Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[CH2:9])[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[C:29]1[O:33][C:32]([CH3:34])=[N:31][CH:30]=1)[NH2:25].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([O:10][C:8]([C:6]1[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=[C:2]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([C:29]3[O:33][C:32]([CH3:34])=[N:31][CH:30]=3)=[C:22]([O:21][CH3:20])[CH:23]=2)[N:7]=1)=[CH2:9])[CH3:12]
Reactant: C=C(OCC)c1cc(COCC(F)(F)F)nc(Cl)n1
Reactant: COc1cc(N)ccc1-c1cnc(C)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(COCC(F)(F)F)nc(Nc2ccc(-c3cnc(C)o3)c(OC)c2)n1
Temperature: 120 °C

Procedure:
2-Chloro-4-(1-ethoxyvinyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (0.10 g, 0.34 mmol) was dissolved in dioxane (5 mL). 3-Methoxy-4-(2-methyloxazol-5-yl)aniline (0.069 g, 0.34 mmol), cesium carbonate (0.220 g, 0.67 mmol), palladium(II) acetate (0.011 g, 0.05 mmol) and 2-(dicyclohexylphosphino)biphenyl (0.018 g, 0.05 mmol) were added. The vial was capped, evacuated and flushed with nitrogen. The mixture was heated by microwave irradiation at 120° C. for 1.5 h. The solvents were evaporated. EtOAc was added and the mixture was filtered through a plug of silica. The solvents were evaporated and the residue was purified by column chromatography on silica eluting with EtAOc to give the title compound as a solid, 138 mg (88%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:11])=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].Cl[C:13]1[N:18]=[C:17]([N:19]([CH:29]2[CH2:31][CH2:30]2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:16]2=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:15]2[N:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>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.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[C:7]([C:6]1[C:5]([F:10])=[CH:4][C:3]([F:11])=[C:2]([NH:1][C:13]2[N:18]=[C:17]([N:19]([CH:29]3[CH2:31][CH2:30]3)[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:16]3=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:15]3[N:14]=2)[CH:9]=1)#[N:8]
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: N#Cc1cc(N)c(F)cc1F
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)c(F)cc3F)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 100 °C
Yield: 86.9 %

Procedure:
A mixture of 5-amino-2,4-difluorobenzonitrile (300 mg, 1.947 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9) (691 mg, 1.947 mmol), Cs2CO3 (1268 mg, 3.89 mmol), DPPF (108 mg, 0.195 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (113 mg, 0.195 mmol), and Pd(OAc)2 (131 mg, 0.584 mmol) in a microwave vial was flushed with nitrogen. Dioxane (16 mL) was added and the vial was sealed and heated at 100° C. for 4 hr. The reaction was diluted with EtOAc and filtered through celite. The solvent was removed and radial silica gel chromatography eluting with hexane containing 5 to 40% EtOAc afforded 2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (799 mg) as a foam.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:4]2[C:3](=[O:8])[CH:2]([CH3:1])[NH:6][C:5]2=[O:7])=[CH:13][CH:12]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC1NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)NC(C)C2=O)cc1
Temperature: 90 °C
Reaction time: 9 h

Procedure:
To a mixture of 5-methylimidazolidine-2,4-dione (2.00 g), 4-methoxybenzyl chloride (2.85 mL) and potassium carbonate (3.15 g) were added N,N-dimethylformamide (20 mL) and potassium iodide (0.29 g), and the mixture was stirred at 90° C. for 9 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was recrystallized from ethyl acetate/diisopropyl ether to give the title compound (2.82 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([F:31])=[C:28]([CH:30]=1)[NH2:29])#[CH:23]>C(O)(C)C>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([F:31])=[C:28]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:30]=1)#[CH:23]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Reactant: C#Cc1ccc(F)c(N)c1
Solvent: CC(C)O
Product: C#Cc1ccc(F)c(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Yield: 63.1 %

Procedure:
4-Chloro-6,7-bis(2-methoxyethoxy)quinazoline (140 mg, 0.447 mmol) and 5-ethynyl-2-fluoroaniline (66 mg, 0.489 mmol) were reacted in refluxing isopropanol (3 mL) overnight under an atmosphere of N2. The solvent was removed by rotary evaporation and the residue was dissolved in CHCl3 and then treated with saturated aqueous NaHCO3. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was chromatographed on silica using 40% acetone/CH2Cl2 to provide 116 mg of the pure title product as its free base. This oil was dissolved in a minimum volume of CHCl3, diluted with several volumes of ether and titrated with 1M HCl in ether to precipitate the title product as a white solid (99 mg; 54%; LC-MS: m/z=412.1664, m/z(calc)=412.1667).
Reaction SMILES: [CH2:1]([S:15][CH2:16][CH2:17][OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26].[NH4+].[Cl-]>C1COCC1.C(OCC)C>[CH2:1]([S:15][CH2:16][CH2:17][O:18][C:25](=[O:27])[CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCSCCO
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCSCCOC(C)=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 72.2 %

Procedure:
2-Tetradecylsulfanyl-ethanol (0.54 g, 1.97 mmol) was dissolved in dry THF (10 ml) and pyridine (0.16 ml, 1.97 mmol) was added followed by acetyl chloride (0.15 m, 2.16 mmol). The resulting mixture was allowed to stir at ambient temperature for 23 hours, then another portion of acetyl chloride (0.075 ml, 1.08 mmol) and pyridine (0.080 ml, 0.95 mmol) was added. The mixture was stirred at ambient temperature for a further 90 minutes and then portioned between diethyl ether (30 ml) and 10% NH4Cl (30 ml). The organic layer was washed with brine (40 ml), dried (Na2SO4) and concentrated in vacuo. Toluene (10 mL) was added to the residue. The solvents were evaporated in vacuo and the crude product was purified by flash chromatography on silica gel (heptane:EtOAc 9:1) to afford 0.45 g (72%) of the title compound as a colorless solid.
Reaction SMILES: C([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[CH2:7][CH2:6]1)(=O)C.[Li+].[OH-]>C1COCC1>[OH:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[CH2:7][CH2:6]1
Reactant: CC(=O)OC1CCc2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2CCC3O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a solution of tert-butyl 4-(7-acetoxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.43 g, 1.2 mmol) in THF (15 mL) was added LiOH (3M, 6 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with 2N HCl (9 mL) and then extracted with DCM (3×100 mL). The organic phase was dried and concentrated. The residue was subject to chromatography on silica gel, eluted by DCM/MeOH (20:1) to afford the tert-butyl 4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.37 g, 97%). 1H NMR (CDCl3, 400 MHz) δ 8.51 (m, 1H), 5.06-5.04 (m, 1H), 3.80-3.69 (m, 4H), 3.56-3.45 (m, 4H), 3.10-3.05 (m, 1H), 2.94-2.86 (m, 1H), 2.51-2.44 (m, 1H), 2.00-1.94 (m, 1H), 1.48 (s, 9H). MS (APCI+) [M+H]+321.
Reaction SMILES: [CH3:1][N:2]1[CH2:29][CH2:28][CH2:27][C@:3]1([CH3:30])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:16]([O:21][CH3:22])[CH2:17][C:18]([OH:20])=[O:19])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5].N1C=CC=CC=1.FC(F)(F)C(O[C:42]1[C:47]([F:48])=[C:46]([F:49])[C:45]([F:50])=[C:44]([F:51])[C:43]=1[F:52])=O>ClCCl>[CH3:1][N:2]1[CH2:29][CH2:28][CH2:27][C@:3]1([CH3:30])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:16]([O:21][CH3:22])[CH2:17][C:18](=[O:20])[O:19][C:42]1[C:43]([F:52])=[C:44]([F:51])[C:45]([F:50])=[C:46]([F:49])[C:47]=1[F:48])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1C)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution (0° C.) of #196 (4.0 g, 9.4 mmol, 1 eq.) in dichloromethane (40 mL) was added dropwise pyridine (2.95 g, 37.6 mmol, 4 eq.) followed by a solution of pentafluorophenyl trifluoroacetate (3.9 g, 13.6 mmol, 1.4 eq.) in dichloromethane (5 mL). The mixture was stirred at room temperature for one hour, and the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 1 to 10% methanol in dichloromethane) to afford compound #197 (4.5 g, 81.2% (over three steps) as white solid.
Reaction SMILES: [CH:1]1([C:5]2[C:10]([F:11])=[C:9]([NH:12]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:8]=[C:7]([CH:32](OCC)[O:33]CC)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.CC#N>O>[NH2:12][C:9]1[C:10]([F:11])=[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[N:6]=[C:7]([CH:32]=[O:33])[CH:8]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(C2CCC2)n1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: Nc1cc(C=O)nc(C2CCC2)c1F
Yield: 89.3 %

Procedure:
Using the Procedure of Example 12, 2-cyclobutyl-6-(diethoxymethyl)-3-fluoro-N-tritylpyridin-4-amine (2.298 g, 4.5 mmol), conc H2SO4 (1 mL), CH3CN (35 mL) and H2O (35 mL) gave 4-amino-6-cyclobutyl-5-fluoropicolinaldehyde (0.780 g, 88%) as a white solid: mp 134-135° C.; 1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 7.22 (d, J=6.7 Hz, 1H), 4.34 (s, 2H), 3.90 (m, 2H), 2.51 (pd, J=9.3, 2.4 Hz, 3H), 2.32 (qt, J=8.5, 2.7 Hz, 3H), 2.03 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 193.39, 151.45 (d, J=14.5 Hz), 148.62 (d, J=5.4 Hz), 148.24 (d, J=253.9 Hz), 141.03 (d, J=12.5 Hz), 107.43 (d, J=3.6 Hz), 35.38 (d, J=2.0 Hz), 27.00 (d, J=1.6 Hz), 18.64; 19F NMR (376 MHz, CDCl3) δ −144.82; HRMS-ESI (m/z) [M+H]+ calcd for C10H11FN2O, 194.0855. found, 194.0855.
Reaction SMILES: [CH:1]([CH:3]1[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1)=[CH2:2].C(O)=O.C1(C)C=CC=CC=1>[Cl-].[Na+].O>[CH:1]([CH:3]1[CH2:12][CH2:11][C:6](=[O:7])[CH2:5][CH2:4]1)=[CH2:2]
Reactant: C=CC1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: O
Product: C=CC1CCC(=O)CC1
Yield: 87.5 %

Procedure:
103.3 g of the compound (22), 86.5 g of 98% formic acid and 200 mL of toluene were added to a reactor under nitrogen atmosphere, and stirred under refluxing and heating for 2 hours. After confirming that the reaction had been completed by GC analysis, the reaction mixture was poured into and mixed with 500 mL of brine at 0° C. The mixture was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with brine, followed by drying over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was distilled under reduced pressure to obtain 66.7 g of 4-vinylcyclohexanone (23) as a colorless transparent liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][C:14](O)=[O:15])[N:12]=2)[CH:5]=[CH:6][CH:7]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2cccc(Br)c2)nc1CC(=O)O
Solvent: C1CCOC1
Product: Cc1oc(-c2cccc(Br)c2)nc1CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A solution of 2-(3-bromophenyl)-5-methyl-4-oxazoleacetic acid (39.1 g, 0.13 mol) in dry THF (175 mL) was treated dropwise with borane-THF complex (227 mL of a 1.0 M solution in THF, 1.3 mol) over 2 h (reaction temperature to 35° C.). After stirring 2 h at room temperature under N2, the reaction was quenched with slow addition of methanol (60 mL) and stirred overnight at room temperature. The reaction was diluted with 1 N NaOH (50 mL) and extracted with CH2Cl2 (2×200 mL). The organic layer was washed with H2O (3×100 mL), dried (MgSO4), and the solvent removed in vacuo to give 38.7 g of crude product that was recrystallized from toluene (200 mL, wash solid with cold hexanes) to give 26.9 g (72%) of 2-(3-bromophenyl)-5-methyl-4-oxazoleethanol as a white powder. Mp 92-93° C.; 1H NMR (300 MHz, d6-DMSO) δ 7.99 (s, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 4.61 (t, J=5.5 Hz, OH), 3.63 (q, J=5.5 Hz, 2H), 2.60 (t, J=6.6 Hz, 2H), 2.32 (s, 3H).
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:7].Cl[C:15]1[C:19]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=2[S:17][N:16]=1.Cl>C(O)C>[C:6]([CH:8]([C:15]1[C:19]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=2[S:17][N:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:7]
Reactant: CCOC(=O)CC#N
Reactant: O=[N+]([O-])c1ccc2snc(Cl)c2c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C#N)c1nsc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A sodium ethoxide solution (previously prepared from ethanol and sodium (1.00 g, 0.0430 mol)) is cooled with an ice-acetone bath, treated portionwise with ethyl cyanoacetate (4.51 g, 0.0398 mol), stirred at room temperature for 30 minutes, treated with 3-chloro-5-nitro-1,2-benzisothiazole (4.27 g, 0.0199 mol), stirred at room temperature overnight, cooled to 0° C., and treated dropwise with 10% hydrochloric acid (15.0 mL). The resultant aqueous mixture is stirred at room temperature for one hour and filtered to obtain a solid. The solid is washed with ethanol and air-dried to give the title product as a yellow solid which is identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:35]
Reactant: CC(C)C(O)C(=O)O
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(C(=O)C(O)C(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.78 mmol) in CH2Cl2 (6 mL) was added triethylamine (217 μL, 1.56 mmol) followed by the addition of 2-hydroxy-3-methylbutanoic acid (120 mg, 1.0 mmol) and HATU (380 mg, 1.00 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O. The aqueous layer was extracted with CH2Cl2, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes gave 2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-methylbutan-1-one (230 mg, 70%). LC/MS: m/z 421.3 (M+H)+ at 2.43 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.45 (m, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.39 (m, 2H), 6.95 (m, 2H), 4.79 (d, J=7.2 Hz, 1H), 4.11 (dd, J=7.0, 5.9 Hz, 1H), 3.87 (m, 8H), 2.52 (s, 3H), 1.91 (m, 1H), 0.88 (dd, J=22.8, 6.7 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](Cl)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([NH2:18])[C:16]#[CH:17]>C(OCC)(=O)C.O>[CH2:15]([NH:18][S:11]([CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:13])=[O:12])[C:16]#[CH:17]
Reactant: C#CCN
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a cooled (0° C.) suspension of 4-nitrophenylmethanesulfonylchloride (0.510 g, 2.16 mmol) in ethyl acetate (3.0 mL) was added a solution of propargyl amine (1.0 mL, 14.5 mmol) in water (1.0 mL). The reaction mixture was stirred for 30 minutes and then diluted with ethyl acetate (30 mL) and washed with 1N HCl (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to provide 4-(prop-2-ynylaminosulfonylmethyl)nitrobenzene as a tan solid (0.437 g), which was used without further purification. 1HNMR (CDCl3): δ 8.25 (d, J=8.7 Hz, 2H), 7.66 (d, J=8.7 Hz, 2H), 4.48 (s, 3H), 3.98 (dd, J=2.7 and 6.3 Hz, 2H), 2.48 (t, J=2.7 Hz, 1H); LCMS: purity: 99%; MS (m/e): 253 (M−).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([CH2:14][C:15]#[N:16])[S:12][CH:13]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3([C:15]#[N:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:12][CH:13]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: BrCCOCCBr
Reactant: N#CCc1nc(-c2cc(F)cc(F)c2)cs1
Product: N#CC1(c2nc(-c3cc(F)cc(F)c3)cs2)CCOCC1
Yield: 59 %

Procedure:
This compound was synthesized from 2-(4-(3,5-difluorophenyl)thiazol-2-yl)acetonitrile using 2-bromoethyl ether as described in example 1 step 2 (1.0 g, yield 59%). MS (ESI) m/z: Calculated for C15H12F2N2OS: 306.06. found: 307.1 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C:11]1[C:12]([C:29]([CH3:32])([CH3:31])[CH3:30])=[C:13]([CH2:26][CH2:27][CH3:28])[C:14]2[O:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]=2[C:21]=1[C:22]([CH3:25])([CH3:24])[CH3:23])(=O)C.O>O1CCCC1>[OH:10][C:11]1[C:12]([C:29]([CH3:30])([CH3:32])[CH3:31])=[C:13]([CH2:26][CH2:27][CH3:28])[C:14]2[O:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]=2[C:21]=1[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCc1c2c(c(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C)CC(C)(C)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c2c(c(C(C)(C)C)c(O)c1C(C)(C)C)CC(C)(C)O2
Temperature: 25 °C
Yield: 32.1 %

Procedure:
Lithium aluminum hydride (0.08 g) was suspended tn tetrahydrofuran (5 ml) under a nitrogen atmosphere. A solution of 5-acetoxy-4,6-di-tert-butyl-2,2-dimethyl-7-propyl-2,3-dihydrobenzofuran (0.60 g) in tetrahydrofuran (5 ml) was added dropwise to the suspension and the mixture was refluxed for 4 h. After cooling the reaction mixture to room temperature, water was added dropwise to quench the excess lithium aluminum hydride. Thereafter 1N aqueous sodium hydroxide (5 ml) was added and the mixture was subjected to extraction with diethyl ether, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (5% ethyl acetate in n-hexane) to afford 5-hydroxy-4,6-di-tert-butyl-2,2-dimethyl-7-propyl-2,3-dihydrobenzofuran [0.17 g (yield, 32%)] as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:6]=2[CH:34]=1.C(O)(=O)C>ClCCl.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][NH:8][CH:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:6]=2[CH:34]=1
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2ccccc2F)=NC3)cc1OC
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2ccccc2F)NC3)cc1OC
Temperature: 0 °C
Yield: 67.1 %

Procedure:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,4-dimethoxy-phenyl)-amine (I-71, 49 mg, 0.10 mmol) was dissolved in dichloromethane (1.8 mL). Acetic acid (0.43 mL) was added and the solution was stirred and cooled to 0° C. Zinc dust (20 mg, 0.31 mmol) was then added and the mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature and stir for 4 hours. Additional zinc dust (10 mg, 0.15 mmol) and acetic acid (0.22 mL) was added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with dichloromethane. The organic layer was separated and washed with 1N NaOH, brine and then dried over magnesium sulfate, filtered and concentrated in vacuo. The yellow powder was purified by column chromatography (silica gel, ethyl acetate) to afford [9-Chloro-7-(2-fluoro-phenyl)-6,7-dihydro-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,4-dimethoxy-phenyl)-amine (I-72) as an orange solid (32 mg, 65%): MS m/z=477.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:33]=[CH:32][C:13]2[CH:14]([C:24]3[C:25](=[O:31])[NH:26][C:27](=[O:30])[NH:28][CH:29]=3)[C:15]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:16]=3[CH:17]=[CH:18][C:12]=2[CH:11]=1.N1C=CN=C1>CN(C)C=O>[CH3:5][C:4]([Si:1]([CH3:3])([CH3:2])[O:9][C:10]1[CH:33]=[CH:32][C:13]2[CH:14]([C:24]3[C:25](=[O:31])[NH:26][C:27](=[O:30])[NH:28][CH:29]=3)[C:15]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:16]=3[CH:17]=[CH:18][C:12]=2[CH:11]=1)([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc2c(c1)C=Cc1cc(O)ccc1C2c1c[nH]c(=O)[nH]c1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C=Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
Tert-butyl dimethylsilylchloride (0.98 g) was added to a mixture of the product from step (i) and imidazole (0.74 g) in dimethylformamide (20 ml). The reaction mixture was stirred for 3 hours and partitioned between water and ethyl acetate. The organic layer was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 50-70% ethyl acetate in isohexane. Yield 0.71 g.