Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:18]C)[CH:5]=[CH:6][C:7]=1[C:8](=[O:17])[CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Br-].[Al+3].[Br-].[Br-]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[CH:6][C:7]=1[C:8](=[O:17])[CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCC(C)C(=O)c1ccc(OC)cc1F
Agent: [Al+3]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCCCCCC(C)C(=O)c1ccc(O)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
Then, 0.57 g (2.14 mmol) of the above (+)-3-fluoro-4-(2-methyloctanoyl) anisole and 6 ml of dried toluene were placed in a flask, to which was added 1.78 g (6.67 mmol) of anhydrous aluminum bromide while cooling on ice water. The resulting mixture was stirred under the cooling on ice water for 30 minutes and at room temperature for 6.5 hours. The reaction mixture was poured into 30 ml of ice water and extracted with toluene. The organic layer was washed with water, dried on magnesium sulfate, filtered and concentrated to obtain 0.55 g (2.18 mmol, yield: 100%) of brown oily 3-fluoro-4-(2-methyloctanoyl) phenol having the aforementioned physical and chemical properties.
Reaction SMILES: [NH3:1].[Cl:2][CH:3]([C:8](=O)[CH2:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5]>>[NH2:1][C:8]([CH2:9][CH3:10])=[C:3]([Cl:2])[C:4]([O:6][CH3:7])=[O:5]
Reactant: N
Reactant: CCC(=O)C(Cl)C(=O)OC
Product: CCC(N)=C(Cl)C(=O)OC
Yield: 80 %

Procedure:
Dry NH3 gas is passed through 48.9 g (0.30 mol) of methyl 2-chloro-3-oxovalerate at 70° C. for a period of 2 h. After removal of volatile constituents in vacuo, the crude product is dissolved in diisopropyl ether and washed with a little ice water. After drying over MgSO4, the solvent is removed in vacuo. Yield: 80.0% [GC]
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=3[F:43])(=[O:35])=[O:34])[C:27]=2[F:44])[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:46]>>[NH2:46][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=3[F:43])(=[O:35])=[O:34])[C:27]=2[F:44])[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(N)n3)s2)CC1
Temperature: 90 °C
Yield: 91.8 %

Procedure:
A suspension of 1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (110 mg, 0.165 mmol) in ammonium hydroxide solution (28%, 2 mL, 51.4 mmol) sealed in a 5-mL microwave tube was heated at 90° C. for 3 h under the microwave conditions. The mixture was concentrated and dried under high vacuum to give 98 mg of the title compound. MS (ESI): 647.3 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:17])[C:3]=1[C:18]#[N:19])=[CH:13][CH:12]=[C:11]([OH:16])[CH:10]=3.ClC[CH2:22][N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH2:24]1.BrCCOCC>>[NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:17])[C:3]=1[C:18]#[N:19])=[CH:13][CH:12]=[C:11]([O:16][CH2:27][CH2:28][N:23]1[CH2:22][CH2:26][CH2:25][CH2:24]1)[CH:10]=3
Reactant: N#Cc1c(N)nc2c(c1N)Cc1ccc(O)cc1O2
Reactant: ClCCN1C=CC=CC1
Agent: CCOCCBr
Product: N#Cc1c(N)nc2c(c1N)Cc1ccc(OCCN3CCCC3)cc1O2

Procedure:
2,4-diamino-8-(2-pyrrolidin-1-ylethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile was prepared from 2,4-diamino-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile in the same manner as described in Example 10, using 1-(2-chloroethyl)pyridine in lieu of 2-bromoethyl-ethylether. The product was isolated as a tan solid (100 mg, 46% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.O=P(Cl)(Cl)Cl.[OH-].[Na+].CN([CH:21]=[O:22])C>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:21]=[O:22])=[C:4]2[N:3]=1
Reactant: Clc1ccn2nccc2n1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine (200 mg, 1.31 mmol) in 1.5 mL DMF was added POCl3 (358 μL, 3.92 mmol). The reaction was stirred at room temperature overnight. The mixture was cooled to 0° C. in ice bath and then neutralized with 6M NaOH. The solid formed was isolated by filtration and air dried to give 165 mg of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde as yellow solid (70% yield). LCMS (M+1=182)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:12])[CH2:9][CH2:10][I:11])[CH:5]=[CH:6][CH:7]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:12])[CH2:9][CH2:10][I:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCI)c1cccc(Cl)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O[C@H](CCI)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
1-(3-Chlorophenyl)-3-iodopropan-1-one: Intermediate 12A (2.415 g, 8.14 mmol) was dissolved in acetone (40.7 mL) and the above solution was cooled to 0° C. and Jones Reagent (6.08 ml, 16.29 mmol) was added dropwise. The reaction mixture turned orange/brown and was allowed to stir at 0° C. for 30 min. To the mixture was added 10 mL of isoproponal (reaction mixture turned green) and was then allowed to stir at rt for 10 min. The reaction mixture was then diluted with EtOAc and water. The organic layer was washed with water (3×) and brine, dried with magnesium sulfate, filtered and concentrated to yield a light yellow oil (which solidified into long yellow needles). The crude product was then purified using silica gel chromatography to yield the desired product as a white solid (2.16 g, 90%). MS (ESI) m/z: 294.8 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.93 (t, J=1.6 Hz, 1H), 7.85-7.81 (m, 1H), 7.59-7.56 (m, 1H), 7.47-7.42 (m, 1H), 3.65-3.60 (m, 2H), 3.49-3.43 (m, 2H) ppm.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][C@H:32]3[CH3:38])[N:27]=[C:26]([CH3:39])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12]CC2C=CC=CC=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][C@H:32]3[CH3:38])[N:27]=[C:26]([CH3:39])[N:25]=2)=[O:21])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCN(C)C[C@H]2C)n1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CCN(C)C[C@H]2C)n1
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To a solution of [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (15.60 g, 28.8 mmol) in methanol (115 mL) was added Pd/C (50% water, 3.1 g). The mixture was hydrogenated under balloon pressure for 2 h, and then filtered through a glass fiber filter. The solution was then concentrated in vacuo and azeotroped with EtOAc (100 mL). The resulting solid was triturated with 70% EtOAc in hexanes, and collected by vacuum filtration. The supernatant was concentrated in vacuo and crystallized from EtOAc-hexanes, and the solid was combined with the first crop of material. The combined solid was dried overnight under high vacuum to give [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide (8.15 g, 18.05 mmol, 62.7% yield) as a white solid. LCMS: (M+H)+: 451.8.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O.C(OCC)(=O)C>O1CCCC1>[N:14]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:4])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(CN1CCOCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 2-bromo-4′-nitroacetophenone (4.0 g) in dry tetrahydrofuran (60 mL) was treated with morpholine (2.84 mL). After stirring at room temperature for a further 30 minutes the reaction mixture was treated with water (100 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with brine (100 mL), then dried over magnesium sulfate and evaporated. The residue was triturated with diethyl ether to give the title compound (2.72 g) as a yellow solid, Rf 0.60 (dichloromethane:methanol:triethylamine, 85:10:5). 1H NMR [(CD3)2SO]: δ 8.32 (d, 2H), 8.20 (d, 2H), 3.90 (s, 2H), 3.58 (t, 4H) and 2.48 (t, 4H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:32]=[C:33]([CH2:35][CH2:36][OH:37])[CH:34]=1)[CH2:12][N:13]1[CH2:31][CH2:30][C:16]2([O:21][CH2:20][CH2:19][N:18]([C:22]([C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)=[O:23])[CH2:17]2)[CH2:15][CH2:14]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[F:8][C:9]1[CH:34]=[C:33]([CH2:35][CH:36]=[O:37])[CH:32]=[C:11]([CH2:12][N:13]2[CH2:31][CH2:30][C:16]3([O:21][CH2:20][CH2:19][N:18]([C:22]([C:24]4[N:25]=[C:26]([CH3:29])[S:27][CH:28]=4)=[O:23])[CH2:17]3)[CH2:15][CH2:14]2)[CH:10]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cc(F)cc(CCO)c4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cc(F)cc(CC=O)c4)CC3)C2)cs1
Reaction time: 0.08 h

Procedure:
TFA (0.08 mL) was added to a solution of (9-(3-fluoro-5-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4-yl)methanone (example 19, step b) (0.46 g) in DCM (5 mL) at 0° C. and the resulting mixture stirred for 5 min. Dess-Martin periodinane (0.68 g) was then added and the mixture stirred at RT for 45 min. Saturated sodium thiosulphate solution (5 mL), saturated sodium bicabonate solution (5 mL) and ethyl acetate (20 mL) were then added and the mixture stirred for 10 min. The aqueous phase was separated and extracted with ethyl acetate (20 mL). The combined organic solutions were washed with brine, acidified with acetic acid (0.1 mL), dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a yellow gum. Yield 0.4 g.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([CH2:20][N:21]2[CH2:25][CH:24]([CH3:26])[NH:23][C:22]2=[O:27])[CH2:3]1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:34][S:35]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([CH2:20][N:21]2[CH2:25][CH:24]([CH3:26])[NH:23][C:22]2=[O:27])[CH2:3]1)(=[O:37])=[O:36]
Reactant: CC1CN(C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1CN(C[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2S,4R)-4-hydroxy-2-(4-methyl-2-oxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (4.30 g) in dichloromethane (50 ml) were added successively pyridine (1.1 ml), 4-(N,N-dimethylamino)pyridine (1.39 g) and methanesulfonyl chloride (0.97 ml) under ice-cooling and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-(4-methyl-2-oxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (4.76 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11](=[O:12])[C:10]([O:13][CH3:14])=[CH:9][N:8]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:7]=1)=[O:5].[CH3:22][Mg+].[Br-]>C1COCC1>[C:4]([C:6]1[C:11](=[O:12])[C:10]([O:13][CH3:14])=[CH:9][N:8]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:7]=1)(=[O:5])[CH3:22]
Reactant: C[Mg+]
Reactant: COc1cn(-c2cccnc2)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cccnc2)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of N,5-dimethoxy-N-methyl-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxamide (0.40 g, 1.4 mmol) in THF (10 ml) was added dropwise 1 M MeMgBr in THF (3.0 ml, 3.0 mmol) at −78° C. After stirring at −78° C. for 2 h, the mixture was quenched with water (0.5 ml) and stirred at room temperature for 0.1 h. The mixture was concentrated under reduced pressure. The residue was partitioned between CHCl3 (25 ml) and brine. The aqueous layer was extracted with CHCl3 (25 ml×3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.21 g, 62% yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 2.70 (3H, s), 3.97 (3H, s), 7.49-7.56 (1H, m), 7.95 (1H, s), 8.01-8.08 (1H, m), 8.72 (1H, dd, J=4.7, 1.3 Hz), 8.95 (1H, d, J=2.6 Hz).
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]1)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.O.[OH-].[Na+]>C1COCC1.O>[CH3:6][NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN[C@H]1CC[C@H](N)CC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To the stirred solution of (trans)-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (4.29 g, 20.0 mmol) in THF (160 ml) (under argon atmosphere) was added LiAlH4 (3.13 g, 80 mmol) in three portions, at 0-5° C. The suspension was heated to 70° C. and stirred for additional 18 h. The reaction mixture was cooled to 0° C. and then subsequently addition of THF-H2O 1:1 (4 ml), 4M NaOH (8 ml) and water (12 ml). Stirring was continued for 3 h at RT. The white suspension was filtered (Celite) and the filtrate was concentrated in vacuo to get the crude title compound as a slightly yellow liquid. This material was used for the next step without further purifications.
Reaction SMILES: C(=O)([O-])[O-].[Cs+:5].[Cs+].[C:7]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]>O.CO>[C:7]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O-:17])=[O:16].[Cs+:5]
Reactant: O=C(O)CCCCCCCC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: O=C([O-])CCCCCCCC(=O)OCc1ccccc1

Procedure:
Aqueous cesium carbonate (1M, 6.3 ml) is added dropwise to a solution of benzyl hydrogen azelate (3.00 g, 10.77 mmol) in 75 ml water/methanol (1:15) until the pH reaches approximately 7, whereupon the solvent is removed under reduced pressure and the residue dried under vacuum overnight. The oily, yellowish semicrystalline residue is dispersed in dry dimethylformamide (50 ml) and evaporated to dryness in vacuo. This procedure is repeated twice, yielding an off-white crystalline product. The product is used without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:34])=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:34])=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1cn(C)c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)c(F)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ncc(-c2nc(-c3c(F)ccc4c(CCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
To a solution of ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1-methyl-1H-indol-3-yl]propanoate (D150) (270 mg) in isopropanol (7 mL) and water (7 mL) was added NaOH (5.6 mL, 0.5 M aq) at room temperature. The reaction suspension was stirred at 90° C. for 2 hours until the solution turned clear. Isopropanol was removed in vacuo and water (8 mL) was added to the residue. The aqueous solution was acidified to pH=1 and extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over sodium sulphate. The organic solution was concentrated and the residue was purified by MDAP to afford 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1-methyl-1H-indol-3-yl]propanoic acid (E108) (72 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.32 (6H, d), 2.53 (2H, t), 2.88 (2H, t), 3.28 (3H, s), 5.39 (1H, m), 7.02 (1H, m), 7.11 (1H, s), 7.75 (1H, m), 8.53 (1H, d), 8.90 (1H, d), 12.07 (1H, s). MS (ES): C22H20ClFN4O4 requires 458; found 459.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:31]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:34]5[CH:33]=[N:32][O:31][CH:35]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Reactant: OB(O)c1cnoc1
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: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cnoc5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 16-4), isoxazol-4-boronic acid (73 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and potassium carbonate (163 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (127 mg, 44%) as an orange solid.
Reaction SMILES: O.[SH-:2].[Na+].F[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]>CN(C=O)C>[SH:2][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)N2CCOCC2)c1
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(S)c(S(=O)(=O)N2CCOCC2)c1
Temperature: 60 °C
Yield: 89.6 %

Procedure:
Sodium hydrosulfide monohydrate (237 mg, 4.3 mmol) was added to a solution of 4-fluoro-3-(morpholine-4-sulfonyl)-benzoic acid (Example 6, 350 mg, 1.2 mmol) in DMF (15 mL) and the reaction mixture was heated at 60° C. for 20 hours under N2. After cooling to room temperature and quenching with 2M HCl, the reaction mixture was partitioned between ethyl acetate and water. Further extraction of the aqueous layer with ethyl acetate, combination of all organic layers, drying and concentration provided a white powder (326 mg, 89% yield): 1HNMR DMSO-d6) δ2.99 (t, J=4 Hz, 4H), 3.58 (t, J=4. Hz, H), 7.48 (d, J=8 Hz,1H), 7.87 (dd, J=8, 2 Hz, 1H), 8.29 (d, J=2 Hz, 1H), 13.20 (s, 1H): MS (ESI) [M−H]− m/z 304.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([CH2:10][C:11]([OH:13])=O)[N:4]=1)[CH3:2].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[CH3:33][N:34]([C@H:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51][CH2:50][CH2:49]1)[C:35]([C:37]1[N:38]=[C:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[S:40][CH:41]=1)=[O:36].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([CH2:10][C:11]([N:45]2[CH2:46][CH2:47][CH:42]([C:39]3[S:40][CH:41]=[C:37]([C:35]([N:34]([CH3:33])[C@H:48]4[C:57]5[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=5)[CH2:51][CH2:50][CH2:49]4)=[O:36])[N:38]=3)[CH2:43][CH2:44]2)=[O:13])[N:4]=1)[CH3:2]
Reactant: CCc1cc(CC)n(CC(=O)O)n1
Reactant: CN(C(=O)c1csc(C2CCNCC2)n1)[C@@H]1CCCc2ccccc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1cc(CC)n(CC(=O)N2CCC(c3nc(C(=O)N(C)[C@@H]4CCCc5ccccc54)cs3)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,5-diethyl-1H-pyrazol-1-acetic acid (135 mg, 0.74 mmol) (i.e. the product of Example 15, Step C) in ethyl acetate (5.0 mL) was treated with 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 1.0 mL, 1.6 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to a stirred suspension of N-methyl-2-(4-piperidinyl)-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide monohydrochloride (i.e. the product of Example 6, Step C) (210 mg, 0.53 mmol), triethylamine (0.5 mL, 3.75 mmol) in ethyl acetate (5 mL). The reaction mixture was then stirred at room temperature for 12 h. The resulting suspension was concentrated in vacuo and purified by MPLC on silica gel using ethyl acetate/hexanes as eluant to give 60 mg of the title product, a compound of the present invention as an oil.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:17]([NH:30][CH2:31][CH2:32][CH3:33])=[N:16][C:15]=2[N:14]([CH3:34])[C:13]1=[O:35])(C(C)(C)C)(C)C.Cl>C(O)C>[ClH:29].[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:18]2[C:19]3[C:20](=[O:21])[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[C:13](=[O:35])[N:14]([CH3:34])[C:15]=3[N:16]=[C:17]2[NH:30][CH2:31][CH2:32][CH3:33])=[CH:28][CH:27]=1
Reactant: CCCNc1nc2c(c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C)n1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: CCCNc1nc2c(c(=O)n(CCCO)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 202.7 %

Procedure:
Step 2 1-(3-((tert-Butyldimethylsilyl)oxy)propyl-7-(4-chlorobenzyl)-3-methyl-8-(propylamino)-1H-purine-2,6(3H,7H)-dione (0.15 g, 0.29 mmol) was dissolved in ethanol (3 mL) and 6N aqueous HCl (0.5 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction solvent was removed under reduced pressure to give 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(propylamino)-1H-purine-2,6(3H,7H)-dione hydrochloride (0.13 g, 100% yield) as a white foam. LCMS retention time=3.021 min and 99% purity, LCMS MH+ 406. 1H NMR (DMSO-d6) δ 7.31 (dd, 4H, J=8 Hz and 42 Hz), 6.15-6.48 (brd s, NH2 and HCl), 5.30 (s, 2H), 3.84 (t, 2H, J=8 Hz), 3.38 (t, 2H, J=8 Hz), 3.34 (s, 3H), 3.26 (t, 2H, J=8 Hz), 1.59-1.68 (m, 2H), 1.46-1.57 (m, 2H), 0.81 (s, 3H, J=8 Hz).