Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH3:29])[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([CH:20]=1)[C:17](O)=[O:18])(=[O:11])=[O:10].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:7][N:8]([CH3:29])[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([CH:20]=1)[C:17]([NH:36][C:32]1[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=1)=[O:18])(=[O:10])=[O:11]
Reactant: Nc1cccnc1
Reactant: CN(C)S(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of oxalyl chloride (0.06 ml, 0.69 mmol) in dichloromethane (5 ml) was added dropwise over 1 minute to a stirred solution of 5-[(dimethylamino)sulfonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 63; 230 mg, 0.69 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 h, and then concentrated under reduced pressure to give the crude acyl chloride as a yellow solid. A solution of this crude acyl chloride in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (64.5 mg, 0.69 mmol) and diisopropylethylamine (0.12 ml, 0.69 mmol) in dichloromethane (20 ml) under nitrogen at 0° C. The reaction mixture was stirred at 25° C. for 1 h. The organic phase was washed with water (25 ml) three times and saturated brine (10 mL) two times, dried over sodium sulfate, and evaporated in vacuo to give the crude product as a orange oil. The product was crystallized from methanol to yield the title compound as a white solid. 170 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].Br[CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]2[O:12][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]([OH:6])[C:4]=2[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: COc1ccc(C=O)c(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2c(ccc(OC)c2Cl)C1O
Yield: 79.6 %

Procedure:
To a solution of (14h) (69.91 g., 0.375 mol) and diethyl bromomalonate (79.9 ml., 0.468 mol) in 2-butanone (400 ml.) was added freshly powdered anhydrous potassium carbonate (51.78 g.). The suspension was stirred vigorously and heated at reflux for 4.5 hours, then filtered and evaporated to dryness. The oil obtained was redissolved in carbon tetrachloride and filtered, then evaporated and recrystallized from chloroform with hexane to yield 79.6% of (15h), m.p. 115.5°-117° C. Analysis (C15H17ClO7) C,H.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[C:11]1[C:20]2[C:15](=CC=CC=2)[CH:14]=[CH:13][C:12]=1C=O>>[C:2]1([C:11]2[CH:20]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: O=Cc1ccc2ccccc2c1Br
Product: O=Cc1cccc(-c2ccccc2)c1

Procedure:
The title compound was synthesized using the same procedure employed for Example 370 (1), but with 3-bromobenzaldehyde as the starting material instead of 1-bromo-2-naphthaldehyde. The product was obtained as a colorless oil (320 mg, 82%).
Reaction SMILES: C(C1C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC(CC)=CN=1)C.Br[C:23]1[C:28]([CH3:29])=[N:27][C:26]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])=[C:25]([CH3:38])[N:24]=1.[C:39]1([NH2:49])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][N:40]=1>>[Cl:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[C:26]1[N:27]=[C:28]([CH3:29])[C:23]([NH:49][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=[CH:41][N:40]=2)=[N:24][C:25]=1[CH3:38]
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1Br
Reactant: Nc1nccc2ccccc12
Agent: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1Nc1nccc2ccccc12

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 2-bromo-5-(2,4-dichlorophenyl)-3,6-dimethylpyrazine and isoquinolin-1-amine, and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 2.36, 2.93, 6.75, 7.38, 7.53, 7.57, 8.96; HRMS (ESI+) calcd for C21H16Cl2N4 (M+H)+ 395.0830, found 395.0821.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][Mg]Br>C1COCC1>[Br:1][C:2]1[C:7]([CH:8]([OH:9])[CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccnc1Br
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cccnc1Br
Temperature: 0 °C

Procedure:
To a solution of 2-bromo-pyridine-3-carbaldehyde (0.14 g, 0.75 mmol) in dry THF (10 mL) was dropwise added methylmagnesium bromide (1.4 M, 0.59 mL, 0.82 mmol) at −20° C. The reaction was allowed to warm to 0° C. for 20 min and then quenched with aqueous ammonium chloride solution. The usual work up gave a crude material, which was purified by chromatography (silica gel, 40% EtOAc/hexanes). 1H NMR (300 MHz, CDCl3) 8.30 (m, 1H), 7.96 (m, 1H), 7.34 (m, 1H), 5.21 (q, 1H), 1.54 (d, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[O:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:24]=[C:25](B(O)O)[C:26]([F:29])=[N:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[Br:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C@@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]([CH3:20])([CH3:19])[O:10][C:9]3=[O:21])=[CH:4][CH:3]=2)[C:26]([F:29])=[N:27][CH:28]=1
Reactant: CC1(C)OC(=O)N(c2ccc(I)cc2)[C@H]1c1ccccc1
Reactant: OB(O)c1cc(Br)cnc1F
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: C1COCCO1
Solvent: O
Product: CC1(C)OC(=O)N(c2ccc(-c3cc(Br)cnc3F)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A microwave vial was charged with (S)-3-(4-iodophenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (Intermediate C)(0.200 g, 0.509 mmol), 5-bromo-2-fluoropyridine-3-boronic acid (0.224 g, 1.017 mmol)(commercially available from Alfa Aesar, Ward Hill, Mass.), sodium carbonate (0.162 g, 1.526 mmol), dioxane (3.0 mL), and water (0.600 mL). Tetrakis(triphenylphosphine)palladium(0) (0.059 g, 0.051 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture was then stirred at 100° C. in the microwave for 1 hour. The resulting reaction mixture was filtered through Celite® brand filter aid and the filtrate was concentrated to afford a yellow oil. The residual oil was purified by column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-25% EtOAc-hexane) to afford (S)-3-(4-(5-bromo-2-fluoropyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.104 g, 0.236 mmol, 46% yield) as a pale tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (s, 3H), 1.64 (s, 3H), 5.52 (s, 1H), 7.07-7.47 (m, 5H), 7.51-7.75 (m, 4H), 8.15-8.44 (m, 2H). m/z (ESI) 441, 443 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:11][S:12]([NH:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)(=[O:14])=[O:13]>>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([CH3:10])=[CH:3][C:2]([C:20]2[CH:21]=[C:16]([NH:15][S:12]([CH3:11])(=[O:13])=[O:14])[CH:17]=[CH:18][CH:19]=2)=[CH:7]1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Cc1cc(Br)cn(C)c1=O
Product: Cc1cc(-c2cccc(NS(C)(=O)=O)c2)cn(C)c1=O

Procedure:
5-Bromo-1,3-dimethylpyridin-2-one was treated with [3-(methanesulfonamido)phenyl]boronic acid in a manner similar to Example 94 to give the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz): 9.74 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.62 (s, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.32 (s, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 3.52 (s, 3H), 3.02 (s, 3H), 2.08 (s, 3H). LCMS (M+H)+ 293.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:33])[N:15]([CH2:20][CH:21]4[CH2:25][CH2:24][CH2:23][N:22]4C(OC(C)(C)C)=O)[CH:16]=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:33])[N:15]([CH2:20][CH:21]4[CH2:25][CH2:24][CH2:23][NH:22]4)[CH:16]=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1Cn1cnc2cc(C#Cc3cccc(F)c3)ccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2ccc(C#Cc3cccc(F)c3)cc2ncn1CC1CCCN1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.6 %

Procedure:
A mixture of tert-butyl 2-((7-((3-fluorophenyl)ethynyl)-4-oxoquinazolin-3(4H)-yl)methyl)pyrrolidine-1-carboxylate (0.74 g) and TFA (4 mL) in dichloromethane (4 mL) was stirred at room temperature for 2.5 h. Then the reaction mixture was adjusted pH to 8-9 with saturated NaHCO3 and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product (0.4 g), which was used for the next step without further purification. MS (ESI): 348 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@H:13]3[NH:17][CH2:16][Si:15]([CH3:19])([CH3:18])[CH2:14]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([NH:24][C@@H:25]([CH:29]([CH3:31])[CH3:30])[C:26](O)=[O:27])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26]([N:17]1[C@H:13]([C:10]2[NH:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[N:9]=2)[CH2:14][Si:15]([CH3:19])([CH3:18])[CH2:16]1)=[O:27])[CH:29]([CH3:31])[CH3:30]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: C[Si]1(C)CN[C@H](c2nc(-c3ccc(Br)cc3)c[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1C[Si](C)(C)C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Yield: 66.1 %

Procedure:
A mixture of (R)-5-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-3,3-dimethyl-[1,3]azasilolidine (350 mg, 0.92 mmol, Preparation 9), (S)-2-methoxycarbonylamino-3-methyl-butyric acid (170 mg, 0.97 mmol), HATU (400 mg, 1.05 mmol), and DIPEA (700 mg, 5.4 mmol), in DCM (50 mL) was stirred at RT overnight. The reaction mixture was washed with water and brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography (20% EtOAc in petroleum ether) to give the title intermediate (300 mg, 66% yield) as a straw yellow solid. (m/z): [M+H]+ calcd for C21H29BrN4O3Si, 493.12 found 493.1.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])C.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([C:41]([CH2:50][C:51]2[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=2)([CH2:45][CH:46]=[C:47]([CH3:49])[CH3:48])[C:42]([OH:44])=O)(=[O:40])=[O:39])=[CH:34][CH:33]=1.[OH-:57].[Na+]>CO>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([C:5]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)([CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[C:4]([OH:29])=[O:3])(=[O:20])=[O:19])=[CH:22][CH:23]=1.[OH:57][NH:14][C:42](=[O:44])[C:41]([S:38]([C:35]1[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:37][CH:36]=1)(=[O:40])=[O:39])([CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)[CH2:45][CH:46]=[C:47]([CH3:48])[CH3:49]
Reactant: CCOC(=O)C(CC=C(C)C)(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: [OH-]
Agent: COc1ccc(S(=O)(=O)C(CC=C(C)C)(Cc2cccnc2)C(=O)O)cc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(CC=C(C)C)(Cc2cccnc2)C(=O)NO)cc1

Procedure:
2-(4Methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4 enoic acid was prepared starting from 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid ethyl ester (4.0 g, 9.5 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 3.2 g, 87%; ivory solid; mp 117-119° C.; MS: 390 (M+H)+. Starting from 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid (2.1 g, 5.4 mmol) and following the procedure as outlined in Example 1, 1.82 g of 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid hydroxyamide was isolated as a colorless solid. Yield: 82%; mp 89-92° C.; MS: 405 (M+H)+; 1H NMR (300 MHz, CDCl3): δ1.63 (s, 3H), 1.76 (s, 3H), 2.62-2.78 (m, 2H), 3.3 (d, J=4.0 Hz, 1H), 3.63 (d, J=4.0 Hz, 1H), 3.82 (s, 3H), 5.26 (m, 1H), 7.12-7.88 (m, 6H), 8.27-8.33 (m. 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[CH:14][N:13]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH2:33]([C:38]1[CH:39]=[N:40]C(Br)=[N:42][CH:43]=1)[CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:33]([C:38]1[CH:39]=[N:40][C:24]([N:21]2[CH2:22][CH2:23][CH:18]([C:15]3[CH:16]=[CH:17][C:12]([CH2:11][O:10][C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[N:4][N:3]=[N:2]5)=[CH:32][CH:31]=4)=[N:13][CH:14]=3)[CH2:19][CH2:20]2)=[N:42][CH:43]=1)[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(-n4cnnn4)cc3)nc2)CC1
Reactant: CCCCCc1cnc(Br)nc1
Product: CCCCCc1cnc(N2CCC(c3ccc(COc4ccc(-n5cnnn5)cc4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tert-butyl 4-[2-[4-(tetrazol-1-yl)phenoxymethyl]pyridin-5-yl]piperidine-1-carboxylate (Example 17) (52 mg, 0.12 mmol) and 5-pentyl-2-bromopyrimidine (41 μL, 0.24 mmol) following a procedure analogous to that in Example 48 as a white crystal (26 mg, yield 45%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])(=O)[O:5]CC)[CH3:2].C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[CH2:9]([P:4]([Cl:23])(=[O:5])[O:3][CH2:1][CH3:2])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCCCCCCCCCP(=O)(OCC)OCC
Solvent: ClCCl
Product: C=CCCCCCCCCCP(=O)(Cl)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10-undecenylphosphonic acid diethyl ester (53.51 g, 180 mmol) in CH2Cl2 (350 mL) was cooled to about −8° C. Oxalyl chloride (32 mL, 370 mmol, 2 eq.) was added slowly to the mixture, the mixture was warmed to room temperature and stirred overnight. Solvent was removed to dryness and the excess oxalyl chloride was azeotropically removed with hexane three times (100 mL). The mixture was dried in a vacuum oven at 40° C. overnight and the product was used without further purification.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15]Br)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]=[C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[NH:20]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15][N:27]3[CH2:26][CH2:25][CH:24]([N:23]4[C:22]5[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=5[NH:20][C:19]4=[O:18])[CH2:29][CH2:28]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CBr)Nc1ccc(C2CCCCC2)cc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)Nc1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A mixture of N-(4-cyclohexyl-phenyl)-2-bromoacetamide (50 mg, 0.17 mmol), 4-(2-keto-1-benzimidazolinyl)-piperidine (41 mg, 0.18 mmol), and potassium carbonate (34 mg, 0.25 mmol) in dimethylsulfoxide (2 mL) was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated to give a yellow oil. The crude oil was purified on reverse phase silica gel column using 100% acetonitrile to give N-(4-cyclohexyl-phenyl)-2-[4-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)-piperidin-1-yl]-acetamide as a yellow solid (21 mg, 30%): mp 130-132° C. 1H NMR (300 MHz, CDCl3) d 9.28 (s, 1 H), 9.05 (s, 1 H), 7.53 (d, 2 H), 7.22 (d, 2 H), 7.11 (m, 4 H), 4.33 (m, 1 H), 3.22 (s, 2 H), 3.12 (d, 2 H), 2.40-2.60 (m, 5 H), 1.70-1.90 (m, 7 H), 1.20-1.60 (m, 5 H). MS m/z 433 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.91 g), ethyl 2-(2-hydroxyphenyl)acetate (1.00 g), anhydrous potassium carbonate (0.76 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate as an oil (1.35 g, 54%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[N:5]2[CH:15]=[C:16]([CH2:18][OH:19])[N:17]=[C:4]2[CH:3]=1.[CH3:20][S:21]([NH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)(=[O:23])=[O:22]>>[OH:19][CH2:18][C:16]1[N:17]=[C:4]2[CH:3]=[C:2]([C:29]3[CH:30]=[C:25]([NH:24][S:21]([CH3:20])(=[O:22])=[O:23])[CH:26]=[CH:27][CH:28]=3)[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=3)[N:5]2[CH:15]=1
Reactant: Cc1cc(Nc2nc(Cl)cc3nc(CO)cn23)n[nH]1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: Cc1cc(Nc2nc(-c3cccc(NS(C)(=O)=O)c3)cc3nc(CO)cn23)n[nH]1

Procedure:
The title compound was synthesized using (7-chloro-5-(5-methyl-1H-pyrazol-3-ylamino)imidazo[1,2-c]pyrimidin-2-yl)methanol and 3-(methylsulfonamido)phenyl boronic acid using the procedure described in Example 278. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H) 3.06 (s, 3H) 4.70 (s, 2H) 6.75 (s, 1H) 7.31 (dd, J=7.96, 1.64 Hz, 1H) 7.50-7.61 (m, 2H) 7.89 (d, J=8.08 Hz, 1H) 8.15 (s, 1H) 8.57 (s, 1H) 10.02 (s, 1H) 10.97 (s, 1H) 12.37 (s, 1H); ESI-MS: m/z calc'd for C18H19N7O3S 413.45; found 414.3 (M+H)+
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[NH2:8][C@:9]([C:13]([OH:15])=[O:14])([CH3:12])[CH2:10][CH3:11].[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1.Cl>O.C(O)(C)C>[Cl:16][C:17]1[N:22]=[C:21]([NH:8][C@:9]([CH3:12])([CH2:10][CH3:11])[C:13]([OH:15])=[O:14])[CH:20]=[CH:19][N:18]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC[C@@](C)(N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC[C@@](C)(Nc1ccnc(Cl)n1)C(=O)O
Temperature: 87.5 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a solution of K2CO3 (526.2 mg, 3.80 mmol) in water (1.6 mL, 6 volume) was added isovaline-HCl (292.4 mg, 1.90 mmol). The resulting solution was stirred for 10 minutes. A solution of [14C] enriched 2,4-dichloropyrimidine (11a**) (0.261 g, 90 mCi) in isopropanol (5.2 mL, 20 volume) was added dropwise at room temperature, and the resulting mixture was heated at 85-90° C. for 18 hours. The mixture was then concentrated to 4 volumes, then 1N NaOH (6 mL) and isopropyl acetate (6 mL) were added. The aqueous phase was separated and the organic phase was extracted with 1N NaOH (6 mL×2). The combined aqueous layer was acidified to pH=3.0-3.5 using 6N HCl (aq). The resulting solution was extracted with isopropyl acetate (15 mL×3). The collected organic layer was concentrated to 3-4 volumes, then 1N HCl etherate (1.73 mL, 1.73 mmol) was added drop wise at 0° C. and stirred for 15 minutes. The organic solvent was decanted and the solid was washed with isopropyl acetate (5 mL×2). The solid was dried under vacuum and obtained 360 mg of (R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a**) with 70% radiochemical purity by instant imager to provide (R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a**).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.[CH2:10]([O:17][C:18](=[O:30])[CH2:19][N:20]1[C:25]([CH3:26])=[C:24]([Cl:27])[N:23]=[C:22](Cl)[C:21]1=[O:29])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOC(C)=O>[CH2:10]([O:17][C:18](=[O:30])[CH2:19][N:20]1[C:25]([CH3:26])=[C:24]([Cl:27])[N:23]=[C:22]([NH:9][CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:21]1=[O:29])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCc1ccccc1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)nc(NCCc2ccccc2)c(=O)n1CC(=O)OCc1ccccc1

Procedure:
2-Phenethylamine (0.38 ml, 3.0 mmol) was added to a stirred mixture of (3,5-dichloro-6-methyl-2-oxo-2H-pyrazin-1-yl)acetic acid benzyl ester (327 mg, 1.00 mmol) in EtOAc (2 ml) and the resulting mixture was heated to reflux under argon. After 2 h the reaction was cooled, diluted with EtOAc (the product is sparingly soluble), washed with 10% citric acid solution and brine, dried (Na2SO4) and evaporated in vacuo to give 1-3 as a crystalline solid. 1H NMR (CDCl3) δ2.21 (s, 3 H, CH3), 2.93 (t, J=7.1 Hz, 2 H, PhCH2), 3.67 (q, J=7.1 Hz, 2 H, CH2NH), 4.79 (s, 2 H, CH2), 5.21 (s, 2 H, CH2), 6.10 (br t, 1 H), 7.20-7.39 (m, 10 H, 2 Ph).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:20][N+:21]1[CH:26]=[C:25]([Cl:27])[N:24]=[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]=1.[C:36]([O:40][CH3:41])(=[O:39])[C:37]#[CH:38].O>CN(C=O)C>[CH2:29]([O:28][C:23]1[C:22]2[N:21]([N:20]=[CH:38][C:37]=2[C:36]([O:40][CH3:41])=[O:39])[CH:26]=[C:25]([Cl:27])[N:24]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C#CC(=O)OC
Reactant: N[n+]1cc(Cl)nc(OCc2ccccc2)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnn2cc(Cl)nc(OCc3ccccc3)c12
Reaction time: 8 h
Yield: 44.2 %

Procedure:
Potassium carbonate (457 mg, 3.31 mmol) was added to a mixture of 1-amino-3-(benzyloxy)-5-chloropyrazin-1-ium 2,4,6-trimethylbenzenesulfonate 5.34 (992 mg, 2.28 mmol) and methyl propiolate (0.24 mL, 2.66 mmol) in DMF (11 mL) at room temperature. After stifling overnight, reaction mixture was poured into water and extracted with ethyl acetate. Combined organics were washed with 50% brine, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-30% ethyl acetate/hexanes) to yield methyl 4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyrazine-3-carboxylate 5.35 (320 mg).