Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][OH:7].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][O:7][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1
Reactant: C1=COCCC1
Reactant: CC(C)(CO)CCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(CCCBr)COC1CCCCO1
Reaction time: 8 h
Yield: 108.2 %

Procedure:
5-Bromo-2,2-dimethyl-1-pentanol (77.4 g, 357 mmol) was dissolved in dichloromethane (400 mL), and p-toluenesulfonic acid (6.9 g, 36 mmol) was added. The mixture was stirred under argon, chilled in an ice-bath, then was added 3,4-dihydro-2H-pyran (37.2 g, 428 mmol) and stirred, gradually letting warn to rt overnight. The reaction mixture was then filtered through neutral alumina (100 g); the alumina was rinsed with additional dichloromethane (600 mL). After evaporating to about 500 mL, the organic layer was extracted with sat. NaHCO3 (3′ 200 mL), then dried over MgSO4. The solution was concentrated under reduced pressure to produce the expected product (107.83 g, 97% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3), d (ppm): 4.55 (m, 1H); 3.83 (m, 1H); 3.51 (m, 1H); 3.47 (d, 1H, J=9.0); 3.38 (t, 2H, J=6.8); 2.98 (d, 1H, J=9.0); 1.94-1.75 (m, 2H); 1.75-1.44 (m, 6H); 1.40 (t, 2H, J=8.5); 0.93-0.87 (m, 6H). 13C NMR (75 MHz, CDCl3), d (ppm): 99.0, 76.2, 61.9, 37.9, 34.6, 34.0, 30.6, 27.9, 25.6, 24.64, 24.56, 19.4. HRMS calcd. for C12H24BrO2 (MH+): 279.0960, found 279.0955.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:7]=1.[S:32]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CO.CN(C=O)C.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:27][C:10]([C:23]([F:25])([F:26])[F:24])([CH2:9][C:8]([C:6]1[CH:7]=[C:2]([C:34]2[CH:35]=[CH:36][S:32][CH:33]=2)[CH:3]=[CH:4][C:5]=1[O:30][CH3:31])([CH3:28])[CH3:29])[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH:14]=[CH:13]1
Reactant: OB(O)c1ccsc1
Reactant: COc1ccc(Br)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
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: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(-c2ccsc2)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
A mixture of 1-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (0.2 g, 0.4 mmol), 3-thiopheneboronic acid (77 mg, 0.6 mmol), sodium carbonate (Na2CO3; 85 mg, 0.8 mmol) in DME-MeOH-DMF (1:1.5:0.5; 3.0 mL) was stirred for 10 minutes and Pd(PPh3)4 (46.2 mg, 0.04 mmol) was added. The mixture was microwaved for 15 minutes at 120° C., cooled to room temperature, and filtered through CELITE® filter aid. The residue was diluted with EtOAc (20 mL) and washed with aqueous NaOH (1.0M, 10 mL), water, and brine, and dried over sodium sulfate, and the volatiles removed in vacuo. The residue was purified by silica gel chromatography and then by reverse phase HPLC to yield 60 mg (30%) of 1-[2-hydroxy-4-(2-methoxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one as a white foam.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH2:39])[CH:34]=[CH:35][C:36]=1[F:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH:39][C:24](=[O:26])[CH2:23][CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:28][CH3:29])=[O:27])[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: NCc1ccc(F)c(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(F)c(Br)c1
Yield: 73.9 %

Procedure:
A solution of 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (1.0 g, 2.478 mmol), 1-(3-bromo-4-fluorophenyl)methanamine (0.648 g, 2.69 mmol), HATU (1.065 g, 2.8 mmol) and triethylamine (0.781 mL, 5.6 mmol) in dichloromethane (45 mL) was stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed with saturated NaHCO3, water and saturated NaCl, and dried over Na2SO4. The organic layer was evaporated to give a pale amber residue. The residue was triturated with a small amount of DCM, then sonicated to give a uniform mixture. A white solid was collected and dried to afford N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (1.08 g, 73.9%) as a crystalline solid. LC-MS m/z 589.1 (M+H)+, 0.79 min (ret time).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.C(OC([N:28]1[C:36]2[N:31]([C:32](=[O:38])[N:33]=[C:34](Cl)[CH:35]=2)[CH2:30][C@@H:29]1[CH3:39])=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:19][O:20][C:34]1[CH:35]=[C:36]2[NH:28][C@@H:29]([CH3:39])[CH2:30][N:31]2[C:32](=[O:38])[N:33]=1
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and (S)-tert-butyl7-chloro-2-meth yl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C[Mg+].[Br-].[CH3:18]COCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH:13]([OH:14])[CH3:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2cccc(Cl)c2)o1
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2cccc(Cl)c2)o1
Reaction time: 0.75 h

Procedure:
To a solution of 5-(3-chlorophenyl)furan-2-carbaldehyde (1.0 equiv.) in THF at 0° C. was added MeMgBr in ether (3.0 equiv.) and stirred for 45 min. The reaction was quenched with water, diluted with ether and filtered through Celite. The organic layer was separated and washed with brine, dried over MgSO4, and concentrated to give the 1-[5-(3-chlorophenyl)-2-furyl]ethan-1-ol.
Reaction SMILES: CC([O:4][C:5]([CH3:7])=[O:6])=O.O[NH:9][C:10](=[NH:24])[CH2:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1.C(OCC)(=O)C>O>[C:5]([O:4][NH:24][C:10](=[NH:9])[CH2:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)(=[O:6])[CH3:7]
Reactant: N=C(Cc1ncccc1-c1ccccc1)NO
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)ONC(=N)Cc1ncccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.94 %

Procedure:
Ac2O (30 mL) was added to N-hydroxy-2-(3-phenyl-pyridin-2-yl)-acetamidine (160) (5.3 g, 23.35 mmol) at room temperature. A purple colored solution was formed, after a few hours a dark brown solution was formed which was stirred for 6 h at room temperature. Silica thin layer chromatography was performed (100% ethyl acetate, Rf=0.6). Cold water was added, the mixture was extracted with ethyl acetate (3×50 mL), the organic part was dried and concentrated, the crude product was purified by a CombiFlash column (eluted at 50% ethyl acetate in hexane) to get 2-(3-phenylpyridin-2-yl)ethanimidamido acetate (161) (2.7 g, 42.94% pure and 2 g mixture) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]=[C:11]([C:13](OC)=[O:14])[CH:10]=[C:9]([F:17])[C:8]=1[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[F:26].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:27])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[C:9]([F:17])[C:8]=1[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[F:26]
Reactant: COC(=O)c1cc(F)c(-c2cc(OC)ccc2F)c(C2CCCC2(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2c(F)cc(CO)cc2C2CCCC2(C)C)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 46.2 %

Procedure:
To a cooled solution of 83.20A (0.7036 g, 1.879 mmol) in dry THF (15 mL) at 0° C. was added LAH (1.0 M in THF) (4 mL, 4.0 mmol) dropwise. Upon complete addition, the reaction was maintained at 0° C. and was monitored by TLC and LCMS. After 45 minutes, 1N NaOH was added to quench the reaction. Gas evolution occurred. The resulting solution was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate, filtration, and concentration, the residue was purified by flash chromatography (SiO2 gel 60, eluted with 0%-50% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide a colorless oil that solidified as 83.20B (300.5 mg, 46% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.16 (1H, s), 7.10 (2H, m), 6.92 (1H, m), 6.77 (1H, dd, J=5.9, 3.1 Hz), 4.74 (2H, s), 3.81 (3H, m), 2.73 (1H, ddd, J=10.3, 8.3, 1.8 Hz), 2.17 (1H, m), 2.04 (1H, m), 1.87 (1H, m), 1.73 (3H, m), 1.42 (1H, m), 0.78 (3H, s), 0.64 (3H, s). Chiral separation of 83.20B was accomplished on Chiracel-OJ (2% IPA in hexane) to provide 83.20C (peak 1) and 83.20D (peak 2). Both enantiomers were used to synthesize example compounds, and both enantiomers gave active compounds.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][C:40]1=[O:45].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11](=[O:12])[N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22]([N:42]3[CH2:43][CH2:44][NH:39][C:40](=[O:45])[CH2:41]3)=[O:23])=[C:15]2[CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CNCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCNC(=O)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 82 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), piperazin-2-one (60 mg, 0.6 mmol), bis(2-oxo-3-oxazolidinyl) phosphonic chloride (0.138 g, 0.54 mmol), triethylamine (0.25 mL, 1.62 mmol) and 8 mL of dichloromethane were added into the reaction flask, and 10 mL of N,N-dimethylformamide was then added to the flask. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-3-[1-(3-oxo-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 19a (140 mg, yield 82%) as a colourness oil.
Reaction SMILES: C(OP([O-])(OCC)=O)C.[C:10]([IH+:14]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])([CH3:12])[CH3:11].[F:25][C:26]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=1[S:36]([OH:39])(=[O:38])=[O:37].N>C(Cl)Cl>[F:35][C:28]1[C:29]([F:34])=[C:30]([F:33])[C:31]([F:32])=[C:26]([F:25])[C:27]=1[S:36]([O-:39])(=[O:38])=[O:37].[C:21]([IH+:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=S(=O)(O)c1c(F)c(F)c(F)c(F)c1F
Agent: CC(C)(C)[IH+](c1ccccc1)C(C)(C)C
Agent: CCOP(=O)([O-])OCC
Agent: N
Solvent: ClCCl
Product: O=S(=O)([O-])c1c(F)c(F)c(F)c(F)c1F
Yield: 76.8 %

Procedure:
Di-tert-butylphenyliodonium diethylphosphate (546 mg; 1 mmol) and perfluorobenzenesulfonic acid (267 mg; 1.1 mmol) were dissolved in methylene chloride (10 ml), and 1% aqueous ammonia (10 ml) was added thereto. After the alkalinity of the solution was confirmed, the solution was stirred vigorously. The thus-obtained mixture was allowed to stand, and the aqueous layer was separated. The aqueous layer was washed with water successively until the aqueous layer exhibited neutral pH. The methylene chloride solution was dried, and the solvent was removed through distillation. The residue was washed in ether by stirring, to thereby precipitate 435 mg of the target compound as white crystals (yield: 68%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([NH2:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>ClC(Cl)C>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][CH:16]([NH:18][CH2:20][C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(CNC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cc1
Temperature: 100 °C
Yield: 34 %

Procedure:
To a solution of 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-amine (20 mg, 80 μmol) in dichloroethane (2 ml) was added 4-(bromomethyl)benzonitrile (17 mg, 87 μmol) and DIPEA (15 μl, 87 μmol). The reaction was heated at 100° C. for 16 hours, concentrated at reduced pressure and purified by FCC (DCM/MeOH/NH3 with gradient, 98:2:1 to 90:10:1) to provide the title compound as colourless oil (10 mg, 33%).
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][C:5]1[CH:30]=[CH:29][C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1.[CH:31]([C:33]1[N:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]2)=[CH:35][CH:34]=1)=O>>[OH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[CH:31][C:33]2[N:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)=[CH:29][CH:30]=1
Reactant: OCCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Agent: [Br-]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=Cc3ccc(CCO)cc3)nc2)CC1

Procedure:
By a method similar to Production Example 108, step 4, [4-(2-hydroxyethyl)benzyl](triphenyl)phosphonium bromide (2.866 g, 6.004 mmol) and tert-butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate (1.458 g, 5.003 mmol) were condensed to give tert-butyl 4-(6-{2-[4-(2-hydroxyethyl)phenyl]vinyl}pyridin-3-yl)piperazine-1-carboxylate (5.684 g, quantitatively) as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH2:65]([NH2:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>CN(C=O)C>[CH2:65]([NH:72][C:31](=[O:32])[CH2:30][C:27]1[CH:28]=[CH:29][C:22]2[O:21][CH2:20][CH2:19][N:18]3[CH:17]=[C:16]([C:15]4[N:11]([CH:8]([CH3:9])[CH3:10])[N:12]=[CH:13][N:14]=4)[N:25]=[C:24]3[C:23]=2[CH:26]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: NCc1ccccc1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(CC(=O)O)ccc1OCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(CC(=O)NCc3ccccc3)ccc1OCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
To a mixture of [2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-yl]acetic acid trifluoroacetic acid salt (100 mg, 0.21 mmol), HATU (96 mg, 0.25 mmol) and NEt3 (63 mg, 0.63 mmol) in DMF (2 mL) was added a solution of benzylamine (27 mg, 0.25 mmol) in DMF (0.2 mL) and the resulting mixture stirred at RT for 3 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-8% tMeOH in DCM) affording 120 as a white solid (78 mg, 84%). LCMS: RT 3.94 min [M+H]+ 443.3. 1H NMR (CDCl3, 400 MHz): δ 8.38 (1H, d, J=2.31 Hz), 7.91 (1H, s), 7.75 (1H, s), 7.27-7.19 (6H, m), 7.04 (1H, d, J=8.36 Hz), 5.89-5.88 (1H, m), 5.79 (1H, s), 4.46-4.43 (6H, m), 3.68 (2H, s), 1.59 (6H, d, J=6.62 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([CH3:23])([CH3:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([CH3:23])([CH3:22])[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C=Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)CCc1ccccc1
Reaction time: 4 h

Procedure:
The product of Example 18, Step 2, and 10% Pd/C are placed in a Parr bottle and mixed with ethyl acetate. The flask is purged with nitrogen and hydrogen and finally pressurized to 35 psi H2. The hydrogenation is run for 4 hours at room temperature. The catalyst is filtered off using a Celite pad and the filtrate is concentrated to give the pure product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[C:10]([CH3:36])=[C:11]([CH3:35])[C:12]2[O:17][C:16]([CH2:19][CH2:20][CH2:21]OS(C3C=CC(C)=CC=3)(=O)=O)([CH3:18])[CH2:15][CH2:14][C:13]=2[C:33]=1[CH3:34].O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[C:10]([CH3:36])=[C:11]([CH3:35])[C:12]2[O:17][C:16]([CH2:19][CH2:20][CH2:21][N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)([CH3:18])[CH2:15][CH2:14][C:13]=2[C:33]=1[CH3:34]
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CCCOS(=O)(=O)c1ccc(C)cc1)O2
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CCCN1CCNCC1)O2
Yield: 91.7 %

Procedure:
To a refluxing solution of 7.2 g (0.085 mol) of piperazine in 50 ml of toluene was added 3.8 g (8.5 mmol) of the 3,4-dihydro-6-methoxy-2-[3-(p-toluenesulfonyloxy)propyl]-2,5,7,8-tetramethyl-2H-benzopyran obtained in the above manner, followed by refluxing for 6 hours. After cooling, the reaction mixture was poured into water and extracted with diethyl ether. The ether layer was dried over anhydrous sodium sulfate and low-boiling substances were distilled off therefrom under reduced pressure and the excess piperazine was then removed by sublimation under reduced pressure. The thus-obtained residue was purified by silica gel column chromatography to give 2.7 g (91.8% yield) of 3,4-dihydro-6-methoxy-2-[3-(piperazin-1-yl)propyl]-2,5,7,8-tetramethyl-2H-benzopyran.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:5][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][N:17](COCC[Si](C)(C)C)[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>CO>[CH3:1][C:2]1([CH3:31])[CH2:5][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1
Reactant: CC1(C)CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC1(C)CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1

Procedure:
3,3-Dimethyl-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.020 g, 0.000046 mol) was treated with trifluoroacetic acid (0.5 mL, 0.006 mol) at rt for 30 min and then evaporated to dry. The residue was then shaked with ethylenediamine (0.2 mL, 0.003 mol) in MeOH (1 mL) for 2 h. The reaction was concentrated and purified on prep HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired prodcut. LCMS calculated for C17H19N6(M+H)+: 307.2; Found: 307.3. 1H NMR (400 MHz, DMSO-d6): δ 12.10 (1H, br s), 8.76 (1H, s), 8.67 (1H, s), 8.40 (1H, s), 7.58 (1H, d, J=3.6 Hz), 7.05 (1H, d, J=3.6 Hz), 3.35 (2H, s), 2.75 (2H, d, J=14 Hz), 2.33 (2H, d, J=14.0 Hz), 1.22 (3H, s), 1.02 (3H, s) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[CH2:15][OH:16].C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1>C1COCC1.O>[O:23]=[C:22]1[NH:1][C:2]2[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=2[CH2:15][O:16]1
Reactant: CCOC(=O)COc1ccc(N)c(CO)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc2c(c1)COC(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.4 %

Procedure:
To a solution of ethyl 2-(4-amino-3-(hydroxymethyl)phenoxy)acetate (0.2 g, 0.888 mmol) in THF (5 mL) was added CDI (0.216 g, 1.332 mmol) at 0° C. and stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate as eluent to yield ethyl 2-((2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-6-yl)oxy)acetate (0.03 g, 13%). 1H NMR: 400 MHZ, DMSO-d6: δ 1.22 (t, J=7.20 Hz, 3H), 4.17 (q, J=6.80 Hz, 2H), 4.72 (s, 2H), 5.23 (s, 2H), 6.79-6.86 (m, 3H), 10.01 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:27]=[CH:26][C:14]([O:15][C:16]4[CH:21]=[CH:20][C:19]([NH:22]C(=O)C)=[CH:18][CH:17]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:4]=2[N:5]=[CH:6][N:7]=1.O.NN>O>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:14]2[CH:26]=[CH:27][C:11]([C:10]3[C:3]4[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=4[N:8]([C:28]([CH3:29])([CH3:31])[CH3:30])[CH:9]=3)=[CH:12][CH:13]=2)=[CH:17][CH:18]=1
Reactant: CC(=O)Nc1ccc(Oc2ccc(-c3cn(C(C)(C)C)c4ncnc(N)c34)cc2)cc1
Agent: NN
Solvent: O
Product: CC(C)(C)n1cc(-c2ccc(Oc3ccc(N)cc3)cc2)c2c(N)ncnc21
Temperature: 25 °C

Procedure:
A mixture of N-{4-[4-(4-amino-7-tert-butylpyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]-phenyl}acetamide (1.8 g), prepared as described in Example 9, industrial methylated spirit (5 ml) and hydrazine hydrate (30 ml) was boiled under reflux for 36 hours. The reaction mixture was cooled to ambient temperature, diluted with water (100 ml) and the mixture extracted with ethyl acetate (3×50 ml) to give 5-[4-(4-amino-phenoxy)phenyl]-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine. The structure was confirmed by 1H nmr.