Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])[C:8]=3[C:4]=2[CH:3]=1.[N:22]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:19][O:18][CH2:17][CH2:16][O:15][C:9]1[C:8]2[C:4]3[CH:3]=[C:2]([C:32]4[CH:31]=[CH:30][C:29]([CH2:28][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:34][CH:33]=4)[CH:21]=[N:20][C:5]=3[NH:6][C:7]=2[CH:12]=[N:11][C:10]=1[C:13]#[N:14]
Reactant: OB(O)c1ccc(CN2CCCCC2)cc1
Reactant: COCCOc1c(C#N)ncc2[nH]c3ncc(Br)cc3c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COCCOc1c(C#N)ncc2[nH]c3ncc(-c4ccc(CN5CCCCC5)cc4)cc3c12
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 31.7 %

Procedure:
A degassed mixture of 3-bromo-5-(2-methoxy-ethoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (50 mg, 0.10 mmol), 4-piperidin-1-ylmethylphenyl boronic acid (31 mg, 0.14 mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (9 mg, 0.012 mmol) in 2N aqueous sodium carbonate solution (0.42 mL) and acetonitrile (0.53 mL) were heated under microwave irradiation at 140° C. for 30 minutes. The reaction mixture was diluted with water (2 mL) and extracted with 10% MeOH in DCM. The combined organic phase was concentrated in vacuo and the resultant residue was purified by flash chromatography (silica, 500 mg column, Si-SPE, 0-20% methanol in DCM). The resultant residue was dissolved in a solution of 0.15M potassium hydroxide in methanol (7 mL) and stirred for 45 minutes. 1N Potassium dihydrogen phosphate (1 mL) was added then the mixture concentrated in vacuo. The resultant residue was diluted with water and the pH adjusted to 7 by the addition of 1N potassium dihydrogen phosphate. The aqueous phase was extracted with DCM (3×10 mL) and 20% ethanol in DCM (10 mL), the combined organic phase was dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography (silica, 500 mg column, Si-SPE, 2-4% methanol in DCM) and trituration with acetonitrile to afford the title compound as a brown solid (14 mg, 32%). 1H NMR (CDCl3, 300 MHz): 9.91 (s, 1H), 9.09 (d, J=2.2 Hz, 1H), 8.93 (d, J=2.2 Hz, 1H), 8.80 (s, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 4.75-4.69 (m, 2H), 3.95-3.89 (m, 2H), 3.58 (s, 2H), 3.47 (s, 3H), 2.51-2.37 (m, 4H), 1.68-1.54 (m, 4H), 1.52-1.41 (m, 2H). LCMS (Method A): RT=6.27 min, M+H+=442.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:10](=[O:26])[N:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][N:15]=[C:14](Cl)[N:13]=1.[CH3:27][N:28]([CH3:39])[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.FC(F)(F)C(O)=O>C(O)(C)C>[CH3:27][N:28]([CH3:39])[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:14]2[N:13]=[C:12]([N:11]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:10](=[O:26])[O:9][C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=3[CH3:8])[CH:17]=[CH:16][N:15]=2)=[CH:34][CH:33]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: Cc1cccc(C)c1OC(=O)N(Cc1ccccc1)c1ccnc(Cl)n1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C)c1OC(=O)N(Cc1ccccc1)c1ccnc(Nc2ccc(OCCN(C)C)cc2)n1
Temperature: 100 °C

Procedure:
A resealable tube was charged with the benzyl-(2-chloropyrimidin-4-yl)carbamic acid 2,6-dimethylphenyl ester (0.093 g, 0.253 mmol), 4-(2-dimethylaminoethoxy)-phenylamine (0.050 g, 0.278 mmol), and isopropanol (4 mL). Trifluoroacetic acid (0.072 g, 0.049 mL, 0.633 mmol) was added and the system was flushed with argon. The tube was sealed and the mixture was heated at 100° C. for 20 h. The reaction mixture was cooled to room temperature and concentrated to afford a pale purple oil. The oil was purified via column chromatography (gradient elution with 0-100% dichloromethane-(90: 10:1, dichloromethane/methanol/ammonium hydroxide)) to afford 2,6-dimethylphenyl 2-((4-((2-(dimethylamino)ethyl)oxy)phenyl)amino)-4-pyrimidinyl(phenylmethyl)carbamate as a white solid. MS (MH+) 512.3; Calculated 511.62 for C30H33N5O3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].C(N(CC)CC)C.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:6])[CH2:4][NH:5][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[Cl:14]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COC(=O)CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CNC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Amino-acetic acid methyl ester (5 g, 40 mmol) was suspended in DMF and treated with triethylamine (13.9 mL, 100 mmol) and 2-chloro-benzoyl chloride (5 mL, 40 mmol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction, and the mixture was extracted with ethyl acetate three times. The organic layers were combined and dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography using ethyl acetate/hexane to yield (2-chloro-benzoylamino)-acetic acid methyl ester as a light yellow solid. LCMS calcd for C10H10ClNO3 (m/e) 227, obsd 228 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10].[OH-].[K+].CCO>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C(C)(C)c1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C(=O)O)c1ccccc1F
Temperature: 130 °C
Yield: 81.3 %

Procedure:
A flask containing a solution of methyl 2-(2-fluorophenyl)-2-methylpropanoate (5.2 g, 27 mmol), KOH (2.9 mL, 106 mmol), water (20.0 mL), and EtOH (100 mL) was sealed and heated at 130° C. for 2 hours. Removal of solvent in vacuo provided a yellow oil that was diluted with water. The aqueous mixture was extracted with DCM (1×100 mL), and the organic layer was separated. The aqueous layer was acidified to a pH of 1 with 5N HCl and then extracted with EtOAc (2×100 mL). The organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to afford 4 g of the product as a solid. MS (m/z)=181 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2.C(N(CC)C(C)C)(C)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN2C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a solution of 5-methoxyindoline (202 mg, 1.35 mmol) and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol) in 4.0 mL of dry dichloromethane was added benzoyl chloride (0.23 mL, 2.0 mmol) at 0° C. After the reaction mixture was stirred at room temperature for 1 h, the reaction mixture was diluted with ethyl acetate. The solution was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 70/30) to obtain 5-methoxy-1-benzoylindoline (224 mg, 65%).
Reaction SMILES: [OH:1][CH:2]([CH2:27][CH2:28][CH2:29][OH:30])/[CH:3]=[CH:4]/[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12]([CH3:14])=[O:13])=[CH:8][C:7]1([OH:26])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[OH:1][CH:2]([CH2:27][CH2:28][CH2:29][OH:30])/[CH:3]=[CH:4]/[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12]([CH3:14])(=[O:39])=[O:13])=[CH:8][C:7]1([OH:26])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CS(=O)C1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)C1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Reaction time: 2 h
Yield: 45.6 %

Procedure:
To a solution of 165 mg of 5-[(E)-4,7-dihydroxyheptenylidene]-4-hydroxy-2-methylsulfinyl-4-(4-phenoxybutyl)-2-cyclopentenone obtained in Example 582 dissolved in 30 ml of dichloromethane was added a solution 117 mg of 3-chloroperbenzoic acid in 5 ml of dichloromethane, and the mixture was stirred for 2 hours. The reaction mixture was poured onto saturated aqueous sodium thiosulfate, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed twice with saturated aqueous sodium hydrogencarbonate and with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After filtration and concentration, the concentrate was subjected to chromatography to give 78 mg (yield 47%) of 5-[(E)-4,7-dihydroxy-2-heptenylidene]-4-hydroxy-2-methylsulfonyl-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]([C:25]2([NH:40]C(=O)OC(C)(C)C)[CH2:30][CH2:29][N:28]([C:31]3[C:32]4[CH:39]=[CH:38][NH:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:27][CH2:26]2)=[O:24])[CH2:16][CH2:17][NH:18][C:19]([NH2:21])=[O:20])=[CH:11][CH:10]=1>>[NH2:40][C:25]1([C:23]([NH:22][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[CH2:16][CH2:17][NH:18][C:19]([NH2:21])=[O:20])=[O:24])[CH2:30][CH2:29][N:28]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CCNC(N)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)NCCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 4.5 %

Procedure:
TFA (3 mL) was added to tert-butyl 4-(1-(4-chlorophenyl)-3-ureidopropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 112) (379 mg, 0.66 mmol). The reaction was left to stir at 20° C. for 4 hours and then vacuumed to dryness. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M NH3/MeOH and pure fractions were evaporated to dryness to afford crude material. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-3-ureidopropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (14.00 mg, 5.60%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:54]([O:58][C:59](=[O:68])[NH:60][C:61]1[CH:62]=[N:63][CH:64]=[C:65](Br)[CH:66]=1)([CH3:57])([CH3:56])[CH3:55]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[C:54]([O:58][C:59](=[O:68])[NH:60][C:61]1[CH:62]=[N:63][CH:64]=[C:65]([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:66]=1)([CH3:57])([CH3:55])[CH3:56]
Reactant: c1cc[nH]c1
Reactant: CC(C)(C)OC(=O)Nc1cncc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cncc(-n2cccc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
Cesium carbonate (214 mg), pyrrole (30 mg), Xantphos (63 mg), and Pd2(dba)3 (50 mg) were added to a 1,4-dioxane solution (5 mL) containing tert-butyl(5-bromopyridin-3-yl)carbamate (100 mg) in a nitrogen atmosphere, followed by stirring at 100° C. for 8 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1 to 1:1), and a light yellow solid of tert-butyl(5-(1H-pyrrol-1-yl)pyridin-3-yl)carbamate (36 mg) was thus obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:17])[C:5]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([CH:15]=[O:16])[CH:9]=[N:8][C:6]=2[N:7]=1.CO.[BH4-].[Na+].O>CC(O)=O>[NH2:1][C:2]1[N:3]=[C:4]([NH2:17])[C:5]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([CH2:15][OH:16])[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CCCc1c(C=O)cnc2nc(N)nc(N)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCCc1c(CO)cnc2nc(N)nc(N)c12
Reaction time: 1 h
Yield: 83.6 %

Procedure:
2,4-Diamino-5-propylpyrido [2,3-d]pyrimidine-6-carboxaldehyde (95 mg, 0.41 mmol) was stirred with MeOH (20 mL), and the near-solution was treated with 3 portions of NaBH4 (17 mg total, 0.45 mmol) added at 15-min intervals. Complete solution occurred after the first addition of NaBH4. The solution was left at 20°-25° C. for 1 hour. The solution was treated with H2O (1 mL), neutralized to pH 7 with glacial AcOH, and evaporated to near dryness. Solid residue was stirred with a little cold H2O (~1 mL), collected, and dried to give a first crop of 6-hydroxymethyl compound (III-1, where R1 is propyl); yield 31% (30 mg). The filtrate from this compound was evaporated to dryness, and the residue was extracted several times with boiling EtOAc to provide additional product (80 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:3]1.[C:17]1([C:23]#[C:24][Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[OH:1][C:2]1([C:24]#[C:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3][C:4]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]2)[O:5][CH2:6]1
Reactant: CCOC(=O)N1CCC2(CC1)CC(=O)CO2
Reactant: Br[Mg]C#Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC2(CC1)CC(O)(C#Cc1ccccc1)CO2
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.2 %

Procedure:
To a solution of ethyl 2-oxo-4-oxa-8-azaspiro[4.5]decane-8-carboxylate (Edwin S. C. Wu, Ronald C. Griffith, James T. Loch III, Alex Kover, Robert J. Murray, George B. Mullen, James C. Blosser, Anthony C. Machulskis, Sally A. McCreedy, J. Med. Chem., 1995, 38 (9), pp 1558-1570, 82 mg, 0.362 mmol) in THF (4 mL) was added dropwise a 1M solution of phenylethynylmagnesium bromide in THF (0.724 mL, 0.724 mmol), stirring at r.t. under anhydrous nitrogen atmosphere. The reaction mixture was stirred at r.t. for 4 h, then at 60° C. for 6 h, then it was quenched with a saturated aqueous solution of ammonium chloride, extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulphate and evaporated to dryness in vacuo. The crude was purified by automated flash chromatography (SP1®TM-Biotage; gradient Petroleum Ether-EtOAc from 75:25 to 4:6) affording the title product as yellow solid. Yield: 87.2%.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:27][CH2:28][CH:29]=[CH2:30])[CH:12]([CH2:13][CH3:14])[O:11][C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][C:32]1([CH3:39])[C:36]([CH3:38])([CH3:37])[O:35][BH:34][O:33]1>ClCCl.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:1]([O:5][C:6]([C:8]1([CH2:27][CH2:28][CH2:29][CH2:30][B:34]2[O:35][C:36]([CH3:38])([CH3:37])[C:32]([CH3:39])([CH3:31])[O:33]2)[CH:12]([CH2:13][CH3:14])[O:11][C:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=CCCC1(C(=O)OC(C)(C)C)NC(c2ccccc2)(c2ccccc2)OC1CC
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC1OC(c2ccccc2)(c2ccccc2)NC1(CCCCB1OC(C)(C)C(C)(C)O1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of 4-but-3-enyl-5-ethyl-2,2-diphenyl-oxazolidine-4-carboxylic acid tert-butyl ester (230 mg, 0.56 mmol) in dichloromethane (2 mL, 0.3 M) was added chlorotris (triphenylphosphine)rhodium(I) (60 mg, 0.065 mmol, 10 mol %) at room temperature. After stirring for 30 min, 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (200 μl, 1.3 mmol, 2 eq) was added to the reaction mixture and stirred overnight. After quenching the reaction with water (3 mL), the resulting solution was diluted with ethyl acetate and washed successively with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-40% ethyl acetate in heptane) gave 5-Ethyl-2,2-diphenyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-butyl]-oxazolidine-4-carboxylic acid tert-butyl ester (152 mg, 0.28 mmol, 50%).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].CCOCC.Cl.Cl>C(Cl)Cl.C(N(CC)CC)C>[CH3:12][C:8]1[CH:9]=[N:10][C:11]2[CH:2]([NH:1][C:20](=[O:21])[C:19]3[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=3)[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=1
Reactant: Cc1cnc2c(c1)CCCC2N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc2c(c1)CCCC2NC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
To 8-amino-5,6,7,8-tetrahydro-3-methylquinoline (4.5g, 2.27 M moles) in CH2Cl2 was added 4-nitrobenzoylchloride (4.2g, 2.26Mmoles) followed by sufficient triethylamine to clear the solution and then form a new precipitate. This material was left overnight and then the solvent removed. The residue was taken up in 2M HCl and washed with ethyl acetate. The aquous layer was then basified with Na2CO3 and extracted with chloroform. The organic solution was dried (MgSO4) and evaporated under reduced pressure to give a residue which was treated with Et2O/HCl to give a white solid identified by infra-red and nmr specroscopy as the hydrochloride of the title compound.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]1([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH:16]([NH2:24])[CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:26]1[N:31]=[C:30]([NH2:32])[N:29]=[C:28]2[NH:33][N:34]=[CH:35][C:27]=12.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.O>[C:8]1([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH:16]([NH:24][C:26]3[N:31]=[C:30]([NH2:32])[N:29]=[C:28]4[NH:33][N:34]=[CH:35][C:27]=34)[CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC1Cc2ccccc2N(c2ccccc2)C1
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(NC2Cc3ccccc3N(c3ccccc3)C2)c2cn[nH]c2n1
Temperature: 120 °C

Procedure:
A solution of 1-phenyl-1,2,3,4-tetrahydroquinolin-3-amine TFA salt (325 mg, 0.96 mmol) and 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (325 mg, 1.92 mmol) in dimethylacetamide (4 mL) was treated with diisopropylethylamine (0.5 ml, 3 eq). The mixture was heated at 120° C. for 20 hours. After cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate. The organic layer was further washed with brine and dried over anhydrous sodium sulfate. The residue was purified by flash column (eluted with ethyl acetate:hexane: 40% to 100% ethyl acetate) to give N4-(1-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine as a yellow a solid (240 mg). M.p.=88-92° C. 1H NMR (DMSO) 400 MHz δ 12.39 (s, 1H), 7.80 (s, br, 1H), 7.64 (d, J=6.8 Hz, 1H), 7.35-7.25 (m, 2H), 7.23 (m, 2H), 7.07 (m, 2H), 6.92 (m, 1H), 6.69 (m, 2H), 5.96 (s, 1H), 4.66 (s, br, 1H), 3.85 (m, 1H), 3.47 (m, 1H), 3.14 (dd, J=5.6 and 10.0 Hz, 1H), 2.88 (m, 1H). LCMS m/e 348 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:15](I)[CH2:16][CH3:17].[I-].[Na+]>>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)[CH2:16][CH3:17]
Reactant: CCCI
Reactant: CCOC(=O)/C=C/c1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Product: CCCOc1ccc(/C=C/C(=O)OCC)cc1
Yield: 93.9 %

Procedure:
Following a procedure similar to that described in Preparation 115, but using 9.61 g of ethyl (E)-p-hydroxycinnamate and 10.20 g of propyl iodide and not using sodium iodide, 11.00 g of the title compound were obtained as a solid material.
Reaction SMILES: Cl.N=[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:4]1[C:5](OCC)=O.[NH2:14][CH:15]([C:19]([NH2:21])=[O:20])[C:16]([NH2:18])=[O:17]>CO>[C:4]1([C:5]2[NH:18][C:16]([OH:17])=[C:15]([C:19]([NH2:21])=[O:20])[N:14]=2)[CH:3]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C1C=CC=CC1=N
Reactant: NC(=O)C(N)C(N)=O
Agent: Cl
Solvent: CO
Product: NC(=O)c1nc(-c2ccccc2)[nH]c1O
Yield: 63.1 %

Procedure:
To a chilled solution of ethyl iminobenzoate hydrochloride (18.57 g) in anhydrous methanol (250 ml) was added aminomalonamide (11.71 g). The mixture was stirred for a half hour at 0°-5° C. and then 1 hour under reflux. After cooling to 0°-5° C. again, the precipitated product was filtered and washed with ethanol, isopropylether to give 2-phenyl-5-hydroxy-1H-imidazole-4-carboxamide (11.81 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:27]1[O:36][C:35]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=2[O:28]1>>[CH2:27]1[O:36][C:35]2[CH:34]=[CH:33][C:31]([NH:32][CH:23]3[CH2:22][CH2:21][N:20]([CH2:19][C:17]4[CH:16]=[CH:15][N:14]=[C:13]([C:5]5[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH:18]=4)[CH2:25][CH2:24]3)=[CH:30][C:29]=2[O:28]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)OCO5)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl-4-piperidone (1.40 g) and 3,4-methylenedioxyaniline (646 mg) were treated in the same manner as described in Preparation Example 29 to give the title compound.
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.[Cl-].[NH4+]>O1CCCC1.CCOCC>[C:6]([O:10][C:11]1[CH:16]=[CH:15][C:14]([B:18]([OH:23])[OH:19])=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)Oc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
A solution of tert-butyllithium (1.7 M in pentane, 12 ml, CAUTION-PYROPHORIC) was added dropwise to a stirring solution of 4-bromophenyl tert-butyl ether (2.33 g) in tetrahydrofuran (20 ml) at -70° C. After a further 5 minutes the resulting solution of anion was added dropwise to a solution of triisopropyl borate (6 ml) in tetrahydrofuran (10 ml) at -70 ° C. After the addition was complete the reaction mixture was allowed to warm to room temperature. After 20 minutes a solution of saturated aqueous ammonium chloride (25 ml) and ether (25 ml) was added. The layers were separated and the aqueous phase washed with ether (50 ml). The combined organic extracts were washed with dilute hydrochloric acid (5%, 25 ml) and were then dried over anhydrous magnesium sulfate. The solution was filtered and concentrated under reduced pressure to give a white solid. This was purified by column chromatography over silica eluting with ether then methanol to give the sub-title compound as a white solid (0.69 g).