Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][CH:4]([C:21]1[CH:30]=[CH:29][C:24]([C:25](OC)=[O:26])=[CH:23][CH:22]=1)[NH:5][C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[CH:13]2)=[CH:10][CH:11]=1.[OH-].[Li+].Cl.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH2:61][CH2:62][CH2:63][C:64]([O:66]C)=[O:65].C(NC(C)C)(C)C.[Cl-].[NH4+]>O1CCCC1>[CH3:31][C:2]([CH3:1])([CH3:32])[CH2:3][CH:4]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:61][CH2:62][CH2:63][C:64]([OH:66])=[O:65])=[O:26])=[CH:29][CH:30]=1)[NH:5][C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[N:14]=[CH:13]2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C(CC(C)(C)C)Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)cc1
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)CC(Nc1ccc(-n2cnc(C(F)(F)F)c2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of methyl 4-(3,3-dimethyl-1-(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridine-3-ylamino)butyl)benzoate (50 mg, 0.11 mmol) in tetrahydrofuran (5 mL) was added 2N lithium hydroxide (5 mL, 10 mmol). The reaction mixture was heated to 70° C. for 12 hours. The mixture was adjusted to pH=2 by addition of 1N aqueous hydrochloric acid and the resulting solution extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in N,N-dimethylformamide (5 mL). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (70.0 mg, 0.184 mmol) was added and the solution stirred at room temperature for 30 minutes. Methyl 3-aminopropionate hydrochloride (19.3 mg, 0.138 mmol) was added followed by diisopropylamine (47.6 mg, 0.37 mmol). The resulting mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (4 mL) and 2N Lithium hydroxide (4 mL, 8 mmol) was added. The mixture was stirred at room temperature for 1 hour. 1N Aqueous hydrochloric acid was added to adjust the pH=2 and the solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Boston Analytics Symmetrix ODS-H 150×30 mm, 5 μm; modifier: formic acid 0.225%; gradient: 39 to 59% acetonitrile in water) gave (+/−)-3-(4-(3,3-dimethyl-1-(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridine-3-ylamino)butyl)benzamido) propanoic acid (22.7 mg, 41%). 1H NMR (400 MHz, CD3OD, δ): 8.21 (s, 1H), 8.01 (s, 1H), 7.72 (s, 1H), 7.65 (d, 2H), 7.36 (d, 2H), 7.26 (d, 1H), 6.94 (m, 1H), 4.48-4.45 (m, 1H), 3.51-3.48 (m, 2H), 2.53-2.49 (m, 2H), 1.81-1.75 (m, 1H), 1.58-1.53 (m, 1H), 0.94 (s, 9H). MS (M+1): 504.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1ccc(CC(=O)Cl)cc1
Product: COc1ccc(CC(=O)NCCc2ccc(OC)c(OC)c2)cc1

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine with 4-methoxyphenyl acetyl chloride.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23]2[O:24][C:25]([CH3:28])=[CH:26][CH:27]=2)(=O)=O)C=CC=CC=1.[OH-].[K+]>CO>[CH3:22][S:19]([C:17]1[CH:18]=[C:13]2[CH:12]=[C:11]([C:23]3[O:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[NH:10][C:14]2=[N:15][CH:16]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(-c2cc3cc(S(C)(=O)=O)cnc3n2S(=O)(=O)c2ccccc2)o1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc3cc(S(C)(=O)=O)cnc3[nH]2)o1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a mixture solution of the compound obtained in Example 11 (2) (421 mg) in methanol (60 ml), a 1N aqueous potassium hydroxide solution (3 ml) was added and the mixture was stirred at 60° C. for 1 hour. The reaction solution was then concentrated under reduced pressure. The residue was washed with water and ether and dried to obtain 252 mg of the desired product as a yellow powder.
Reaction SMILES: Br[C:2]1[N:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH3:13]>C(O)C>[NH2:13][C:2]1[N:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: CC(C)c1ccc(C#N)c(Br)n1
Solvent: CCO
Product: CC(C)c1ccc(C#N)c(N)n1
Yield: 93 %

Procedure:
To a solution of the product of Example 8C (21 g, 0.093 mol) and liquid ammonia (250 mL) in 500 mL of ethanol were reacted in a sealed high-pressure vessel at 130° C. for 20 hours. The reaction mixture was concentrated under vacuum and the residue ground to a fine powder then washed with water (2×50 mL) and dried in a vacuum oven for 24 hours to provide the title compound as a beige solid (14 g, 93%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.[CH:17]1(B(O)O)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:17]1([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[C:7]([CH3:15])[C:6]=3[CH:16]=2)[CH2:19][CH2:18]1
Reactant: OB(O)C1CC1
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(Br)cc12
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)C(C)C)oc2ccc(C3CC3)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
To a solution (20 mL) of 1-(5-bromo-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (1.0 g) synthesized in Example A182(1) in toluene were added cyclopropaneboronic acid (0.92 g), 2N aqueous sodium carbonate solution (5.3 mL), and the mixture was stirred at room temperature for 10 min under argon atmosphere. To the reaction mixture were added 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.18 g) and tris(dibenzylideneacetone)dipalladium (0) (0.10 g), and the mixture was heated under reflux under argon atmosphere overnight. The reaction mixture was cooled to room temperature, and filtered through celite, and the residue was washed with diethyl ether. Water was added to the filtrate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10, volume ratio) to give the title object compound (0.80 g, 93%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]([Cl:22])=[CH:3][C:4]1([CH3:21])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:20])[C:8]([CH3:19])=[C:9]([O:15]COC)[C:10]=2[CH3:14])[O:5]1>CO.Cl>[Cl:22][C:2]([Cl:1])=[CH:3][C:4]1([CH3:21])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:20])[C:8]([CH3:19])=[C:9]([OH:15])[C:10]=2[CH3:14])[O:5]1
Reactant: COCOc1c(C)c(C)c2c(c1C)CCC(C)(C=C(Cl)Cl)O2
Agent: Cl
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C=C(Cl)Cl)O2
Yield: 50.1 %

Procedure:
A solution 160 mg of 2-(2,2-dichloro-vinyl)-6-methoxymethoxy-2,5,7,8-tetramethyl-chroman in 5 ml of methanol and 0.1 ml of conc. HCl was stirred overnight. The methanol was removed and the residue was mixed with ethyl acetate and water. Regular work-up and flash column chromatography on silica gel (15% ethyl acetate in hexane) afforded 70 mg of 2-(2,2-Dichloro-vinyl)-2,5,7,8-tetramethyl-chroman-6-ol. NMR (1H, CDCl3): 6.01 (1H, s), 4.26 (1H, s), 2.63 (2H, m), 2.48 (1H, m), 2.19 (3H, s), 2.16 (3H, s), 2.13 (3H, s), 1.78 (1H, m), 1.62 (3H, s). LC-MS: 301 (M+H, 100%), 323 (M+Na, 78%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([F:12])[C:8]([CH2:13][C:14]([OH:16])=O)=[CH:7][CH:6]=2.O.[NH2:18][NH2:19]>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([F:12])[C:8]([CH2:13][C:14]([NH:18][NH2:19])=[O:16])=[CH:7][CH:6]=2
Reactant: O=C(O)Cc1ccc2ncc(Br)cc2c1F
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)Cc1ccc2ncc(Br)cc2c1F

Procedure:
A solution of (3-bromo-5-fluoro-quinolin-6-yl)-acetic acid (800 mg, 2.7 mmol) and hydrazine hydrate (98%, 2 mL) in methanol (15 mL) was heated to reflux for 1 h. The solvent was removed in vaco to obtain a white solid which was washed with methanol and dried to return the title compound (750 mg, 94%) as a white solid. 1H-NMR (DMSO-d6, 300 MHz): 9.34 (s, 1H), 8.996-9.00 (d, 1H), 8.72-8.73 (d, 1H), 7.85-7.88 (d, 1H), 7.73-7.79 (m, 1H), 4.26-4.27 (d, 2H), 3.64-3.66 (d, 2H); MS: m/z 299 [M+H+]+.
Reaction SMILES: [Br-:1].[K+].N[CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:5]([OH:7])=[O:6]>Br>[CH2:16]([O:15][C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C@H:4]([Br:1])[C:5]([OH:7])=[O:6])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: [Br-]
Agent: Br
Agent: [K+]
Product: O=C(NCCCC[C@H](Br)C(=O)O)OCc1ccccc1
Temperature: 0 °C

Procedure:
(S-2-Amino-6-{[(benzyloxy)carbonyl]amino}hexanoic acid, 20.0 g (0.14 mole), and potassium bromide, 28.9 g (0.24 mole), were dissolved in 80 mL of ˜6N aqueous HBr, previously chilled to 0° C. A stream of nitrogen was bubbled through the solution and the mixture was chilled to −10° C. by means of a cold bath. Sodium nitrite, 5.9 g (0.86 mole) was added in portions over 30 min with stirring, while maintaining the temperature of the reaction from −13° C. to −10° C. After 6 hours stirring at −10° C., the mixture was extracted with ethyl ether, 4×50 mL and the resulting solution dried with magnesium sulfate. The mixture was filtered to remove the drying agent and evaporated to give an orange oil. The oil was purified by flash chromatography, chloroform-hexanes to give a clear and colorless oil. The yield was 20.0 g, i.e., 81%, based on starting 2-amino-6-{[(benzyl-oxy)carbonyl]-amino}hexanoic acid. NMR is consistent with structure. (Nicolaides et al.)
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C1COCC1>[CH3:26][S:27]([O:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1)(=[O:29])=[O:28]
Reactant: Cc1cccc(C(C#N)=C2C=CC(=NO)C=C2)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cccc(C(C#N)=C2C=CC(=NOS(C)(=O)=O)C=C2)c1
Temperature: 0 °C
Yield: 48.6 %

Procedure:
25 g (0.11 mol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-(3-methylphenyl)-acetonitrile are dissolved in 150 ml of THF and cooled in an ice bath. After adding 22 ml (0.16 mol) of triethylamine to the solution, 9.0 ml (0.12 mol) of methanesulfonyl chloride are added dropwise, keeping the temperature below 5° C. The reaction mixture is stirred in the ice bath for 30 min. The reaction mixture is poured into 200 ml of water, and extracted with ethyl acetate. The organic phase is washed with hydrochloric acid solution, water, and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by recrystallization from toluene. 16.8 g (51%) of (4-Methylsulfonyloxyimino-cyclohexa-2,5-dienylidene)-(3-methylphenyl)-acetonitrile are obtained in the form of yellow crystals having a melting point of 159-161° C. (dec.).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][NH:3]1.I[C:29]1[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32].CNCCNC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C.[Cu](I)I>[CH3:34][O:33][C:31]([C:30]1[CH:35]=[CH:36][CH:37]=[CH:38][C:29]=1[N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:10][CH2:11]2)[N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4]1)=[O:32]
Reactant: COC(=O)c1ccccc1I
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Product: COC(=O)c1ccccc1N1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 75 °C
Yield: 61.7 %

Procedure:
A mixture of benzyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.79 g, 7.63 mmol, 1 equiv), methyl 2-iodobenzoate (2 g, 7.63 mmol, 1 equiv) potassium carbonate (2.11 g, 15.26 mmol, 2 equiv), copper(II) iodide (145.32 mg, 0.763 mmol, 0.1 equiv) and N,N′-dimethyl ethylenediamine (164.25 μl, 1.526 mmol, 0.2 equiv) in acetonitrile was heated at 75° C. for 16 h. Upon cooling 10% citric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.3, gradient—5%-30% ethyl acetate in hexanes) to afford the title compound as a white powder (2.35 g, 61.57%); 1H NMR (400 MHz, DMSO-d6): δ 1.85 (d, 2H, J=14 Hz); 2.35-2.51 (m, 2H); 3.49 (bs, 2H); 3.98-4.03 (m, 2H); 5.14 (s, 2H); 6.84-6.87 (m, 3H); 7.22-7.26 (m, 2H); 7.32-7.39 (m, 5H); 7.49-7.53 (m, 1H); 7.65 (dd, 1H, J=1.6 and 1.2 Hz); 7.70-7.75 (m, 1H); 7.86 (dd, 1H, J=1.2 and 1.6 Hz); MS for C29H29N3O5 m/z 500.21 (M+H)+.
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[N-:13]=[N+:14]=[N-].[Na+]>Cl>[N:5]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cccc(O)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: [N-]=[N+]=Nc1cccc(O)c1
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
An aqueous solution (15 mL) of NaNO2 (3.79 g, 54.98 mmol) was added dropwise to 3-aminophenol (5.0 g, 45 mmol) in 2 N HCl (100 mL) at 0-5° C. The solution was stirred for 30 minutes, followed by addition of an aqueous solution of sodium azide (4.5 g, 69 mmol, in 35 mL water). The mixture was stirred at room temperature for 24 h, and extracted with 300 mL of ethyl acetate. The combined organic layer was washed with water, and dried over MgSO4. Solvents were removed by rotary evaporation, and the residue was purified by column chromatography (EtOAc/hexanes, 1/4) to give the desired product as a dark red oil (4.52 g, 73% yield): 1H NMR (acetone-d6, 300 MHz, ppm): 8.69 (s, 1H, Ar—OH), 7.24 (t, 1H, J=8.1 Hz, Ar—H), 6.70-6.53 (m, 3H, Ar—H). 13C NMR (CDCl3, 75 MHz, ppm): 157.2, 141.6, 130.9, 112.4, 111.5, 106.5. FT-IR (cm−1): 3348, 2109.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:16]=[N:17][N:18]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:19]=2)O1.Br[C:28]1[N:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[CH:32]=[C:31]2[NH:39][O:40][CH2:41][CH3:42]>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(OCC)(=O)C.O.C(#N)C>[CH2:41]([O:40][NH:39][C:31]1[C:30]2[C:35](=[CH:36][CH:37]=[C:28]([C:15]3[CH:16]=[N:17][N:18]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH:19]=3)[N:29]=2)[NH:34][C:33](=[O:38])[CH:32]=1)[CH3:42]
Reactant: CC1(C)OB(c2cnn(-c3cccnc3)c2)OC1(C)C
Reactant: CCONc1cc(=O)[nH]c2ccc(Br)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCONc1cc(=O)[nH]c2ccc(-c3cnn(-c4cccnc4)c3)nc12
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To Na2CO3 (151 mg, 1.41 mmol) was added water (1.5 ml) and acetonitrile (2 ml) and the solution was degassed for 5 min with argon. 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyridine (84 mg, 0.31 mmol), 6-bromo-4-(ethoxyamino)-1H-1,5-naphthyridin-2-one (80 mg, 0.28 mmol) and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added sequentially followed by addition of acetonitrile (2 ml). The mixture was stirred at 100° C. for 15 h then allowed to cool to ambient temperature. Water and ethyl acetate were added then the phases were separated. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. Purification by chromatography afforded of 4-(ethoxyamino)-6-[1-(3-pyridyl)pyrazol-4-yl]-1H-1,5-naphthyridin-2-one.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:36][CH3:37])[C@@H:33]([OH:35])[CH3:34]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:36][CH3:37])[C@@H:33]([OH:35])[CH3:34])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Reactant: CC[C@@H](N)[C@H](C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCCCO
Product: CC[C@@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)[C@H](C)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.2 mL, 10.96 eq, 1.14 mmol) followed by (2S,3R)-3-amino-pentan-2-ol (60 mg, 5.5 eq, 0.58 mmol). The reaction mixture was placed in a preheated oil bath at 160° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and water (50 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 22 mg (57%). (80% de 3R,2S: 20% de 3R,2R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.90, 1.05 (2×t, 3H, J=6.95 & 7.42 Hz, —NHCH (CH2CH3)CH(CH3)OH), 1.17 & 1.25 (2×d, 3H, J=6.32 & 6.16 Hz, —NHCH (CH2CH3)CH(CH3)OH) 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.77-2.09 (m, 2H, —NHCH(CH2CH3)CH(CH3)OH), 3.91-4.03 (m, 2H, —NHCH(CH2CH3)CH(CH3)OH), 4.58-4.69 (m, 1H, —CH(CH3)2), 4.83-5.00 (m, 3H, —HNCH2-Pyr & OH), 6.16 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 7.24-7.33 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.55 (m, 1H, Pyr-H), 7.74 (d, 1H, J=7.42 Hz, Pyr-H), 8.67 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 370 ([M+H]+, 100), 324 (35), 289 (37), 243 (65), 199 (85). Accurate Mass (M+H): Actual: 370.2355, Measured: 370.2347.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@:8]([NH:17][S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])([CH:14]([F:16])[F:15])[CH2:9][C:10](OC)=[O:11])[CH:7]=1.[BH4-].[Li+].C(OCC)(=O)C.[NH4+].[Cl-]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@@:8]([NH:17][S@:18]([C:20]([CH3:22])([CH3:21])[CH3:23])=[O:19])([CH2:9][CH2:10][OH:11])[CH:14]([F:16])[F:15])[CH:7]=1
Reactant: COC(=O)C[C@](N[S@@](=O)C(C)(C)C)(c1cc(Br)ccc1F)C(F)F
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@](=O)N[C@@](CCO)(c1cc(Br)ccc1F)C(F)F
Temperature: 23 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
(S)-methyl 3-(5-bromo-2-fluorophenyl)-3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (intermediate E3.1) (1.65 g, 3.83 mmol) was dissolved in tetrahydrofuran (80 ml) and lithium borohydride (668 mg, 30.7 mmol) was added at 5° C. in two portions. The turbid solution was stirred at 23° C. for 16 hours. The reaction mixture was poured into ice water and ethyl acetate was added. Saturated NH4Cl solution (50 ml) was added slowly and the mixture was stirred vigorously for 45 min until the gas evolution finished. The organic layer was separated, dried over Na2SO4, filtered and evaporated to give a yellow oil. The residue was purified by chromatography on 50 g silica gel with ethyl acetate/heptane 0-80% to give (S)—N—((S)-2-(5-bromo-2-fluorophenyl)-1,1-difluoro-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (815 mg, 2.03 mmol, 52.8% yield) as a colourless oil. MS (ISN): m/z=399.9 [M−H]− and 401.9 [M+2−H]−.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:19]
Reactant: O=C(NOCCc1ccccn1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(NOCCc1ccccn1)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 49.8 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-N-[2-(pyridin-2-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 126 (0.26 g, 0.65 mml) in methanol (20 mL) was added 5% Pd/C (0.25 g). The mixture was hydrogenated at 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2S,5R)-6-hydroxy-7-oxo-N-[2-(pyridin-2-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 127 (0.10 g, 50%) as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=2)=[O:19])[CH2:9][N:8](C(OCCCC)=O)[CH2:7]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[NH:17][C:6]2([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:35])[CH2:9][NH:8][CH2:7]2)=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CN(C(=O)OCCCC)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CNC2)cc1
Yield: 25.2 %

Procedure:
A solution of tent-butyl 3-(2-ethoxy-2-oxoethyl)-3-(3-(4-octylphenyl)ureido)azetidine-1-carboxylate (0.5 mmol) in CH2Cl2 (5 mL) was cooled with an ice/water bath and treated with trifluoroacetic acid (0.5 mL). The reaction was monitored (TLC) to completion (3-4 hrs) at which point the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was purified by column chromatography to obtained the title compound (49 mg, 65%). 1H NMR (400 MHz, CD3OD) δ 7.21 (d, 2H, J=8.4 Hz), 7.07 (d, 2H, J=8.4 Hz), 4.14 (q, 2H, J=6.8 Hz), 3.80 (d, 2H, J=9.6 Hz), 3.69 (d, 2H, J=9.6 Hz), 3.11 (s, 2H), 2.55 (t, 2H, J=7.6 Hz), 1.60-1.55 (m, 2H), 1.33-1.21 (m, 13H), 0.90 (t, 3H, J=6.4 Hz); MS ESI 390.3 [M+H]+, calcd for [C22H35N3O3+H]+ 390.54.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C@H:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][OH:15])C1C=CC=CC=1>C(O)C.[Pd]>[C:20]([O:19][C:17](=[O:18])[NH:16][C@H:13]([CH2:14][OH:15])[CH2:12][CH2:11][NH2:10])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CO)CCN

Procedure:
Preparation takes place in analogy to Example 81A from 237 mg (0.7 mmol) of benzyl{(3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutyl}carbamate (Example 236A) in 50 ml of ethanol with the addition of 23 mg of palladium on activated carbon (10%).