were suspended in DMF (2 ml) and the mixture was stirred for 15 minutes. Acetic hydrazide (0.02 g) was then added and the mixture stirred under nitrogen for 18 h. Solvents were removed by concentration in vacuo and the residue partitioned between DCM and water. The layers were separated and the organic phase was washed with saturated aqueous sodium bicarbonate solution, then concentrated and applied to an SPE cartridge (aminopropyl, 1 g) which was eluted with methanol. Concentration in vacuo afforded Intermediate 4 (0.043 g). LCMS showed MH+=331; TRET=2.38 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH:7]=1.[Cl:22][CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[Cl:22][CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH:7]=1)=[O:28]
Reactant: COc1ccc(C(=O)Nc2cc(N)ccc2C)cc1OC
Reactant: O=C(Cl)c1cccc(CCl)c1
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(CCl)c3)ccc2C)cc1OC
Yield: 87 %

Procedure:
Using an analogous procedure to that described in Example 2, N-(5-amino-2-methylphenyl)-3,4-dimethoxybenzamide was reacted with 3-(chloromethyl)benzoyl chloride to give the title compound in 87% yield; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.82 (s, 6H), 4.84 (s, 2H), 7.06 (d, 1H), 7.23 (d, 1H), 7.57 (m, 5H), 7.80 (s, 1H), 7.9 (d, 1H), 8.0 (s, 1H), 9.76 (s, 1H), 10.26 (s, 1H); Mass Spectrum: M+H+ 439.
Reaction SMILES: [CH2:1]([C:3]([CH:18]([N+:20]([O-:22])=[O:21])[CH3:19])=[CH:4][C:5](=[N:16][OH:17])[CH2:6][NH:7][C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1.C(Cl)(Cl)Cl>CC(C)=O>[CH2:1]([C:3]([CH:18]([N+:20]([O-:22])=[O:21])[CH3:19])=[CH:4][C:5](=[N:16][OH:17])[CH2:6][NH:7][C:8]([C:10]1[CH:11]=[N+:12]([O-:31])[CH:13]=[CH:14][CH:15]=1)=[O:9])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(=CC(CNC(=O)c1cccnc1)=NO)C(C)[N+](=O)[O-]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CCC(=CC(CNC(=O)c1ccc[n+]([O-])c1)=NO)C(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of N-(4-ethyl-2-hydroxyimino-5-nitro-3-hexen-1-yl)-3-pyridinecarboxamide (306 mg), 3-chloroperbenzoic acid (323 mg), chloroform (15 ml) and acetone (40 ml) was stirred at room temperature for 10 hours. The resulting precipitates were collected and washed with acetone to give N-(4-ethyl-2-hydroxyimino-5-nitro-3-hexen-1-yl)-3-pyridinecarboxamide 1-oxide.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13]([OH:15])=O)[C:10]=2[CH3:12])[S:5](=[O:18])(=[O:17])[CH2:4][CH2:3]1.[CH2:19]([N:21]1[C:25]([OH:26])=[CH:24][CH:23]=[N:22]1)[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13]([C:24]3[CH:23]=[N:22][N:21]([CH2:19][CH3:20])[C:25]=3[OH:26])=[O:15])[C:10]=2[CH3:12])[S:5](=[O:18])(=[O:17])[CH2:4][CH2:3]1
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2C
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(C)CCS3(=O)=O)c1O
Yield: 68.3 %

Procedure:
A 50-ml eggplant type flask was charged with 0.76 g (2.8 mmol) of 4,5,8-trimethylthiochroman-6-carboxylic acid-1,1-dioxide, 0.35 g (2.1 mmol, 1.1 equivalents) of 1-ethyl-5-hydroxypyrazole and 5 ml of t-amyl alcohol, and a solution of 0.70 g (3.4 mmol, 1.2 equivalents) of N,N'-dicyclohexylcarbodiimide (DCC) in 5 ml of t-amyl alcohol was added at room temperature. The mixture was allowed to react at room temperature for 2 hours, then, 0.58 g (2.8 mmol, 1.5 equivalents) of potassium carbonate was added, and the mixture was allowed to react at 100° C. for 6 hours. The solvent was distilled off, the residue was distributed into 30 ml of water and 30 ml of ethyl acetate, and a DCC urea material as an insoluble material was separated by filtration. An organic layer was extracted with 10 ml of a 5% potassium carbonate aqueous solution twice. The aqueous layers were combined and acidified with concentrated hydrochloric acid and thereafter extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate, and the solvent was distilled off to give 0.77 g of a crude product. The crude product was recrystallized from ethanol to give 0.52 g (yield 51%) of 4,5,8-trimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 44).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.[F-].[K+]>C1COCC1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:12])=[CH:3][CH:4]=1)=[O:7]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccccc2C)cc1
Yield: 91.5 %

Procedure:
Methyl 4-chlorobenzoate (172 mg, 1.01 mmol) reacted with 2-methylphenylboronic acid (210 mg, 1.54 mmol) using 1/2 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (190 mg, 3.39 mmol) in THF at 100° C. to give the title compound (209 mg, 92%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 8.13 (d, 2H, J=8.24 Hz), 7.44 (d, 2H, J=8.20 Hz), 7.33-7.25 (m, 4H), 3.98 (s, 3H), 2.30 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 166.98, 146.69, 140.79, 135.10, 130.44, 129.47, 129.36, 129.21, 128.53, 127.78, 125.85, 52.06, 20.33. GC/MS(EI): m/z 226 (M+), 195, 165, 152. Anal. Calcd for C15H14O2: C, 79.62; H, 6.24. Found C, 79.33; H, 6.26.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].[C:18]([OH:23])(=[O:22])[C:19]([CH3:21])=O.C([BH3-])#N.[Na+]>>[C:18]([CH:19]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[CH3:21])([OH:23])=[O:22]
Reactant: CC(=O)C(=O)O
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(N[C@@H](C)C(=O)N1C2CCCCC2C[C@H]1C(=O)O)C(=O)O

Procedure:
As described in Example 5, react 1 -[(S)-alanyl ]octahydroindole-2(S)-carboxylic acid (prepared as described in Example 1) and pyruvic acid with sodium cyanoborohydride to obtain the title compound.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:13][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)Cc1cc(C(=O)O)no1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(CC(C)C)on1
Yield: 85.4 %

Procedure:
To a solution of 5-isobutylisoxazole-3-carboxylic acid (1.0 g, 5.91 mmol) in a mixture of dichloromethane (18 mL) and methanol (6 mL) was added trimethylsilyldiazomethane (2.0 M in ether) (5.91 mL, 11.8 mmol) dropwise until the yellow color persisted and the bubbling ceased (˜3.9 mL was required). The solvent was removed under reduced pressure, and the residue was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a 5% mixture of ethyl acetate in hexane afforded methyl 5-isobutylisoxazole-3-carboxylate (0.925 g, 5.05 mmol, 85% yield) as a flakey, white solid. The product had an HPLC ret. time=1.83 min.−Column: (condition A); LC/MS M+1=184.1. 1H NMR (500 MHz, CDCl3) δ ppm [mixture of isobutyl rotomers] 0.96-1.00 (m, 6H), [1.94-2.03 (m, 0.1H) and 2.03-2.14 (m, 0.9H)], [2.62 (d, J=7.21 Hz, 0.2H) and 2.70 (d, J=7.21 Hz, 1.8H)], 3.96-3.99 (m, 3H), and [6.41-6.44 (m, 0.9H) and 6.80 (s, 0.1H)].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1.[Cl:14][S:15](O)(=[O:17])=[O:16]>ClCCl>[Cl:1][C:2]1[C:10]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1
Reactant: CCOc1cc(Cl)ccc1C(=O)O
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCOc1cc(Cl)c(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 5 °C

Procedure:
4-Chloro-2-ethoxybenzoic acid (9.4 g, 47 mmol) was added in several portions to cold chlorosulfonic acid (55 mL, Aldrich) stirring at 0-10° C., and the resulting solution was heated at ˜60° C. for 2 h. The resulting dark solution was poured into ice (800 g), and then 500 mL of dichloromethane was added. After stirring for 15 min, the layers were separated and the aqueous layer was extracted with 200 mL of dichloromethane. The organic layers were washed in turn with brine, combined, dried over magnesium sulfate, filtered, and concentrated at room temperature. Crystallization from ether/hexane gave 3.4 g of 4-chloro-5-chlorosulfonyl-2-ethoxybenzoic acid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH:11]2[O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]3[O:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:32]=3[CH:42]=2)=[CH:6][CH:5]=1)(O)=[O:2].[O:43]([CH2:50][CH2:51][NH2:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:41][O:40][CH2:39][CH2:38][CH2:37][N:33]1[C:32]2[CH:42]=[C:28]([CH2:27][O:26][CH:11]3[CH:10]([C:7]4[CH:6]=[CH:5][C:4]([C:1](=[O:2])[NH:52][CH2:51][CH2:50][O:43][C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)=[CH:9][CH:8]=4)[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[CH2:12]3)[CH:29]=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)O)cc3)cc21
Reactant: NCCOc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)NCCOc4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 0.36 g of benzyl 4-(4-carboxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate and 0.125 g of 2-phenoxyethylamine in 5 ml of N,N-dimethylformamide is admixed under argon with 0.172 g of 3-dimethylaminopropyl ethyl carbodiimide hydrochloride and 0.0037 g of 4-dimethylaminopyridine. The reaction solution is stirred at room temperature over 3 days, subsequently poured onto 25 ml of water and extracted with 50 ml of tert-butyl methyl ether. The organic phase is dried over potassium carbonate, filtered and concentrated. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.16 (2:1 EtOAc-heptane); Rt=5.18.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:30]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[O:20][C:21]5[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[C:4]=12>CC(C)=O>[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:30]3[CH2:34][CH2:33][NH:32][CH2:31]3)[N:10]=[C:11]([C:12]3[CH:13]=[CH:14][C:15]([NH:18][C:19]4[O:20][C:21]5[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:22]=5[N:23]=4)=[CH:16][CH:17]=3)[C:4]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCNC5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 45 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
6 N Hydrochloric acid (10 mL) was added to a solution of rac-tert-butyl 3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyrrolidinecarboxylate (1.029 g) in acetone (10 mL) and the reaction mixture was stirred at 45° C. for 5 h. The reaction mixture was filtered, and the resulting opaque filtrate was concentrated to afford an orange solid. Purification by preparative RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 20 min at 21 mL/min using a 8 μm Hypersil HS C18, 250×21 mm column, tr=6.2-7.5 min) afforded rac-N2-[4-(4-amino-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine as an off-white solid (0.148 g, 35%). 1H NMR (DMSO-d6, 400 MHz) 2.15-2.22 (m, 2H), 2.40 (s, 3H), 2.50 (s, 3H), 2.93-4.04 (m, 5H), 5.31 (m, 1H), 6.79 (s, 1H), 7.11 (s, 1H), 7.66 (d, 2H), 7.93 (d, 2H), 8.24 (s, 1H), 10.85 (s, 1H); RP-HPLC Rt 10.603 min, 99% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 441 (MH+).