Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([C:19]2[S:20][C:21]([CH2:25][O:26][CH3:27])=[CH:22][C:23]=2[Br:24])=O)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].Cl>N1C=CC=CC=1>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([C:19]2[S:20][C:21]([CH2:25][O:26][CH3:27])=[CH:22][C:23]=2[Br:24])=[N:2][OH:3])[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: NO
Reactant: COCc1cc(Br)c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: Cl
Solvent: c1ccncc1
Product: COCc1cc(Br)c(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
Add hydroxylamine hydrochloride (2.29 g, 45.27 mmol, 2.00 equivalents) to a stirred solution of 4-[1-(3-bromo-5-methoxymethyl-thiophen-2-yl)-methanoyl]-piperidine-1-carboxylic acid tert-butyl ester (9.47 g, 22.64 mmol, 1.00 equivalents) in pyridine (42.40 mL). Stir the resulting solution at room temperature overnight and then at 70° C. for 4 hours. Cool the reaction mixture slightly, add hydrochloric acid (3N, 100 mL) and extract the resulting mixture with dichloromethane (100 mL). Wash the extract with water (100 mL), dry over magnesium sulfate, filter and evaporate to yield the desired product as a yellow oil (9.48 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([OH:20])(C(OCC)=O)[C:10]([O:12]CC)=[O:11].[OH-].[K+]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([OH:20])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(O)(C(=O)OCC)c1cc(C)ccc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C)c(C(O)C(=O)O)c1
Temperature: 25 °C

Procedure:
A sample of the diethyl (2,5-dimethylphenyl)-hydroxymalonate (21 parts) was reacted with a solution of potassium hydroxide (21 parts) in water (84 parts) at 98° C. for 5 hours. After cooling to ambient temperature, the reaction was washed with diethyl ether and acidified with 10M hydrochloric acid. After heating to 98° C. for a further 2 hours, the cooled materials was extracted into diethyl ether. The separated organic phase was dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude amber coloured oil (15 parts) solidified on standing. Recrystallisation from toluene gave 2,5-dimethylmandelic acid (7 parts). The 1Hnmr, 13Cnmr and mass spectra were all consistent with the structure.
Reaction SMILES: C[O:2][C:3](=[O:38])[C@H:4]([CH2:28][NH:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH2:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][NH:21]3)=[O:14])=[CH:9][C:8]=1[Cl:26].O.[OH-].[Li+]>O1CCCC1.CO.O>[C:30]([NH:29][CH2:28][C@@H:4]([C:3]([OH:38])=[O:2])[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH2:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][NH:21]3)=[O:14])=[CH:9][C:8]=1[Cl:26])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(NCc1cccc2[nH]ccc12)c1ccc(C(=O)N[C@@H](CNC(=O)c2ccccc2)C(=O)O)c(Cl)c1
Yield: 74.3 %

Procedure:
3-(Benzoylamino)-L-alanine methyl ester (Example 299; 77 mg, 0.35 mmol) was mixed with 2-chloro-4-[[(1H-indol-4-yl-methyl)amino]carbonyl]benzoic acid (Example 36; 115 mg, 0.35 mmol), HOBT (57 mg, 0.42 mmol) and EDCI (80.5 mg, 0.42 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 16 h and then diluted with water (about 20 ml). The solution was extracted with ethyl acetate (3×10 ml) and the ethyl acetate layer was washed with dilute aqueous NaCl solution and then brine, dried (Na2SO4), concentrated, and chromatographed (40–80% ethyl acetate/hexanes) to give 3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine methyl ester (88 mg, 47%). A solution of the ester (51 mg, 0.096 mmol) and lithium hydroxide monohydrate (8 mg, 0.19 mmol) in tetrahydrofuran/methanol/water (3:1:1; 2 mL) was stirred at room temperature for 3 h. The solvent was removed and the product was purified by HPLC to give 3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine (37 mg, 75%) as a white fluffy powder.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[OH:28][C@@H:24]1[C@@H:25]([OH:27])[CH2:26][N:22]([C:3]2[C:2]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using 5-bromo-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 70.1) and pyridin-3-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.01 min, m/z=461.1 [M+H]+, m/z=459.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.94 (d, J=11.74 Hz, 2H) 3.37-3.45 (m, 2H) 3.85 (d, J=2.69 Hz, 2H) 5.04 (br. s, 2H) 7.35 (d, J=8.31 Hz, 2H) 7.51 (dd, J=7.09, 4.89 Hz, 1H) 7.81 (d, J=7.83 Hz, 1H) 7.86 (d, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.59 (dd, J=4.77, 1.59 Hz, 1H) 8.64 (d, J=1.96 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]([CH2:11][C:12](OCC)=[O:13])[CH:8]=[CH:7][CH:6]=1>C(O)C>[CH3:3][O:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][OH:13])[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)Cc1cccc(OC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(CCO)n1
Temperature: 25 °C

Procedure:
Sodium borohydride (1.3 g, 34.8 mmol) was added to a solution of ethyl 2-(6-methoxypyridin-2-yl)acetate (0.68 g, 3.48 mmol) in ethanol (20 mL). The resulting solution was stirred at room temperature over night. The solvent was removed in vacuo. Ethyl acetate and saturated NaHCO3 solution were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated to give the product. Yield: 0.23 g (44%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH2:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[O:24]1[CH2:26][CH:25]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CCO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH2:26][CH:25]([OH:24])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN)ccc3c2)CC1
Reactant: CCOC(=O)C1CO1
Solvent: CCO
Product: CCOC(=O)C(O)CNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1

Procedure:
(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methanamine (311 mg, 1.0 mmol, 1.0 eq.) and ethyl oxirane-2-carboxylate (116 mg, 1.0 mmol, 1.0 eq.) was dissolved in EtOH (5 mL). Then the mixture was refluxed for 2 h. The mixture was concentrated and purified by silica gel column chromatography using DCM/MeOH (10/1) as eluent to give product as a slight yellow oil (311 mg, 35%). EDI-MS (M+1)+: 428.1. HPLC: 92.02%. 1H NMR (400 MHz, CDCl3) δ 7.70-7.64 (m, 3H), 7.38 (dd, 1H), 7.13-7.11 (m, 2H), 4.31-4.21 (m, 4H), 3.93 (q, 2H), 3.06-2.88 (AB, 2H), 2.60 (b, 2H), 2.28-2.26 (m, 2H), 1.90-1.87 (m, 2H), 1.45-1.41 (m, 2H), 1.26 (t, 3H), 1.20-1.09 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[Cl:58][C:59]1[CH:64]=[CH:63][C:62]([NH:65][CH:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)=[CH:61][C:60]=1[S:72][C:73]([F:76])([F:75])[F:74]>CN(C)C=O.ClCCl.O1CCCC1>[Cl:58][C:59]1[CH:64]=[CH:63][C:62]([NH:65][CH:66]2[CH2:71][CH2:70][N:69]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([F:2])([F:22])[F:23])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:68][CH2:67]2)=[CH:61][C:60]=1[S:72][C:73]([F:76])([F:74])[F:75]
Reactant: FC(F)(F)Sc1cc(NC2CCNCC2)ccc1Cl
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc(Cl)c(SC(F)(F)F)c2)CC1
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (16 mg; 0.05 mmol, prepared in accordance with Example 3), diisopropylethyl amine (18 μL; 0.10 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of (4-chloro-3-trifluoromethylsulfanyl-phenyl)-piperidin-4-yl-amine hydrochloride (17 mg; 0.05 mmol, prepared in accordance with Example 16) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 90 minutes at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (5 mg; 0.01 mmol). The structure was confirmed using Protocol I-B. Calculated mass=609; observed mass=609; HPLC retention time=4.89 min.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:8][CH:7]([CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]3[N:17]=[C:16]4[NH:21][C:22](=[O:24])[NH:23][C:15]4=[CH:14][C:13]=3[CH:12]=2)[O:6]C1=O)[CH3:3].[OH-].[Na+].Cl>>[OH:6][CH:7]([CH2:8][NH:4][CH:2]([CH3:3])[CH3:1])[CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]2[N:17]=[C:16]3[NH:21][C:22](=[O:24])[NH:23][C:15]3=[CH:14][C:13]=2[CH:12]=1
Reactant: CC(C)N1CC(COc2ccc3nc4[nH]c(=O)[nH]c4cc3c2)OC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)NCC(O)COc1ccc2nc3[nH]c(=O)[nH]c3cc2c1

Procedure:
A mixture of 1,3-dihydro-7-[[3-(1-methylethyl)-2-oxo-5-oxazolidinyl]methoxy]-2H-imidazo[4,5-b]quinolin-2-one (3.00 g, 8.8 mmol) and 2N sodium hydroxide solution (25 mL) was refluxed for 5.5 hours and then neutralized by addition of dilute hydrochloric acid solution. A grey solid (2.15 g, 77%) was filtered off, washed with water and air dried. Crystallization from methanol afforded 1,3-dihydro-7-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]-2H-imidazo[4,5-b]quinolin-2-one as a partial hydrate (1.53 g, 55%), m.p. 262°-264° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:20]#[N:21])=[C:11](I)[S:12][C:13]=1[C:14]1[NH:18][CH:17]=[N:16][N:15]=1.[Cl-].[Li+].O1CCOCC1.CCCC[Sn]([C:43]1[CH:48]=[CH:47][N:46]=[C:45]([S:49][CH3:50])[N:44]=1)(CCCC)CCCC>[Cu]I.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>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:20]#[N:21])=[C:11]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([S:49][CH3:50])[N:44]=2)[S:12][C:13]=1[C:14]1[NH:18][CH:17]=[N:16][N:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: N#Cc1c(I)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CSc1nccc(-c2sc(-c3nnc[nH]3)c(-c3ccc(Cl)cc3Cl)c2C#N)n1
Yield: 47.3 %

Procedure:
4-(2,4-dichlorophenyl)-2-iodo-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (0.140 g, 0.313 mmol), Lithium chloride (0.0398 g, 0.939 mmol), Copper(I) iodide (0.0179 g, 0.0939 mmol), and Tetrakis(triphenylphosphine)palladium(0) (0.0362 g, 0.0313 mmol) were combined in a 100 mL round-bottom flask under an atmosphere of Argon. 1,4-Dioxane (8.75 mL, 0.112 mol) was added followed by 4-tributylstannyl-2-thiomethylpyrimidine (0.194 g, 0.470 mmol). The solution was heated to reflux for 2 hours. The solvent was concentrated in vacuo and the residue was purified using ISCO chromatography on silica gel, elution 20% ethyl acetate in hexanes to ethyl acetate to afford the title compound (0.066 g, 47%). LCMS: (FA) ES+, 445, 447. 1H NMR (400 MHz, d1-chloroform) δ: 8.67 (d, J=5.21 Hz, 1H), 8.21 (s, 1H), 7.86 (d, J=5.20 Hz, 1H), 7.60-7.55 (m, 1H), 7.44-7.34 (m, 2H), 2.66 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][CH2:13][OH:14])[CH:6]=[CH:5]2.[CH3:15][O:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[C:20](B(O)O)=[CH:19][N:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.N>C(O)(C)C.O.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>[CH3:15][O:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[C:20]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([CH2:12][CH2:13][OH:14])[CH:6]=[CH:5]3)=[CH:19][N:18]=1
Reactant: OCCc1ccc2cc(Br)ccc2c1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)O
Product: COc1ncc(-c2ccc3cc(CCO)ccc3c2)c(OC)n1
Temperature: 65 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A mixture of the product from Example 1E (0.1020 g, 0.41 mmol), 2,4-dimethoxypyrimidin-5-yl-boronic acid (0.0920 g, 0.50 mmol), dichlorobis (triphenylphosphine)-palladium (II) (0.0096 g, 0.014 mmol), and K3PO4.H2O in isopropyl alcohol (5 mL) and H2O (2 mL) was stirred at 65° C. for 2 hours. The reaction mixture was cooled to room temperature then concentrated under reduced pressure. The residue was partitioned between brine and ethyl acetate. The aqueous layer was washed with ethyl acetate, and the combined organic extracts were dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (7:3 hexane/ethyl acetate). Fractions containing product were combined to provide (0.0376 g, 30% yield). 1H NMR (CDCl3, 300 MHz), δ 8.37 (s, 1H), 7.95 (s, 1H), 7.86-7.82 (d, J=6 Hz, 2H), 7.71 (s, 1H), 7.64-7.59 (d, J=9 Hz, 1H), 7.46-7.6 (s, J=9 Hz, 1H), 4.08 (s, 3H), 4.06 (s, 3H), 3.89-3.84 (t, J=7.5 Hz, 2H), 3.30-2.98 (t, J=7.5 Hz, 2H). MS (DCI-NH3) [M+H]+ at 311.
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[O:12][CH2:11][CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.N.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)[N:32]=1>CN(C)C=O.O>[C:1]1([C@H:7]([N:9]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:32])=[O:21])=[CH:18][CH:17]=3)[O:12][CH2:11][CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Reactant: C[C@H](c1ccccc1)N1CCOC(c2ccc(C(=O)O)cc2)CC1
Agent: N
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1CCOC(c2ccc(C(N)=O)cc2)CC1
Reaction time: 24 h

Procedure:
To a solution of 4-[4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-7-yl]-benzoic acid (diastereomer type A) (0.96 g, 2.9 mmol) and 7 mol/L methanol solution of ammonia (2 mL, 14 mmol) in N,N-dimethylformamide (10 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (1.25 g, 4.5 mmol) at room temperature and the mixture was stirred for one day. The reaction mixture was poured into water. The resulting white solid material was collected by filtration and dried under reduced pressure at 50° C. for 5 hours to yield 4-[4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-7-yl]-benzamide (diastereomer type A) (0.58 g, 1.78 mmol, 61%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[O:13][CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:8][C:7]=1[O:13][CH3:14]
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Reactant: CCO[C@@H](Cc1ccc(O)cc1OC)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1OC)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2-methoxy-phenyl)-propionic acid methyl ester (example 24 c]) was reacted with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (examples 2 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](B(O)O)[CH:7]=[CH:6]2.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([F:26])[C:22]=1[CH:23]([OH:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:26][C:21]1[CH:20]=[N:19][CH:18]=[C:17]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[C:22]=1[CH:23]([OH:25])[CH3:24]
Reactant: CC(O)c1c(F)cncc1Br
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2cc(-c3cncc(F)c3C(C)O)ccc2c1
Yield: 50.9 %

Procedure:
A mixture of 6-methoxynaphthalen-2-ylboronic acid (333 mg, 1.650 mmol), 1-(3-bromo-5-fluoropyridin-4-yl)ethanol 4a (330 mg, 1.5 mmol), sodium carbonate (2M in water, 1.5 mL, 3.00 mmol), PdCl2(dppf).CH2Cl2 adduct (61.2 mg, 0.075 mmol) in DMF (6 mL) was heated to 100° C. for 2 hrs. The mixture was quenched with sat NaHCO3 and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The residue was purified via Biotage (20-60% EtOAc/heptane; SNAP25 column) giving the title compound (227 mg, 51%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.62 (dd, J=6.7, 1.0 Hz, 3H), 3.96 (s, 3H), 4.99 (q, J=6.7 Hz, 1H), 7.19-7.26 (m, 2H), 7.36 (dd, J=8.4, 1.7 Hz, 1H), 7.70 (s, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 8.40 (s, 1H), 8.48 (d, J=2.7 Hz, 1H). LC-MS (M+1) 298.0, t=1.49 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([CH:9]2[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Clc1nccc(C2CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
2,4-Dichloropyrimidine (15 g, 101 mmol), cyclopropylboronic acid (8.65 g, 101 mmol), PdCl2(dppf)-CH2Cl2 adduct (8.22 g, 10.07 mmol), and potassium phosphate (53.4 g, 252 mmol) were combined in a 1 L flask. THF (503 mL) was added and the suspension was heated to reflux with stirring overnight. The reaction was then cooled to room temperature, concentrated to −100 mL under reduced pressure, extracted with ethyl acetate, washed with sat NaHCO3, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc/Hexanes to give 2-chloro-4-cyclopropylpyrimidine (10.124 g, 58.3 mmol, 58% yield) as an 89:11 mixture with EtOAc.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH2:9]O.C1C=CC(P([N:25]=[N+:26]=[N-:27])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.CC(=O)OCC>C1(C)C=CC=CC=1>[N:25]([CH2:9][C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[Cl:1])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1nn(C)c(Cl)c1CO
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1nn(C)c(Cl)c1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 2 (538 mg, 3.36 mmol) in toluene (10 mL) was added DPPA (1.1 mL, 5.04 mmol) and DBU (0.6 mL, 6.72 mmol) at 0° C. After stirring for 1 hr, the reaction mixture was warmed to room temperature and stirred for 24 hr. EA (20 mL) was added and the mixture was washed with water, brine, concentrated to give a yellow solid which was used without further purification. LCMS (ESI) m/z=186 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH2:18])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[Cl:24][C:25]1[CH:30]=[C:29](Cl)[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=1>C(O)C.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH:18][C:29]3[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=[C:25]([Cl:24])[CH:30]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2C1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3cc(Cl)ncc3[N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the 7-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (5.2 g, 21.0 mmol) in ethanol (60 mL) and THF (15 mL) was added NaHCO3 (5.3 g, 63.0 mmol) followed by the product of Example 1, Step 3 (4.05 g, 21.0 mmol), and the reaction mixture was stirred overnight rt. The reaction mixture was concentrated then taken up in EtOAc and H2O extracted with EtOAc, the organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude material was crystallized from EtOAc/hexane to give the title compound as a yellow solid. MS (ES+) m/e 406 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.Br[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]2[CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:18]2[CH:23]=[CH:22][N:21]3[N:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]3[CH:19]=2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Reactant: Fc1cc2c(c(C3CCCN3)c1)OCCO2
Product: CCOC(=O)c1cnn2ccc(N3CCCC3c3cc(F)cc4c3OCCO4)cc12

Procedure:
The title compound (Int-63) was prepared by the method similar to that for Int-84 using 2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine ((Int-56A) and Ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate to afford as pale brown solid. LCMS (ESI): m/z 412.85 (M+H).