Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([NH:10][C:11]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][N:14]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].IC.[NH4+].[Cl-]>C1COCC1>[C:6]([NH:10][C:11]([C:13]1[C:18]([CH3:1])=[C:17]([Cl:19])[CH:16]=[CH:15][N:14]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: [Li]CCCC
Reactant: CC(C)(C)NC(=O)c1cc(Cl)ccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(Cl)ccnc1C(=O)NC(C)(C)C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 29 mL, 72 mmol) is added dropwise to N-tert-butyl-4-chloropyridine-2-carboxamide (7.00 g, 32.9 mmol) in THF (70 mL) at −78° C. After 1 h at −78° C. iodomethane (6.8 mL, 109 mmol) is added and stirring is continued for 1 h. Saturated NH4Cl (10 mL) is added and the organic layer is separated, dried and evaporated under reduce pressure to give a residue that is purified by flash chromatography (eluent 0-20% EtOAc/cyclohexane) to furnish N-tert-butyl-4-chloro-3-methyl-pyridine-2-carboxamide (5.7 g, 76%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:10]1([C:2]2[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1cccc(Br)c1
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Product: OCc1cccc(-c2ccccc2)c1
Yield: 129.7 %

Procedure:
This compound was prepared in a manner analogous to that of Example 4, Step B, using 10.0 grams (0.054 mole) of 3-bromophenyl-methanol, 7.2 grams (0.059 mole) of phenylboronic acid, 0.25 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0), and 66 mL (0.135 mole) of aqueous 2M sodium carbonate in 50 mL of toluene. The crude product from this reaction was combined with a previous smaller run conducted on 4.6 grams (0.020 mole) of 3-bromophenylmethanol. The combination was subjected to column chromatography on silica gel. Elution was accomplished using 20:1 methylene chloride and ethyl acetate. The appropriate fractions were combined and concentrated under reduced pressure, yielding 12.9 grams of 3-phenylphenylmethanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: O1C=C(CN)N=C1.[CH3:8][N:9]1[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][NH2:16])=[N:10]1.[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=3)[C:31](O)=[O:32])[C:24]2=[O:37])=[CH:20][CH:19]=1>>[CH3:8][N:9]1[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][NH:16][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][N:36]=[C:28]([N:25]3[CH2:26][CH2:27][N:23]([CH2:22][C:21]4[CH:20]=[CH:19][C:18]([F:17])=[CH:39][CH:38]=4)[C:24]3=[O:37])[CH:29]=2)=[N:10]1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: Cc1cc(CN)nn1C
Agent: NCc1cocn1
Product: Cc1cc(CNC(=O)c2ccnc(N3CCN(Cc4ccc(F)cc4)C3=O)c2)nn1C
Yield: 70 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (1,5-dimethyl-1H-pyrazol-3-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, N-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 70% yield: mp 150-152° C.; 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.33 (d, J=5.1 Hz, 1H), 7.38-7.36 (m, 1H), 7.28-7.23 (m, 2H), 7.05-6.97 (m, 2H), 6.87 (br s, 1H), 5.98 (s, 1H), 4.53 (d, J=5.1 Hz, 2H), 4.42 (s, 2H), 4.02 (t, J=8.1 Hz, 2H), 3.71 (s, 3H), 3.35 (t, J=8.1 Hz, 2H), 2.21 (s, 3H); MS (ES+) m/z 422.9 (M+1).
Reaction SMILES: [SH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:4]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][CH2:32][CH2:33]2>>[C:28]1([O:27][CH2:26][CH2:25][CH2:24][CH2:23][S:1][CH2:2][CH:3]2[CH2:7][O:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:4]2)[C:29]2[CH2:30][CH2:31][CH2:32][CH2:33][C:34]=2[CH:35]=[CH:36][CH:37]=1
Reactant: BrCCCCOc1cccc2c1CCCC2
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OCC(CS)S1
Product: CCOC(=O)CCC1(CCC(=O)OCC)OCC(CSCCCCOc2cccc3c2CCCC3)S1

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 1 (2.0 g, 0.006 mol) and the bromide produced in Example 7 (1.7 g, 0.006 mol). The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 2.5 g (77%) of the product as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27]#[N:28])=[CH:19][CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[Cl:8][C:7]1[C:2]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27]#[N:28])=[CH:19][CH:18]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CC1(C)OB(c2ccc(C#N)c3ccccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2nccnc2Cl)c2ccccc12
Temperature: 80 °C
Yield: 242.8 %

Procedure:
A mixture of 2,3-dichloropyrazine (2.98 g, 2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthonitrile (0.558 mmol, 2 mmol) palladium tetrakis triphenylphoshine (0.069 g, 0.06 mmol) and aqueous sodium carbonate solution (2M, 3 mL, 6 mmol) in dioxane (7 mL) was heated to 80° C. for 12 hours. The reaction mixture cooled to room temperature, washed with water, extracted with ethyl acetate and purified by chromatography to yield 4-(3-chloropyrazin-2-yl)-1-naphthonitrile (0.36 g, 68%).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6](=[O:15])[CH:7]=[CH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:4].C(N(CC)CC)C.Cl>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH2:3]([O:5][C:6](=[O:15])/[C:7](/[Br:1])=[CH:8]/[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:4]
Reactant: BrBr
Reactant: CCOC(=O)C=CC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(Br)=C/C1CCCCC1
Temperature: -10 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
Add a solution of bromine (43.5 mL, 848 mmol) in carbon tetrachloride (500 mL) to a solution of 3-cyclohexyl-acrylic acid ethyl ester (154.5 g, 848 mmol) in dichloromethane cooled to −10° C. such that the temperature does not exceed 0° C. Stir the reaction mixture for 2 h at −10° C., and then add triethylamine (143 mL, 1.02 mol), again such that the temperature does not exceed 0° C. Allow the stirred reaction mixture to warm to r.t. overnight. Then dilute it with dichloromethane (500 mL), cool the resulting mixture to 0° C., and adjust the pH to a value of less than 2 by the careful addition of 1 N aqueous hydrochloric acid. Separate the resulting two layers, and extract the aqueous phase with dichloromethane (1 L). Combine the extract and the first organic layer, dry them over magnesium sulfate, and concentrate them under vacuum to afford a yellow oil. Apply a solution of this oil in dichloromethane to a silica gel column, and elute with a 1:1 mixture of dichloromethane and cyclohexane to afford the title compound as a yellow oil (103.5 g). MS (m/e): 262 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:23])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:14]=1)[C:9]([OH:11])=O.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:28]1[N:29]=[C:25]([NH:24][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([O:5][C@@H:4]([CH3:23])[CH2:3][O:2][CH3:1])[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:12]=2)[S:26][CH:27]=1)[CH3:35]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(F)cc2)cc(C(=O)O)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=O)c2cc(Oc3ccc(F)cc3)cc(O[C@@H](C)COC)c2)n1

Procedure:
{2-[3-(4-Fluoro-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoylamino]-thiazol-4-yl}-acetic acid ethyl ester was prepared from 3-{(1S)-2-methoxy-(methylethyl)oxy}-5-{[4-fluoro phenyl]oxy}benzoic acid (prepared as described in general synthetic descriptions F) and ethyl 2-aminothiazol-4-ylacetate following general procedure A.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH:18]([OH:20])[CH3:19])[CH:11]=[CH:10]1.N1C=CN=C1>O1CCCC1>[Si:1]([O:20][CH:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[NH:9][CH:10]=[CH:11]2)[CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)c1cccc2cc[nH]c12
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)c1cccc2cc[nH]c12
Temperature: 20 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
Add tert-butyldimethylsilyl chloride (16.4 g, 108 mmol) in anhydrous tetrahydrofuran (100 ml) to 1-(indol-7-yl)ethan-1-ol (10.7 g, 66.4 mmol) and imidazole (11.8 g, 173 mmol) in anhydrous tetrahydrofuran (100 ml). Stir at 20° C. for 2 hours. Dilute with hexanes (400 ml). Wash with 0.25 M aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. Dry over magnesium sulfate and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with hexane containing 10-25% ethyl acetate to provide the desired compound (16 g, 87%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:42]=[CH:41][CH:40]=[CH:39][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:38])=[C:8]([CH3:37])[C:9]=1[C:10]([C:12]1[CH:31]=[CH:30][C:15]([O:16][S:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([OH:29])[CH:21]=2)(=[O:19])=[O:18])=[C:14]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:13]=1)=[O:11].[I-].[Mg+2].[I-].[C:46](OC(=O)C)(=[O:48])[CH3:47]>CCOCC>[C:46]([O:29][C:22]1[CH:21]=[C:20]([S:17]([O:16][C:15]2[CH:30]=[CH:31][C:12]([C:10]([C:9]3[C:8]([CH3:37])=[C:7]([CH3:38])[O:6][C:5]=3[CH2:4][C:3]3[CH:39]=[CH:40][CH:41]=[CH:42][C:2]=3[Br:1])=[O:11])=[CH:13][C:14]=2[CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)(=[O:19])=[O:18])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])(=[O:48])[CH3:47]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1oc(Cc2ccccc2Br)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2ccc(C(=O)c3c(Cc4ccccc4Br)oc(C)c3C)cc2C2CCCC2)ccc1C(=O)O
Yield: 25 %

Procedure:
The title compound was prepared according to the procedure in Example 22 using 4-{4-[2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoic acid (0.318 g, 0.487 mmol), magnesium iodide (0.132 g, 0.475 mmol) and acetic anhydride (3.8 mL) in ether. Purification on 2% H3PO4/MeOH treated silica gel, eluting with a 30% EtOAc/pet ether gave 0.083 g (25%) of the title compound as a solid, mp 79° C. 1H NMR (DMSO-d6) δ 1.27-1.33 (m, 2H), 1.51-1.54 (m, 2H), 1.63-1.73 (m, 4H), 1.79 (s, 3H), 2.17 (s, 3H), 2.24 (s, 3H), 2.93 (quintet, 1H), 3.91 (s, 2H), 7.13-7.17 (m, 2H), 7.21 (d, 1H), 7.30 (dt, 1H), 7.51 (dd, 1H), 7.55 (dd, 1H), 7.60 (d, 1H), 7.85 (d, 1H), 7.90 (dd, 1H), 8.14 (d, 1H)13.8 (br s, 1H). mass spectrum (−ESI) m/z 693/695 (M−H). Anal. Calcd. for C34H31BrO9S: C, 58.71; H, 4.49; N, 0.00. Found: C, 58.04; H, 4.52; N, 0.04.
Reaction SMILES: C1(O[C:8](=[O:33])[CH2:9][C@H:10]([O:22][C:23](=[O:32])[CH:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])C=CC=CC=1.Cl[Si](C)(C)C>[Zn].CCOCC>[CH2:25]([C:24]1[C:23](=[O:32])[O:22][C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:9][C:8]=1[OH:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCC[C@H](CC(=O)Oc1ccccc1)OC(=O)C(Br)CCCCCC
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CCOCC
Product: CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.3 %

Procedure:
In a flame-dried flask under N2 a mixture of 336 mg (5.14 mmol) zinc and 510 mg (0.99 mmol) (R)-3-[(2-bromo-1-oxooctyl)oxy]tetradecanoic acid phenyl ester in 5.0 mL 20% v:v Et2O:chlorotrimethylsilane was heated at reflux with rapid stirring for 20 minutes. The mixture was cooled to room temperature and suction filtered through a coarse fritted funnel, using a pad of celite, and washing with 5 mL Et2O. The homogenous filtrate was cooled in an ice/H2O bath and 5 mL tap H2O was added with stirring. After 10 min, the mixture was poured into 50 mL tap H2O and extraction with 3×25 mL Et2O was performed. The combined organic layers were washed with 25 mL brine and dried over MgSO4. The Et2O was removed by rotary evaporation, giving a white solid. The solid was stirred with 6.0 mL hexanes for 30 min, followed by suction filtration through a medium fritted funnel. The product was washed with 2.0 mL hexanes and dried under 26" vacuum at room temperature for 1.5 h, giving 235 mg (67%) (R)-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-2H-pyran-2-one as a white powder, mp=109°-111° C.; [α]20D=-43.5° (1% in dioxane).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O1CCCC1>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:18]2[CH2:19][CH2:20][N:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[F:8])[CH2:16][CH2:17]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)cc1)N1CCN(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
Triethylamine (1.37 mL, 9.78 mmol) was added at 0° C. to a stirred solution of 1-(2-fluorophenyl)piperazine (0.705 g , 3.91 mmol) in tetrahydrofuran (12 mL) and the reaction mixture was stirred at room temperature for 15 minutes. 4-Bromo-benzenesulfonyl chloride (1.00 g, 3.91 mmol) was added to the reaction mixture at room temperature and the reaction mixture was stirred at room temperature for 5 hours. Tetrahydrofuran was evaporated off under reduced pressure. The residue was diluted with ethyl acetate (20 mL), and the inorganic salts were filtered through a celite bed. The filtrate was washed with 2.0 N aqueous HCl (8 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to provide 1.40 g (89%) of 1-(4-bromobenzenesulfonyl)-4-(2-fluoro-phenyl)piperazine as white solid. MS cald. for C16H16BrFN2O2S [M+] 399, obsd. 399.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:7]=1.[Cl:32][C:33]1[N:38]=[C:37](Cl)[C:36]([F:40])=[CH:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:28]([O:27][C:25]([NH:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:35]2[C:36]([F:40])=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=2)=[CH:7][C:6]=1[CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(Nc3nc(Cl)ncc3F)ccc2NC(=O)OC(C)(C)C)c1
Yield: 63.7 %

Procedure:
To a solution of tert-butyl [3-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)phenyl]carbamate (0.4 g, 0.9 mmol) and 2,4-dichloro-5-fluoropyrimidine (0.156 g, 0.936 mmol) in N,N-dimethylformamide (7 mL) was added potassium carbonate (0.662 g, 4.79 mmol). The resultant mixture was stirred overnight at rt overnight. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to give the desired product (0.32 g, 61%). LCMS for C28H33ClFNaN5O4 (M+Na)+: m/z=580.2.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:14](Cl)[CH2:15]Cl.CI.[CH3:20][C:21]([OH:23])=[O:22]>C(Cl)Cl.[Zn]>[C:1]([O:13][C@H:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:14][CH3:15])[CH2:20][C:21]([OH:23])=[O:22])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCC(=O)O
Reactant: ClCCCl
Reactant: CC(=O)O
Agent: [Zn]
Solvent: ClCCl
Solvent: CI
Product: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCCCC

Procedure:
A solution of the compound prepared in Example 1-(2) (2.5 g, 5.68 mmol) was treated with undecanoic acid (1.16 g, 6.25 mmol) and EDC.MeI (2.08 g, 7.0 mmol) in CH2Cl2 (60 mL) and then deprotected as described in Example 1-(3) with zinc (9.3 g, 142 mmol) in AcOH (40 mL) to afford (R)-3-undecanoyloxytetradecanoic acid as a colorless oil: 1H NMR (CDCl3) δ 0.89 (t, 6 H, J=6.7 Hz), 1.0-1.75 (m, 44 H), 2.29 (m, 2 H), 2.61 (m, 2 H), 5.22 (m, 1 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CC(N(C)C)=O>[CH3:12][O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH2:18][CH2:17]1
Reactant: COCCN1CCNCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Solvent: CC(=O)N(C)C
Product: COCCN1CCN(c2ccc([N+](=O)[O-])cc2C)CC1

Procedure:
A solution of 0.95 g (6.06 mmol) 2-fluoro-5-nitrotoluene and 0.99 g (6.67 mmol) 1-(2-methoxyethyl)piperazine in 10 ml dimethylacetamide is stirred at 120° C. for 20 h. After that the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, EtOAc) to afford the title compound as an oil.
Reaction SMILES: [F-].[K+].[Si]([C:7]([F:10])([F:9])[F:8])(C)(C)C.[CH2:11]([O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26](I)[CH:27]=2)[N:22]=[N:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN1CCCC1=O.[Cu]I>[CH2:11]([O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:7]([F:10])([F:9])[F:8])[CH:27]=2)[N:22]=[N:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Ic1ccc2nncc(OCc3ccccc3)c2c1
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc2nncc(OCc3ccccc3)c2c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Into a 500 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed CuI (6.4 g, 33.68 mmol, 1.20 equiv), a solution of KF (1.97 g, 33.97 mmol, 1.20 equiv) in 1-methylpyrrolidin-2-one (250 mL), TMS-CF3 (4.828 g, 34.00 mmol, 1.20 equiv) and 4-(benzyloxy)-6-iodocinnoline (as prepared in the previous step, 10.2 g, 28.18 mmol, 1.00 equiv). The reaction mixture was stirred for 24 h at 50° C. in an oil bath. The reaction was then quenched by the addition of 30 mL of ammonia and 300 mL H2O. The resulting solution was extracted with 3×300 mL of ether, and the combined ether portions was washed with 2×200 mL of brine, dried (Na2SO4), and concentrated under vacuum. The title compound was obtained as a brown solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]([CH3:18])[CH3:17])=[C:9]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:8]=2)[CH2:3]1.[C:33]([OH:38])([CH2:36][CH3:37])(C)C.C([O-])(O)=O.[Na+].C(Cl)(=O)C=C>C(Cl)Cl>[CH:16]([N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:33](=[O:38])[CH:36]=[CH2:37])[CH2:3]1)=[N:8][C:9]=2[NH:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1)([CH3:18])[CH3:17]
Reactant: CCC(C)(C)O
Reactant: CC(C)n1cnc2c(Nc3ccc(N4CCN(C)CC4)cc3)nc(N3CC[C@H](N)C3)nc21
Agent: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1CCN(c2nc(Nc3ccc(N4CCN(C)CC4)cc3)c3ncn(C(C)C)c3n2)C1
Yield: 33 %

Procedure:
(S)-2-(3-Aminopyrrolidin-1-yl)-9-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl) -9H-purin-6-amine (315 mg, 0.7 mmol) was dissolved in DCM:tert-pentyl alcohol (15 mL:1.5 mL) and sat. aq. NaHCO3 (6 mL) was added in one portion. The bi-phasic mixture was stirred vigorously and acryloyl chloride (90 μL, 1.1 mmol, 1.5 mol eq) was added in one portion and the resulting mixture was stirred at ambient temperature for 2 hr. The reaction was diluted with DCM (30 mL) and the organic layer was separated, and the product was extracted with more DCM:tert-pentyl alcohol (9:1, 30 mL). The combined organics were dried over Na2SO4 and evaporated to give a residue that was purified via silica flash chromatography with gradient of 100% ethyl acetate to 100 ethanol to give a crude purity at ˜90%. This crude was triturated with ethyl acetate:heptane (4:1, 15 mL). The resulting white solid was collected by filtration, washed with ethyl acetate:heptane (4:1, 10 mL) and dried to give the title product as a white solid (118 mg, 33% yield, ˜95% purity). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (s, 1 H) 8.36 (d, J=6.72 Hz, 1 H) 7.91 (s, 1 H) 7.85 (d, J=8.80 Hz, 2 H) 6.87 (d, J=8.93 Hz, 2 H) 6.18-6.34 (m, 1 H) 6.03-6.15 (m, 1 H) 5.59 (dd, J=9.96, 2.02 Hz, 1 H) 4.62 (dt, J=13.33, 6.54 Hz, 1 H) 4.43 (d, J=5.14 Hz, 1 H) 3.71-3.87 (m, 1 H) 3.63 (dt, J=12.62, 6.46 Hz, 2 H) 3.43 (dd, J=11.25, 3.30 Hz, 1 H) 3.07 (m, J=4.65 Hz, 4 H) 2.45 (m, J=4.40 Hz, 4 H) 2.22 (s, 4 H) 1.89 (dd, J=11.37, 5.87 Hz, 1 H) 1.51 (d, J=6.72 Hz, 6 H). m/z (APCI+) for C26H35N9O 490.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][N:26]([CH3:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[C:31]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CN(C)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3cccc(N(C)C)c3)n2n1
Temperature: 110 °C
Yield: 25.5 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 80 mg, 0.232 mmol), 3-(dimethylamino)phenylboronic acid (49.8 mg, 0.302 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17 mg, 23 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.774 mL of 1,4-dioxane and 0.387 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (35-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (25.4 mg, 26%). 1H NMR (DMSO-d6) δ: 11.09 (s, 1H), 7.90-7.98 (m, 2H), 7.86 (s, 1H), 7.48-7.60 (m, 2H), 7.31-7.38 (m, 1H), 7.28-7.32 (m, 1H), 7.19 (d, J=8.1 Hz, 1H), 6.92 (dd, J=8.1, 2.3 Hz, 1H), 6.30 (s, 1H), 2.91 (s, 6H), 2.33 (s, 3H), 1.39 (s, 6H); ESI-MS: m/z 430.3 (M+H)+.