Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]([CH3:17])([CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[N+]=[N-].[H][H]>C(OCC)(=O)C.[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[CH3:17][C:4]([NH2:1])([CH3:16])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:10][CH:11]=1
Reactant: CC(C)(Cc1ccc(C(F)(F)F)cc1)N=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(N)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.8 %

Procedure:
25.4 g of 1-(2-azido-2-methylpropyl)-4-(trifluoromethyl)benzene was dissolved in 210 mL of ethyl acetate and mixed with 0.84 g of 20 wt % palladium hydroxide carbon. The atmosphere in the reaction vessel was replaced with hydrogen gas, and the reaction solution was stirred at room temperature for 18 hours. After completion of the reaction, the palladium hydroxide carbon was filtered off, and the filtrate was mixed with 3 M hydrochloric acid and separated. The aqueous layer was basified with 5 M sodium hydroxide and extracted with methylene chloride. The organic layer was concentrated under reduced pressure to give 4.27 g of the desired product as a brown liquid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[N:14]=[CH:13][N:12]=[C:11]2[O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:37])=[CH:31]2.CCN(C(C)C)C(C)C.CO>ClCCl>[Cl:1][CH2:2][C:3]([N:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][O:18][C:17]2[CH:16]=[C:15]3[C:10]([C:11]([O:27][C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[NH:33][C:32]([CH3:37])=[CH:31]5)=[N:12][CH:13]=[N:14]3)=[CH:9][C:8]=2[O:7][CH3:6])[CH2:26][CH2:25]1)=[O:4]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCN(C(=O)CCl)CC1
Reaction time: 1 h

Procedure:
Chloroacetyl chloride (0.09 ml) was added dropwise to a solution of 6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[2-(piperazin-1-yl)ethoxy]quinazoline (0.45 g), prepared as described in Example 13, and PS-DIEA resin (0.66 g) in dichloromethane (15 ml). After 1 hour at ambient temperature, methanol was added and the reaction mixture was filtered. Solvents were removed by evaporation in vacuum and the residue was triturated under diethyl ether, filtrated and dried to give 7-{2-[4-(chloroacetyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline (0.36 g) as a solid.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15]O)=[CH:14][C:9]=2[N:8]=[N:7]1>C(OCC)C.O>[Br:2][CH2:15][C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH3:5])[N:7]=[N:8][C:9]=2[CH:14]=1
Reactant: Cn1nnc2cc(CO)ccc21
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: Cn1nnc2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus tribromide (0.230 ml, 2.45 mmol) is added to a stirred solution of (1-methyl-1H-1,2,3-benzotriazole-5-yl)methanol (0.4 g, 2.45 mmol) in diethyl ether (25 ml) under an inert atmosphere of Argon. After stirring overnight at room temperature, the reaction mixture is diluted with water (5 ml) and stirred vigorously for 10 minutes. The organic portion is separated, washed with water (2×5 ml), brine (2×5 ml) and concentrated in vacuo to yield the titled product which is used crude in the next step. (MH+ 226).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH2:9])[CH2:3]1.CN(C)/[CH:12]=[C:13](/[C:19](=[O:28])[C:20]1[CH:25]=[C:24]([I:26])[CH:23]=[CH:22][C:21]=1F)\[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>O>[I:26][C:24]1[CH:25]=[C:20]2[C:21](=[CH:22][CH:23]=1)[N:9]([CH2:8][CH:4]1[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]2=[O:28]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Reactant: CN1CCCC(CN)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(CC2CCCN(C)C2)c2ccc(I)cc2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
1-(1-Methylpiperidine-3-yl)methanamine (500 mg, 3.9 mmol) was added to the solution of (Z)-ethyl 3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.34M, 10.4 mL, 2.25 mmol) and the mixture was heated at 50° C. for 3 h. The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1.5 h. The residue was then dissolved in dimethyl formamide (7 mL) and potassium carbonate powder (695 mg, 5.1 mmol) was added. The reaction was heated at 70° C. for 3 h then cooled to room temperature. Water (30 mL) was added and the suspension was extracted with 1:1 ethyl acetate:methyl tert-butyl ether (3×50 mL). The organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. The residue was suspended in methyl tert-butyl ether (20 mL) and stirred at 40° C. for 1 h. The suspension was filtered and the solid dried to give 1.12 mg (69% yield) of ethyl 6-iodo-1-((1-methylpiperidin-3-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellowish powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CO.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2nn(-c3c(F)cccc3F)c3c(Cl)cnc(OC)c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ncc(Cl)c2c1c(-c1ccc(C(=O)O)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
To a mixture of methyl 4-(7-chloro-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4.3-c]pyridin-3-yl)benzoate (118 mg) in a mixed solvent of methanol (2 mL) and THF (1 mL) was added 1N aqueous sodium hydroxide solution (1 mL) at room temperature, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was neutralized with 1N hydrochloric acid under ice-cooling, and the mixture was concentrated under reduced pressure. The obtained solid was washed with water to give the title compound (78.0 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH:39]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[CH:39]1([NH:44][CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)[NH:16][N:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Reactant: NC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCNC4CCCC4)CC3)n[nH]c12
Yield: 6.8 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-Chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-fluorophenyl)-1H-indazole-7-carboxamide (Example 38a) (0.222 mmol) in DMF (4 mL) was reacted with K2CO3 (61 mg, 0.444 mmol) and cyclopentyl amine (110 uL, 1.11 mmol) to afford the title compound (8 mg, 7% for 2 steps).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2.[Cl:14][CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1>[Cl:14][CH2:15][CH2:16][N:10]1[C:11]2[C:7](=[CH:6][C:5]([O:4][CH3:3])=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(ccn2CCCl)c1
Temperature: 25 °C
Yield: 35.7 %

Procedure:
Into a flask of 500 ml capacity fitted with a stirrer and cooling tube, there were introduced 7.2 g (corresponding to 0.21 mol) of an oil dispersion of NaH, and 50 ml of tetrahydrofuran, and stirred on an ice-water bath. To this mixture there was added dropwise, a little at a time, a solution of 30.87 g (0.21 mol) of 5-methoxyindole dissolved in 100 ml of tetrahydrofuran. After completion of the dropwise addition, the ice-water bath was removed and the mixture was cooled for one hour at room temperature. Then, 49.29 g (0.21 mol) of 2-chloroethyl-p-toluene sulfonate were added, and reacted for 15 hours while stirring, heating under reflux. After completion of the reaction, the insoluble material was removed by filtration, and concentration was performed under reduced pressure. The reaction mixture was then purified by column chromatography using silica gel, to obtain 15.7 g of 1-(2-chloroethyl)-5-methoxyindole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[I:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[C:13]([O-])([O-])=O.[K+].[K+].CI>O>[CH3:13][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[I:11])[C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2cc(O)c(I)cc21
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1cc2c(cc1I)C(=O)CC2

Procedure:
The product of Example 60 was added to methyl ethyl ketcne (50 ml), K2CO3 (5 g) and methyl iodide (5 ml) then heated at reflux for 4 1/2 hrs. The reaction was cooled, H2O added, followed by an EtOAc extraction. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and evaporated. Trituration of the residue afforded the desired compound after filtration, m.p. 129° C.-30° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH:10]1(B(O)O)[CH2:12][CH2:11]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:10]1([C:2]2[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=2[F:8])[CH2:12][CH2:11]1
Reactant: OB(O)C1CC1
Reactant: Nc1ccc(F)c(Br)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(F)c(C2CC2)c1
Temperature: 100 °C
Yield: 63.7 %

Procedure:
To a solution of 3-bromo-4-fluorophenylamine (synthesized as described in J. Org. Chem. 1981, 46, 2280-2286) (415 mg, 2.18 mmol), cyclopropyl boronic acid (244 mg, 2.84 mmol), potassium phosphate (1.62 g, 7.64 mmol), and tricyclohexyl phosphine (61 mg, 0.22 mmol) in toluene (10 ml) and water (0.5 ml) was added palladium acetate (25 mg, 0.11 mmol) and the reaction mixture was heated to 100° C. overnight. The mixture was then cooled to RT and diluted with water and extracted with ether. The organic phases were combined, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography to give 3-cyclopropyl-4-fluorophenylamine (210 mg, 64%). MS (ISP) 152.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH2:8]([O:19][C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)=[N:24][CH:25]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH2:8]([O:19][C:20]1[CH:25]=[N:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:4][C:3](=[O:5])[C@@H:2]([CH3:1])[CH2:6][CH3:7])=[CH:28][CH:27]=2)=[N:22][CH:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCC(C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCOc1cnc(-c2ccc(OC(=O)[C@@H](C)CC)cc2)nc1
Yield: 70 %

Procedure:
Pour 0.328 g of 2-methylbutanoic acid synthesized from (s)-amylalcohol ([α]D23 -5.8° (neat)), 1.1 g of 4-(5-n-undecyloxy-2-pyrimidinyl)phenol, 8 ml of anhydrous chloroform and 0.662 g of 4-dimethylaminopyridine, S,S'-dicyclohexylcarbodimide into a 25 ml flask and allow to react for one whole day at room temperature. After the reaction, filter and separate the insoluble matters, and extract the reaction product with chloroform. The organic layer is washed with water, 2N hydrochloric acid and water, dried and evaporated to remove the organic solvent. The reaction product is purified with silica gel chromatography and re-crystallized crystal, and then optically active (s)-5-n-undecyloxy-2-[4-(2-methylbutanoyloxy)phenyl]pyrimidine is obtained at a yield of 70%.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[N:7]2[C:8]3[CH:9]=[C:10]([C:15](O)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C1COCC1.C(Cl)Cl.C1COCC1>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([NH:26][C:15]([C:10]2[CH:11]=[CH:12][C:13]3[CH:14]=[C:6]4[C:5](=[O:18])[NH:4][CH2:3][C:2]([CH3:19])([CH3:1])[N:7]4[C:8]=3[CH:9]=2)=[O:16])[CH:28]=1
Reactant: Nc1cccnc1
Reactant: CC1(C)CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)CNC(=O)c2cc3ccc(C(=O)Nc4cccnc4)cc3n21
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a suspension of 24 mg (0.093 mmol) of 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid in 2:1 CH2Cl2/THF (3 mL) was added 16 μL (0.19 mmol) oxalyl chloride followed by two drops of 10% DMF in THF. After stirring for 1 h, the mixture was concentrated and 1 mL of CH2Cl2 was added followed by 17 mg (0.19 mmol) of 3-aminopyridine and 33 μL (0.19) of diisopropylethylamine. The mixture was stirred overnight, concentrated, and chromatographed (0-8% MeOH in CH2Cl2) to provide 30 mg of the title compound. ESI-MS m/z 3335 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH:23]=[CH:24][C:25]([O:27][CH3:28])=[O:26])=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[S:11][C:5]=2[N:4]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3]1=[O:33]>[Pd].C(O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:20])([F:21])[F:22])[S:11][C:5]=2[N:4]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:3]1=[O:33]
Reactant: COC(=O)C=Cc1c(Cc2ccccc2C(F)(F)F)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1c(Cc2ccccc2C(F)(F)F)sc2c1c(=O)n(C)c(=O)n2CC(C)C

Procedure:
A slurry of 10% palladium on charcoal in ethanol was added to a solution of 3-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-[[2-(trifluoromethyl)phenyl]methyl]thieno[2,3-d]pyrimidin-5-yl]-2-propenoic acid, methyl ester, (2.17 g, Example 3 step a)) in ethanol (75 ml) and hydrogenated at 4 bar for 48 hours. The solution was filtered through a glass fibre filter and the filtrate concentrated under reduced pressure. The residue was purified by flash silica chromatography eluting with 1% ethanol in dichloromethane to give the sub-title compound as a white solid (1.27 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:50])([CH3:49])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH2:34][CH2:33][C:32]([CH3:40])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH:30]=2)[CH:9]=1.C1C(=O)N([Br:58])C(=O)C1>C(#N)C>[CH3:46][Si:45]([CH3:48])([CH3:47])[CH2:44][CH2:43][O:42][CH2:41][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:49])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH2:34][CH2:33][C:32]([CH3:40])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH:30]=2)[C:9]=1[Br:58]
Reactant: CCOC(=O)C1(C)CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)C1(C)CC=C(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
Ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-methylcyclohex-3-enecarboxylate (Int-18f, 152 mg, 0.212 mmol) was dissolved in acetonitrile (5 mL) and NBS (38 mg, 0.212 mmol) was added. The mixture was stirred at room temperature for 3 h and then concentrated. The residue was purified with a column (silica gel, 0-30% ethyl acetate in hexane) which gave ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-methylcyclohex-3-enecarboxylate (Int-18g) (139 mg). HPLC-MS tR=3.04 min (UV254 nm); mass calculated for formula C39H54BrN5O4Si2 791.3, observed LCMS m/z 792.2 (M+H).
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([Cl:20])=[CH:15][N:14]=2)[CH:9]=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])(=[O:5])[OH:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CC(=O)CC>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([Cl:20])=[CH:15][N:14]=2)[CH:9]=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])(=[O:4])[O:5][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH3:2]
Reactant: CCP(=O)(O)c1cc(Oc2ncc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCP(=O)(OCC(=O)OC)c1cc(Oc2ncc(Cl)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of P-ethyl-2-nitro-5-(3,5-dichloro-2-pyridyloxy)phenylphosphinic acid (0.42 g., 1.2 mmol), potassium carbonate (2.0 mg), methyl bromoacetate (0.2 ml., 2.4 mmol), and 2-butanone (20 ml.) is heated under reflux for 2 hours. The reaction mixture is filtered and concentrated, and the crude product is purified by prep. TLC (50% ethyl acetate/hexane) to give methoxycarbonylmethyl P-ethyl-2-nitro-5-(3,5-dichloro-2-pyridyloxy)phenylphosphinate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C[O-].[Na+].[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25%) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10% HCl was added and the mixture extracted with 4×75 mL ethyl acetate. The extracts were dried over MgSO4, filtered and concentrated to afford 8.47 g (94%) of a brown oil which was carried on without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.C(N(CC)C(C)C)(C)C.[CH3:23][Si:24]([CH2:27][CH2:28][O:29][CH2:30]Cl)([CH3:26])[CH3:25]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:13])=[CH:3][C:2]=1[O:1][CH2:30][O:29][CH2:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23]
Reactant: COc1cc2c(cc1O)CCC2=O
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OCOCC[Si](C)(C)C)CCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 5-hydroxy-6-methoxy-indan-1-one (21.1 g, 0.118 mol, see preparation in J. Org. Chem. 57, 1992, 589-594) and N,N-diisopropylethylamine (21.6 mL, 0.124 mol) in CH2Cl2 (200 mL) was added SEMCl (21.3 mL, 0.121 mol). The mixture was stirred at room temperature for 2 hours and diluted with NaHCO3 solution. After separation, the organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography eluted with EtOAc/hexane (3:7 to 1:1) to give 26.3 g (72%) of the desired product as brown oil. MS (ESI) m/z: 309.0 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm −0.01 (s, 9H) 0.96 (t, J=8.25 Hz, 2H) 2.66 (t, J=5.70 Hz, 2H) 3.03 (t, J=5.70 Hz, 2H) 3.80 (t, J=8.25 Hz, 2H) 3.90 (s, 3H) 5.36 (s, 2H) H) 7.20 (s, 1H) 7.22 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C([Li])CCC.C[O:17][B:18](OC)[O:19]C>C1(C)C=CC=CC=1.C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:18]([OH:19])[OH:17])=[CH:3][C:4]=1[O:9][CH3:10]
Reactant: COc1cc(Br)ccc1Cl
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(B(O)O)ccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To 4-bromo-1-chloro-2-methoxybenzene (2.2 g, 9.9 mmol) in toluene/THF (16/6 mL) at −78° C. was added n-butyl lithium (8.7 mL, 1.6 M in hexane, 14 mmol) dropwise. The reaction was stirred at −78° C. for 30 min, then trimethylborate (2.2 mL, 19.8 mmol) was added. The reaction was allowed to warm to rt and stirred overnight and then quenched with 1 M HCl (15 mL). The organic layer was separated and dried over sodium sulfate. The solvent was removed and the crude product was purified by flash column chromatography to give 50A (1.2 g, 65% yield) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.87 (m, 3H) 7.11 (d, J=7.83 Hz, 1H) 7.20 (s, 1H) 7.29 (d, J=7.83 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([C@H:18]2[O:20][C@@H:19]2[CH2:21][OH:22])[CH:15]=[CH:16][CH:17]=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C@@H:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=2)[C@H:19]([OH:20])[CH2:21][OH:22])=[CH:4][CH:3]=1
Reactant: OC[C@H]1O[C@@H]1c1cccc(F)c1
Reactant: Fc1ccc2cc[nH]c2c1
Product: OC[C@@H](O)[C@H](c1cccc(F)c1)n1ccc2ccc(F)cc21

Procedure:
In an analogous manner to EXAMPLE 117, step 5. (2S,3S)-3-(6-fluoro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol was prepared from 6-fluoro-1H-indole and [(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47 step 3). MS (ESI) m/z 304.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:28][CH2:29][N:30]([CH:33]3[CH2:35][CH2:34]3)[C:31](=[O:32])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]1[CH:76]=CC(CN(CCO)C(C2C(OCC3C=CC=CC=3)=C(O)N=C(CC3(C4C=CC=CC=4)CCCC3)N=2)=O)=[CH:39][CH:38]=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:28][CH2:29][N:30]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:36])=[CH:76][CH:35]=3)[C:31](=[O:32])[C:10]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Reactant: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)Cc1ccc(F)cc1
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1Cc1ccc(F)cc1
Yield: 52.2 %

Procedure:
This compound was prepared following the same method as described for 9-benzyloxy-2-cyclopropyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (286) from 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (4-fluoro-benzyl)-(2-hydroxyethyl)-amide (313) (91 mg, 0.16 mmol). The product was obtained as a colorless sticky solid (46 mg, 52.2%).