Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:9]([NH:11][OH:12])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>CN(C)C=O.O>[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[C:13]([N:11]([C:9](=[O:10])[C@@H:2]([CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1)[NH2:1])[OH:12])=[O:23])([OH:18])=[O:17]
Reactant: N[C@H](Cc1c[nH]cn1)C(=O)NO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: N[C@H](Cc1c[nH]cn1)C(=O)N(O)C(=O)c1ccccc1C(=O)O
Reaction time: 4 h
Yield: 44.9 %

Procedure:
D-Histidine hydroxamic acid (1.9 g, 11.2 mMol) was dissolved in dimethylformamide (75 ml) and water (100 ml). Phthalic anhydride (1.65 g, 11.2 mMol) was added, the solution stirred 4 hours, evaporated to an oil which was crystallized from water/ethanol, and crystallized again from water to yield 1.6 g, m.p. 175° (dec.) of N-(2-carboxybenzoyl)-D-histidine hydroxamic acid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](O)=[O:20].C(N=C=NCCCN(C)C)C>ClCCl>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][NH:12][C:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1)=[O:20]
Reactant: O=C(O)c1ccccn1
Reactant: NNC(=S)NC1CC2C=CC1C2
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(NNC(=S)NC1CC2C=CC1C2)c1ccccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.9 %

Procedure:
A mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.545 mmol), picolinic acid (67 mg, 0.545 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (104 mg) in dichloromethane (5 mL) was stirred at room temperature for 24 h and isolated as a white solid (47 mg, 30%). 1H NMR (CDCl3): 10.57 (s, 1H), 9.20 (s, 1H), 8.63 (d, J=4.2 Hz, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.89-7.83 (m, 1H), 7.51-7.47 (m, 1H), 7.02 (brs, 1H), 6.16-6.06 (m, 2H), 4.11 (s, 1H), 2.96 (s, 1H), 2.83 (s, 1H), 1.84-1.76 (m, 1H), 1.38-1.28 (m, 3H).
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][C:15]#[C:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][C:15]#[C:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N(CCC#Cc1cccs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)N(CCC#Cc1cccs1)C(=O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 100 mg of 1d in 1 ml of dioxane was mixed with a solution of 40 mg of KOH in 400 μl of water and stirred for 16 hr at RT. The mixture was diluted with 5 ml of water and acidified to pH3 with 0.5 N HCl. The product was extracted with ethyl acetate and the extracts were washed once with sat. NaCl, dried and concentrated, to provide 65 mg of essentially pure 1e as colorless oil; MS-ESI: [M+1] 280.16; NMR (CDCl3) δ 1.54 (s, 9, tertC4H9), 2.80 (m, 2, CH2), 4.10 (bm, 2, CH2), 6.94, 7.13, 7.20 (3×m, 3, thiophene-H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[C:25]=3[F:26])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: OB(O)c1cccc(F)c1F
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cccc(F)c3F)cccc2c1N
Yield: 55.8 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2,3-difluorophenyl boronic acid (153 mg, 0.97 mmol) were reacted to afford the title compound (63 mg, 57.6% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.95 (dd, J=8.0 Hz, J′=1.7 Hz, 1H), 7.70-7.85 (m, 2H), 7.15-7.30 (m, overlapped with CHCl3), 3.46 (q, J=6.7 Hz, 2H), 1.66 (m, J=7.3 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H) MS APCI, m/z=343 (M+H) HPLC 2.08 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])([O-])=O.[K+].[K+].[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20].O>N1C=CC=CC=1>[F:23][C:22]([F:25])([F:24])[S:19]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)(=[O:20])=[O:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1cccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Oc1cccc2ncccc12)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 5-hydroxy-quinoline (8 g, 55 mmol) and K2CO3 (15.2 g, 110 mmol) in anhydrous pyridine (60 mL) under nitrogen was cooled to −20° C. Tf2O (13.97 mL, 83 mmol) was added drop-wise via syringe. The reaction mixture was stirred 1 hour at −20° C. then warmed to 0° C. for 1 hour then stirred at ambient temperature for 48 hours. The reaction mixture was then poured into H2O (200 mL) and extracted in CH2Cl2 (2×200 mL). The aqueous layer was acidified with 1 N HCl (100 mL) and back extracted with CH2Cl2 (2×200 mL). The organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (40% EtOAc/Hexanes) affording 13.97 g (90%) of the product as a pink oil: MS EI m/e 277 (M+).
Reaction SMILES: I[C:2]1[N:3]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:4]=[C:5]([C:7]([NH:9][C@H:10]([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:8])[N:6]=1.[C:40]([NH:46][C:47]1[N:48]=[C:49]([OH:59])[C:50]2[CH:56]=[C:55]([C:57]#[CH:58])[CH:54]=[N:53][C:51]=2[N:52]=1)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42].C(N(CC)CC)C>C(#N)C>[C:40]([NH:46][C:47]1[N:48]=[C:49]([OH:59])[C:50]2[CH:56]=[C:55]([C:57]#[C:58][C:2]3[N:3]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:4]=[C:5]([C:7]([NH:9][C@H:10]([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:8])[N:6]=3)[CH:54]=[N:53][C:51]=2[N:52]=1)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Reactant: COC(=O)CC[C@H](NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1)C(=O)OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@H](NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)n1)C(=O)OC
Yield: 66 %

Procedure:
Following the procedure of Example 1, dimethyl N-(2-iodo-1-triphenylmethylimidazol-4-ylcarbonyl)-L-glutamate (638 mg, 1.0 mmol), 2-pivaloylamino4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine (541 mg, 2.0 mmol), Pd(PPh)2Cl2 (35 mg, 0.05 mmol), cuprous iodide (19 mg, 0.1 mmol), triethylamine (0.7 mL), and acetonitrile (50 mL) yield dimethyl N-(2-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethynyl]-1-triphenylmethylimidazol-4-ylcarbonyl}-L-glutamate [515 mg, 66% after flash column chromatography (ethyl acetate:hexanes, 2:1), mp 93-95° C]: 1H NMR (CDCl3) δ 12.05 (br s, 1H), 8.43 (br s, 1H), 8.26 (s, 1H), 7.93 (d, 1H, J=2.2 Hz), 7.61 (s, 1H), 7.54 (d, 1H, J=7.6 Hz), 7.33-7.28 (m, 9H), 7.18-7.12 (m, 6H), 4.77 (m, 1H), 3.74 (s, 3H), 3.65 (s, 3H), 2.45 (m, 2H), 2.32 (m, 1H), 2.05 (m, 1H), 1.30 (s, 9H). HRMS calcd for C44H41N7O7 779.3067, found 779.3088.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:7])=[CH:4][CH:3]=1.[CH2:25]([NH:32][CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])[CH2:9][CH2:10][CH2:11][C:12]([N:32]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:13])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(c1ccccc1)N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCNCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(c1ccccc1)N(CCCC(=O)N(CCCC(=O)O)Cc1ccccc1)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(1-phenylethylamino)butyric acid and ethyl 4-benzylaminobutyrate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chorobenzoyl)-4-(1-phenylethylamino)butyryl]-4-benzylaminobutyric acid.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18](O)=[O:19])=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].CC[N:28](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N>CN(C=O)C>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18]([NH2:28])=[O:19])=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(C(=O)O)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: C=CCn1c(C(N)=O)nc2c1c(=O)n(CCCC)c(=O)n2CCCC

Procedure:
A stirred solution of 1,3-dibutyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid (1.0 g, 2.9 mmol) in anhydrous DMF (10 ml) was sequentially treated with DIPEA (1.1 ml), PyBOP, and 2M NH3 (3.6 ml). After 2 hours the product mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with sat. NaHCO3 (aq) solution, brine, then dried (MgSO4) and concentrated giving an orange oil (ca. 2 g). The product was purified by Biotage™ chromatography eluting with 5%→40% EtOAc/cyclohexane mixtures. The appropriate fractions were combined and concentrated to give the amide 90% pure (790 mg, 78%). m/z. 392.3[M+formic acid−H]−.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]3[CH:11]=[C:10]([CH2:12][OH:13])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1>C(Cl)Cl.CN(C=O)C.O=[Mn]=O>[CH:12]([C:10]1[N:9]=[C:7]2[N:6]([CH:11]=1)[C:5]1[CH:14]=[CH:15][C:2]([F:1])=[CH:3][C:4]=1[S:8]2)=[O:13]
Reactant: OCc1cn2c(n1)sc1cc(F)ccc12
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1cn2c(n1)sc1cc(F)ccc12

Procedure:
2-Formyl-7-fluoro-imidazo[2,1-b]-benzthiazole was prepared according to the procedure outlined in Example 1, (Step 3). Starting from 7-fluoro-imidazo[2,1-b]-benzthiazole-2-methanol (1.5 g 6.7 mmol) in methylene chloride/DMF(300 mL: 50 mL) and active MnO2 (12 g, excess), 1.1 g (78% Yield) of the aldehyde derivative was isolated as brown solid. (M+H) 221.
Reaction SMILES: O[CH:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[N+:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:18])=[O:17].[OH-].[K+].C(O)C>O>[N+:16]([CH:19]([CH:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:18])=[O:17]
Reactant: OC1c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C1c2ccccc2Oc2ccccc21)[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
9-Hydroxyxanthene (9.9 g, 50 mmol) and ethyl nitroacetate (6.1 mL, 55 mol) are mixed and heated at 100° C. (oil bath) for 1.5 hours. After cooling, a waxy mixture is suspended in 40 mL of absolute alcohol and 40 mL of 1.25 M of ethanolic potassium hydroxide solution is added. The solution is stirred for 45 minutes at room temperature and ethanol is stripped off. The remaining solid is suspended in water and extracted with diethyl ether. The aqueous portion is acidified with 85% phosphoric acid to pH 2 to 3 to give a white suspension which is cooled overnight. The precipitate is collected by filtration and dried in a vacuum oven at 50° C. This gives 9.18 g of the title compound as a white solid; mp 89°-91° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:3]=[CH:4][C:5]=1[O:15][CH3:16])=[O:14]
Reactant: COc1ccc(Br)cc1NC(=O)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C#C[Si](C)(C)C)cc1NC(=O)C(F)(F)F
Temperature: 60 °C
Yield: 43.1 %

Procedure:
To an oven-dried flask under N2 was added N-[5-bromo-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (1.53 g, 0.005 mol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)palladium(II) (0.45 g, 0.6 mmol), copper(I) iodide (73 mg, 0.38 mmol), and trimethylsilylacetylene (1.26 g, 13 mmol). Next, triethylamine (5.19 g, 50 mmol) was added dropwise and the resulting mixture was heated at 60° C. overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.68 g, 42%) as an off white solid. ESIMS (M−H)−=314.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[CH:18]=O)=[CH:4][CH:3]=1.[F:20][C:21]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:22]=1[NH2:23].[B][B][B][B][B][B][B][B][B][B]>C(O)(=O)C.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[CH2:18][NH:23][C:22]2[C:24]([F:29])=[CH:25][CH:26]=[C:27]([F:28])[C:21]=2[F:20])=[CH:4][CH:3]=1
Reactant: Nc1c(F)ccc(F)c1F
Reactant: CCOC(=O)c1cnc(C=O)n1-c1ccc(F)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cnc(CNc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
A solution of ethyl 1-(4-fluorophenyl)-2-formyl-1H-imidazole-5-carboxylate (16) (150 mg, 0.57 mmol), 2,3,6-trifluoroaniline (60.4 μL, 0.57 mmol), decaborane (14 mg, 0.11), acetic acid (2 drops), and methanol (6 mL) was stirred at room temperature overnight. The reaction was concentrated and the residue was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield ethyl 1-(4-fluorophenyl)-2-(((2,3,6-trifluorophenyl)amino)methyl)-1H-imidazole-5-carboxylate (23).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][N:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:15][CH3:16])[C:8](=[O:17])[C:7]([C:18]([OH:20])=O)=[CH:6]1.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C@H:39]([NH2:41])[CH3:40])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:22][O:21][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[CH:6]=[C:7]([C:18](=[O:20])[NH:41][C@@H:39]([C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)[CH3:40])[C:8](=[O:17])[C:9]([O:15][CH3:16])=[C:10]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)O)cn1CC(OC)OC
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: CC#N
Product: COC(=O)c1c(OC)c(=O)c(C(=O)N[C@H](C)c2ccc(F)cc2)cn1CC(OC)OC
Reaction time: 2 h

Procedure:
1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 0.500 g, 1.59 mmol), was suspended in acetonitrile (6 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.550 mL, 3.17 mmol), (R)-1-(4-fluorophenyl)ethanamine (0.242 mg, 1.74 mmol) and HATU (0.661 g, 1.74 mmol). The reaction mixture was stirred for 2 hours and partitioned between ethyl acetate and water. The organic layer was separated and washed with HCl (10% aq), sodium bicarbonate (1M aq), dried over sodium sulfate, filtered and concentrated to afford crude (R)-methyl 1-(2,2-dimethoxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate which was used without purification in the next step: LCMS-ESI+ (m/z): [M+H]+ calculated for C21H26FN2O2: 437.17; found: 437.1.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][Si](C(C)(C)C)(C)C)[C:19]=3[F:33])[CH2:14][CH2:13]2)[CH:9]=[CH:8][N:7]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:33][C:19]1[C:20]([CH2:24][OH:25])=[CH:21][CH:22]=[CH:23][C:18]=1[N:15]1[CH2:16][CH2:17][N:12]([C:10]2[CH:9]=[CH:8][NH:7][C:6](=[O:5])[CH:11]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)Oc1cc(N2CCN(c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)CC2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1cc(N2CCN(c3cccc(CO)c3F)CC2)cc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
1-(2-tert-Butoxypyridin-4-yl)-4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (3.14 g) was mixed with CH2Cl2 (50 ml), and TFA (5.1 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with MeOH (2 ml). A 8 M NH3/MeOH solution (10 ml) was added thereto at 0° C., followed by stirring at room temperature for 2 hours. The solid in the reaction mixture was collected by filtration, washed with MeOH, and dried at 50° C. under reduced pressure to obtain 4-{4-[2-fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyridin-2(1H)-one (1.76 g).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C@@H:14]([NH2:16])[CH3:15])[CH2:3][CH2:2]1.Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C@@H:14]([NH:16][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH3:15])[CH2:3][CH2:2]1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1C1CC1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CC1
Temperature: 100 °C
Yield: 48.8 %

Procedure:
A mixture of (S)-1-(1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (166 mg, 0.76 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (180 mg, 0.76 mmol) and DIPEA (0.7 mL, 3.8 mmol) in n-butanol (3 mL) was heated at 100° C. for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 374 as a white solid (125 mg, 49%). LCMS (Method K): RT 2.72 min [M+H]+ 338.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.23-8.09 (2H, m), 7.90 (1H, br s), 7.56 (1H, dd, J=8.77, 4.94 Hz), 7.37 (1H, dd, J=9.27, 2.53 Hz), 7.05-6.97 (1H, m), 5.94 (1H, br s), 3.43-3.36 (1H, m), 1.69 (3H, d, J=6.80 Hz), 1.33-1.00 (4H, m)
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].[F:34][CH2:35][CH:36](O)[CH2:37][F:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:34][CH2:35][CH:36]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH2:37][F:38]
Reactant: OC(CF)CF
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2ccccc2)cc(OC(CF)CF)c1
Reaction time: 48 h
Yield: 113.6 %

Procedure:
DIAD (7.63 mL, 38.7 mmol) was added in a dropwise fashion to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (5.00 g, 19.4 mmol), 1,3-difluoropropan-2-ol (3 mL, 38.7 mmol), and triphenylphosphine (10.16 g, 38.7 mmol) in THF (100 mL) under an inert atmosphere at 0° C. The solution was allowed to reach RT and left to stir for 2 days. The THF was removed in vacuo and the residual oil slurried with a mixture of 20% ethyl acetate in isohexane. After allowing to stir for 90 minutes the mixture was filtered and the filtrate evaporated. The residual was oil chromatographed on silica, eluting with 30% ethyl acetate in isohexane, to give the desired compound (7.41 g).
Reaction SMILES: [CH2:1]([Si:3]([CH2:21][CH3:22])([CH2:19][CH3:20])[O:4][CH:5]([CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH:7]=C)[CH3:2].C[N+]1([O-])CC[O:27]CC1.O.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.[Os](=O)(=O)(=O)=O>[CH2:1]([Si:3]([CH2:21][CH3:22])([CH2:19][CH3:20])[O:4][CH:5]([CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH:7]=[O:27])[CH3:2]
Reactant: C=CCC(CCOCc1ccccc1)O[Si](CC)(CC)CC
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC[Si](CC)(CC)OC(CC=O)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10.0 g (31.2 mmol) of 4-Triethylsilyloxy-6-benzyloxy-1-hexene in 310 mL of tetrahydrofuran at 0°C. were added 4.38 g (37.4 mmol) of 4-methylmorpholine N-oxide, 6.24 mL (1.248 mmol) of osmium tetroxide (0.2M in benzene) and 45 mL of water and stirred overnight at room temperature. To the mixture at 0° C. were added 185 mL of water and 20.02 g (93.6 mmol) of sodium periodate and stirred at room temperature for 1 hour, followed by partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated for the next reaction. 1H NMR (CDCl3): δ 9.79 (t, J=2.4 Hz, 1H, CH═O), 7.35-7.31 (m, 5H, ArH), 4.51 (d, J=12.0 Hz, 1H, ArCH2O), 4.46 (d, J=12.0 Hz, 1H, ArCH2O), 4.40 (p, J=6.0 Hz, 1H, CH—O), 3.55 (m, 2H, CH2—O), 2.56 (m, 2H, CH2C═O), 1.85 (m, 2H, CH2), 0.94 (t, J=8.1 Hz, 9H, TES CH3), 0.59 (q, J=8.1 Hz, 6H, TES CH2). 13C NMR (CDCl3): δ 201.94, 138.14, 128.31, 127.60, 127.55, 72.99, 66.31, 65.49, 51.14, 37.71, 6.84, 4.88.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH:12]([C:14]([O:16]CC)=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CC(NC(=O)OC(C)(C)C)CC1CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC1CC(NC(=O)OC(C)(C)C)CC1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
A 250 mL round-bottomed flask was charged with ethyl 4-(tert-butoxycarbonylamino)-2-ethylcyclopentanecarboxylate (3.00 g, 10.5 mmol) in THF (96 mL) to give a colorless solution. An aqueous solution of NaOH (1 N, 16.0 mL, 16.0 mmol) was added and the reaction mixture was stirred for about 24 h at ambient temperature. Additional aqueous NaOH (1 N, 5.00 mL, 5.00 mmol) was added and stirring was continued for about 48 h at room temperature. The reaction mixture was heated to about 50° C. for about 24 h. The solvent was removed under reduced pressure. AcOH was added until pH 5 was reached. EtOAc (50 mL) was added and the layers were partitioned. The aqueous layer was further extracted with EtOAc (2×30 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give a yellow oil. The oil was further dried under high vacuum, resulting in formation of a solid that was dissolved in DCM and concentrated to dryness, re-suspended in DCM and re-concentrated to dryness. The residue was then suspended in Et2O and concentrated to dryness and further dried under vacuum for about 3 h to give 4-(tert-butoxycarbonylamino)-2-ethylcyclopentanecarboxylic acid (2.36 g, 87%): LC/MS (Table 2, Method a) Rt=2.09 min; MS m/z: 256 (M−H)−.