Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=1)([CH3:11])[CH3:10]>C(Cl)(Cl)Cl>[Br:1][C:17]1[C:12]([CH:9]([CH3:11])[CH3:10])=[N:13][C:14]([NH2:18])=[N:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1ccnc(N)n1
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(N)ncc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.6 %

Procedure:
N-Bromosuccinimide (0.5 g, 2.8 mmol) was added to a solution of 4-isopropylpyrimidin-2-amine (0.39 g, 2.81 mmol) in chloroform. The resultant yellow solution was stirred at ambient temperature for 1 h and concentrated in vacuo. The residue was purified by column chromatography (3-10% 9:1 methanol:ammonium hydroxide in chloroform) to afford 5-bromo-4-isopropylpyrimidin-2-amine (0.69 g, 3.18 mmol, 113%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (1H, s), 6.75 (2H, s), 3.10-3.23 (1H, m), 1.14 (6H, d, J=6.80 Hz). MS (LC/MS) R.T.=2.58; [M]+=216.09.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][N:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1.[Cl-].[NH4+]>C(O)C>[CH3:3][O:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1
Reactant: CON1CCC(=O)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CON1CCC(O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
Under an atmosphere of argon, 200 ml ethanol was cooled to 10° C. and 3.7 g sodium borohydride was added. A solution of 25 g 1-methoxy-piperidin-4-one (prepared according to J. Org. Chem. 1961, 26, 1867-74) in 200 ml ethanol was added to the stirred suspension, while the temperature was kept in the range of 15-20° C. Then the mixture was stirred at ambient temperature for 3 hours. 50 ml aqueous ammonium chloride was added slowly and then the solvent evaporated. The residue was purified by chromatography on silica gel, using ethyl acetate as a solvent. Thus, 22.8 g 1-methoxy-piperidin-4-ol was obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]O)[CH2:13][CH2:12][CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OCCCCCCCCC1CCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCCCCCC1CCCC1
Reaction time: 8 h
Yield: 76.9 %

Procedure:
2.4 g of N-bromosuccinimide were added portionwise to a solution of 2.27 g of cyclopentane-octanol and 3.22 g of triphenylphosphine in 40 ml of dichloromethane in an ice bath. The reaction mixture was left to stand at room temperature overnight, filtered and the filtrate was concentrated. The residue was partitioned between 50 ml of methanol/water (vol.) 4:1 and 40 ml of hexane and the methanol phase was separated. The hexane phase was washed twice with 20 ml of methanol/water 4:1 each time and concentrated. Distillation of the residue in a bulb-tube at 130°-150° C./0.05 Torr gave 2.3 g of (8-bromooctyl)-cyclopentane as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([C:11]1[CH2:12][O:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:16][CH:15]=2)(=[O:10])[CH3:9].S(=O)(=O)(O)O.C(OCC)C>COCOC.O1CCCC1.[Zn]>[OH:10][C:8]([C:11]1[CH2:12][O:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:16][CH:15]=2)([CH3:9])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CC(=O)C1=Cc2cc(-c3ccccc3)ccc2OC1
Reactant: CCOC(=O)CBr
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: C1CCOC1
Solvent: COCOC
Solvent: CCOCC
Product: CCOC(=O)CC(C)(O)C1=Cc2cc(-c3ccccc3)ccc2OC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.35 g (0.0665 At-g) of activated zinc are covered with 12 ml of dimethoxymethane, and then 1 ml (9 mmol) of pure ethyl bromoacetate is added under an argon atmosphere. After induction of the reaction by heating, a solution of 6.38 ml (57.5 mmol) of ethyl bromoacetate in 20 ml of dimethoxymethane is added in such a manner as to maintain reflux. After the zinc has been completely consumed and the reaction mixture has returned to room temperature, a solution of 11.1 g (43.5 mmol) of 3-acetyl-6-phenyl-2H-chromene in 60 ml of anhydrous tetrahydrofuran is added dropwise over a period of from 10 to 15 minutes. After one hour's stirring at room temperature, the mixture, cooled to +4° C., is treated with 25 ml of a 10% sulphuric acid solution. After addition of 70 ml of diethyl ether, the aqueous phase is separated off, and the ethereal phase is washed with 3×20 ml of water and then dried over magnesium sulphate. The solvents are evaporated off under reduced pressure, yielding a solid which is used in the following step without additional purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[C:25]1([S:31]([C:34]2[CH:39]=[CH:38][C:37](CO)=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[C:25]1([S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH2:20][Cl:24])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=S(=O)(c1ccccc1)c1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccc(CCl)cc1
Temperature: 100 °C
Yield: 101.6 %

Procedure:
Triphenylphosphine (5.98 g, 22.8 mmol), carbon tetrachloride (9 mL, 93 mmol), (4-benzenesulfonyl-phenyl)-methanol (2.83 g, 11.4 mmol) and tetrahydrofuran (42 mL) were combined and heated at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was dried over MgSO4, filtered, and concentrated to give the crude product as an oily solid. A solution of this crude product and dichloromethane was evaporated over silica gel, and the resulting silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (15%-35% ethyl acetate in hexanes) afforded 3.09 g (100%) of 4-(benzenesulfonyl)benzyl chloride as a white, crystalline solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.89-8.04 (m, 4 H), 7.53-7.75 (m, 5 H), 4.81 (s, 2 H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:11]1[CH:15]=[C:14]([C:16](OC)=[O:17])[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8].[OH-].[K+]>O1CCCC1>[C:7]([N:11]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)c1cnn(C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)n1cc(CO)cn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 94.8 %

Procedure:
In a nitrogen atmosphere, 1.25 g of lithium aluminum hydride was suspended in 100 ml of tetrahydrofuran, and a solution of 5.01 g of methyl 1-t-butyl-1H-pyrazole-4-carboxylate in 50 ml of tetrahydrofuran was added dropwise at 0° C. over 30 minutes. Thereafter, the mixture was stirred at room temperature for 7 hours. The reaction mixture was cooled to 0° C. and 10 ml of a 1 mol/L aqueous potassium hydroxide solution was then added dropwise. Produced precipitates were filtered and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 4.02 g of (1-t-butyl-1H-pyrazol-4-yl)methanol.
Reaction SMILES: C(OC[N:9]1[C:17]2[N:16]=[C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[N:14]([CH3:30])[C:13]=2[C:12](=[O:31])[N:11]([CH2:32][C:33]#[CH:34])[C:10]1=[O:35])(=O)C(C)(C)C.O1CCCC1.CO.O.[OH-].[Li+]>ClCCl.CO>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([C:19]#[C:18][C:15]2[N:14]([CH3:30])[C:13]3[C:12](=[O:31])[N:11]([CH2:32][C:33]#[CH:34])[C:10](=[O:35])[NH:9][C:17]=3[N:16]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: C#CCn1c(=O)c2c(nc(C#Cc3ccc(OC)c(OC)c3)n2C)n(COC(=O)C(C)(C)C)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C#CCn1c(=O)[nH]c2nc(C#Cc3ccc(OC)c(OC)c3)n(C)c2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {8-[(3,4-dimethoxyphenyl)ethynyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydro-3H-purin-3-yl}methyl pivalate (471 mg, 0.98 mmol) in a 4:1 mixture of dry tetrahydrofurane and methanol (20 mL) was added lithium hydroxide monohydrate (127 mg, 1.63 mmol). The mixture was stirred at room temperature for 3 h (TLC-control: dichloromethane/methanol, 9.5:0.5, Rf=0.40 for the product). Subsequently the solvent was removed under reduced pressure, the remaining residue was dissolved in water (30 mL) and acidified with diluted hydrochloric acid. The precipitate was filtered under reduced pressure, washed with water and dried at 70° C., yielding 334 mg (93 yield for the deprotection reaction) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.[Br:10]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[C:3]([CH2:9][Br:10])=[N:4][C:5]([F:8])=[CH:6][CH:7]=1
Reactant: Cc1nc(F)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Fc1ccc(Br)c(CBr)n1
Reaction time: 24 h
Yield: 100.4 %

Procedure:
To a solution of 3-bromo-6-fluoro-2-methyl-pyridine (1.9 g, 10.0 mmol, 1.0 equiv) in CCl4 (40 mL) was added N-bromo-succinimide (2.14 g, 12.0 mmol, 1.2 equiv) followed by 2,2′-azobis(2-methylpropionitrile) (0.16 g, 1.0 mmol, 0.1 equiv). The mixture was heated at reflux for 16 h, then left to stand at ambient temperature for 24 h. Water (100 mL) was added and the product was extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford 3-bromo-2-bromomethyl-6-fluoro-pyridine (2.7 g) which was used without further purification. 1H NMR (400 MHz, CDCl3): 7.94 (1H, m), 7.84 (1H, m), 4.62 (2H, s).
Reaction SMILES: I[C:2]1[CH2:3][CH2:4][C:5](=[O:17])[N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:7]=1.C(Cl)Cl.[NH2:21][C:22]1[C:23]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([F:39])[CH:30]=2)=[N:24][C:25](Br)=[CH:26][N:27]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[NH2:21][C:22]1[C:23]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([F:39])[CH:30]=2)=[N:24][C:25]([C:2]2[CH2:3][CH2:4][C:5](=[O:17])[N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[CH:7]=2)=[CH:26][N:27]=1
Reactant: COc1ccc(CN2C=C(I)CCC2=O)cc1
Reactant: COC(=O)c1ccc(-c2nc(Br)cnc2N)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2nc(C3=CN(Cc4ccc(OC)cc4)C(=O)CC3)cnc2N)cc1F
Temperature: 90 °C
Yield: 42.5 %

Procedure:
5-iodo-1-(4-methoxybenzyl)-3,4-dihydropyridin-2(1H)-one (630 mg, 1.836 mmol), PdCl2(dppf).CH2Cl2 adduct (150 mg, 0.184 mmol), methyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (1028 mg, 2.75 mmol) and Na2CO3 (2754 μl, 5.51 mmol) were combined in a flask and then DME (Volume: 6120 μl) was added. The mixture was degassed and purged with nitrogen and then finally heated at 90° C. for 2 h upon which complete consumption of starting material was observed. The reaction mixture was diluted with EtOAc and water and the organic layer was separated and dried (MgSO4), filtered and concentrated in vacuo and the residue purified by flash chromatography (0-60% EtOAc/DCM) to afford 361 mg of the desired product as a yellow solid. LCMS (m/z): (MH+), 463.1, 0.88 min.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)(=[O:5])=[O:4]
Reactant: Oc1ccccc1N1CCOCC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1ccccc1N1CCOCC1)C(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
2.78 ml (16.4 mmol) of trifluoromethanesulphonic anhydride are slowly added dropwise to a solution, cooled to −10° C., of 2 g (10.9 mmol) of 2-(4-morpholinyl)-phenol and 4.57 ml (32.8 mmol) of triethylamine in 15 ml of dichloromethane. The mixture is stirred at −10° C. for 30 min and then at 0° C. for 30 min. It is washed successively with 10% strength sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo, and the residue is dried under high vacuum. 3.48 g (87.6% of theory) of the title compound are obtained.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:15]([F:16])=[CH:14][C:13]([B:17]([OH:19])[OH:18])=[CH:12][C:11]=1[F:20])(C(C)(C)C)(C)C>C(O)(=O)C>[F:16][C:15]1[CH:14]=[C:13]([B:17]([OH:18])[OH:19])[CH:12]=[C:11]([F:20])[C:10]=1[CH2:9][OH:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1c(F)cc(B(O)O)cc1F
Solvent: CC(=O)O
Product: OCc1c(F)cc(B(O)O)cc1F
Temperature: 40 °C
Reaction time: 5 h

Procedure:
[4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3,5-difluorophenyl]boronic acid (19.3 g, 63.9 mmol; crude material, prepared by the method of Hattori, Bioorg. Med. Chem. 2006, 14, 3258-3262) was dissolved in 400 mL aqueous acetic acid (66%) and stirred at 40° C. for 5 h. The solution was then evaporated under reduced pressure, and the residue was purified by flash chromatography over silica gel (gradient elution from 0% to 2% methanol in dichloromethane) to give 3.46 g (25% of th., LC-MS purity 87%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH2:15][CH3:16])[CH:8]=2)[N:3]=1.Cl.[CH3:18][O:19][NH2:20].C(O)C>>[CH3:18][O:19][N:20]=[CH:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:14][CH2:15][CH3:16])=[CH:6][CH:5]=2
Reactant: CCOc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CCOc1ccc2nc(Cl)c(C=NOC)cc2c1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-6-ethoxyquinoline-3-carbaldehyde (0.235 g, 1.0 mmol) in ethanol O-methylhydroxylamine hydrochloride (0.10 g, 1.1 mmol) was added. The reaction mixture was heated to reflux for 0.5 hours. After cooling to room temperature the precipitated compound was filtered and dried. Yield 180 mg. M.p. 142-4° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][CH2:14][CH2:15]Cl)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.Cl.[F:18][C:19]1[CH:20]=[CH:21][C:22]2[C:26]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][S:24][C:23]=2[CH:33]=1.C(N(C(C)C)CC)(C)C>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][CH2:14][CH2:15][N:30]3[CH2:31][CH2:32][CH:27]([C:26]4[C:22]5[CH:21]=[CH:20][C:19]([F:18])=[CH:33][C:23]=5[S:24][CH:25]=4)[CH2:28][CH2:29]3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C2(CCCN3CCC(c4csc5cc(F)ccc45)CC3)OCCO2)cc1
Yield: 29 %

Procedure:
A mixture of 1.5 g of 2-(4-fluorophenyl)-2-(3-chloropropyl)-1,3-dioxolane, 1.5 g of 4-(6-fluorobenzo[b]thiophen-3-yl)piperidine hydrochloride, 3.3 ml of diisopropylethylamine and 2.5 ml of methanol was stirred with heating under reflux for 25 hours. The reaction mixture was separated with chloroform and a saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer was extracted with chloroform. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by a flush chromatography (silica gel: Merckkieselgel 60 230-to 400-mesh, eluent: hexane-ethyl acetate=1:2) to obtain 0.71 g of 2-(4-fluorophenyl)-2-[3-[4-(6-fluorobenzo[b]thiophen-3-yl)piperidin-1-yl]propyl]-1,3-dioxolane.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7](B(O)O)[CH:6]=1.Br[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[CH3:26])[CH:6]=1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: COCOc1ccc(C)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(O)ccc2C)c(C)c1

Procedure:
In a manner similar to that of Example 11(d), by reaction of 3.7 g (18.8 mmol) of 4-methoxymethoxy-1-methylbenzene-2-boronic acid with 3.9 g (17 mmol) of methyl 4-bromo-3-methylbenzoate, 17 mL of 2.0M potassium carbonate solution and 1 mg (0.85 mmol) of tetrakis(triphenylphosphine)palladium, followed by deprotection in methanol, the desired product is obtained in the form of a thick, colourless oil (m=2.87 mg; Y=51%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[NH:24]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH2:25]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]([C:8]1[C:7]([N:24]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH2:25]2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[C:10]([Cl:17])[CH:9]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: CCC(=O)N[C@H]1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(=O)N[C@H]1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Temperature: 65 °C
Yield: 14.5 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.19 g, 0.27 mmol, from Example 47, Step 2), N-[(3S)-pyrrolidin-3-yl]propanamide hydrochloride (0.040 g, 0.22 mmol), palladium acetate (1.0 mg, 0.0045 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.2 mg, 0.0067 mmol), and cesium carbonate (0.28 g, 0.85 mmol) in tetrahydrofuran (4 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated. The residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (11 mg, 14%). LCMS calculated for C18H21ClN3O2 (M+H)+: m/z=345.1; Found: 346.3.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].Cl.[NH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=1
Reactant: CCOC(=O)CN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)CNc1nc(Cl)nc(Cl)n1

Procedure:
36.9 g of cyanuric chloride, 27.9 g of ethyl glycinate hydrochloride and 33.6 g of sodium bicarbonate were heated under reflux in 200 ml of dioxane for 30 minutes. At the end of this time, the dioxane was removed by distillation under reduced pressure, and a mixture of ethyl acetate and water was added to the resulting residue, after which the mixture was shaken.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[C:22](=[O:23])[C:14]3[CH:15]=[C:16]4[N:21]([C:13]=3[CH:12]=[N:11]2)[CH2:20][CH2:19][CH2:18][CH2:17]4)[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:50]=[C:44]3[CH2:45][N:46]([CH3:49])[CH2:47][CH2:48][N:43]3[N:42]=2)[C:26]1=[O:51].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH3:24][N:25]1[C:26](=[O:51])[C:27]([NH:40][C:41]2[CH:50]=[C:44]3[CH2:45][N:46]([CH3:49])[CH2:47][CH2:48][N:43]3[N:42]=2)=[CH:28][C:29]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[C:22](=[O:23])[C:14]4[CH:15]=[C:16]5[N:21]([C:13]=4[CH:12]=[N:11]3)[CH2:20][CH2:19][CH2:18][CH2:17]5)[N:5]=[CH:4][CH:3]=2)=[CH:30]1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c(cc3n2CCCC3)c1=O
Reactant: CN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6c(cc7n6CCCC7)c5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 55.9 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-(1-oxo-6,7,8,9-tetrahydropyridazino[4,5-b]indolizin-2(1H)-yl)nicotinaldehyde 193f (200 mg, 0.60 mmol), 1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo-[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 135a (230 mg, 0.60 mmol), sodium acetate (100 mg, 1.2 mmol), K3PO4 (320 mg, 1.2 mmol), PdCl2(dppf) (50 mg, 0.060 mmol), acetonitrile (25 mL), and water (1 mL). After bubbling nitrogen through the resulting mixture for 30 minutes, the mixture was heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 20:1 methylene chloride/methanol to afford 204a (185 mg, 55%) as a brown solid. MS-ESI: [M+H]+ 552.3.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][N:42]=1>>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([C:41]2[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][N:42]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Reactant: Fc1ccnc(Cl)c1
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2cc(F)ccn2)o1
Yield: 51 %

Procedure:
The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (130 mg, 0.196 mmol) and 2-chloro-4-fluoropyridine following General Procedure A. Flash chromatography (10% EtOAc/hexanes) yielded the title compound as a thick oil (48 mg, 51%): 1H NMR (CDCl3, 400 MHz) δ 8.59 (dd, 1H, J=8.5, 5.6 Hz), 7.69 (s, 1H), 7.38 (dd, 1H, J=9.4, 2.3 Hz), 7.28-7.24 (m, 2H), 7.18-7.15 (m, 3H), 6.96 (ddd, 1H, J=8.2, 5.6, 2.4 Hz), 4.87 (dd, 1H, J=7.0, 6.2 Hz), 2.60 (t, 2H, J=7.6 Hz), 1.96 (m, 2H), 1.62 (m, 2H), 1.36 (m, 4H), 0.91 (s, 9H), 0.11 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 170.4, 167.8, 166.1, 152.4 (d, J=7.6 Hz), 150.2, (d, J=7.6 Hz), 149.8 (d, J=4.6 Hz), 142.7, 128.3, 128.2, 126.2, 125.5, 110.5 (d, J=15.2 Hz), 106.9 (d, J=18.2 Hz), 68.7, 36.4, 35.9, 31.4, 29.1, 25.7, 25.7, 25.1, 18.2, −5.0, −5.2.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:48])([CH3:47])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12](COCC[Si](C)(C)C)[CH:11]=2)=[N:6]1.FC(F)(F)C(O)=O.N>>[OH:1][CH2:2][C:3]([CH3:47])([CH3:48])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)=[N:6]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccn(CC(C)(C)CO)n3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccn(CC(C)(C)CO)n5)c34)n(-c3ccccc3)c(=O)c12
Yield: 59.5 %

Procedure:
(S)-2-(1-((5-(1-(3-Hydroxy-2,2-dimethylpropyl)-1H-pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (4 mg, 0.01 mmol) was treated with trifluoroacetic acid (1 mL, 13 mmol) and a solution of ammonia (7N in methanol, 5 mL, 35 mmol) according to the method described in Example 27 to give 3.2 mg (100% yield) of the title compound. Purity 85%.