Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH2:19][CH2:20][CH:21]=[CH2:22])=[N:14]1.C(=O)([O-])[O-:24].[Na+].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH2:19][CH2:20][CH:21]2[O:24][CH2:22]2)=[N:14]1
Reactant: C#CCOc1cc(-n2nc(CCC=C)[nH]c2=O)c(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: C#CCOc1cc(-n2nc(CCC3CO3)[nH]c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.4 %

Procedure:
To a solution of 500 mg (1.48 mmol) of 2-[2,4-dichloro-5-(2-propynyloxy)-phenyl]-2,4-dihydro-5-(3-butenyl)-3H- 1,2,4-triazol-3-one in 20 mL of dichloromethane was added 172 mg (1.63 mmol) of sodium carbonate and 970 mg of m-chloroperoxybenzoic acid (50-60%, 2.81 mmol) in an ice bath. The reaction mixture was stirred at room temperature for 24h. The mixture was filtered and the filtrate was evaporated in vacuo to give 500 mg of the title compound of Step 3 as yellow solid. The crude product was used in the following reaction without further purification. 1H NMR (CDCl3, 400 MHz) δ 11.25 (s,1H), 7.55 (s,1H), 7.2 (s,1H), 4.8 (s,2H), 3.05 (m,1H), 2.8 (t,1H), 2.8 (t,2H), 2.6 (s,1H), 2.75 (d,1H), 2.2 (m,1H), 1.8 (m,1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20](S(C2C=CC(C)=CC=2)(=O)=O)[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:23][CH:22]=2)=[O:18].[OH-].[Na+].Cl>O1CCOCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:23][CH:22]=2)=[O:18]
Reactant: CCCCOc1ccc2c(c1)cc(C(=O)c1cnn(-c3ccc4[nH]c(C)nc4c3)c1N)n2S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCOc1ccc2[nH]c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc2c1
Yield: 68 %

Procedure:
A mixture consisting of [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[5-butoxy-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone (70 mg), dioxane (3 ml), and an aqueous solution of 5 M sodium hydroxide (300 μl) was stirred under reflux for two hours. The reaction mixture was cooled in an ice bath, and acidified with an aqueous solution of 5 M hydrochloric acid. The solvent was distilled off under reduced pressure. Water was added to the residue obtained by concentration under reduced pressure. The solid was collected by filtration, washed with water, and dried to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(5-butoxy-1H-indol-2-yl)-methanone (35 mg, 65%).
Reaction SMILES: [NH2:1][C:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH2:5][OH:6])[CH2:3][OH:4].[CH2:23](C(CC)(CC)C([O-])([O-])[O-])[CH3:24].C(O)(=O)C>C(#N)C>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:2]2([CH2:5][OH:6])[CH2:3][O:4][C:23]([CH3:24])=[N:1]2)=[CH:10][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(CO)(CO)CCc1ccc(OCc2ccccc2)cc1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC1=NC(CO)(CCc2ccc(OCc3ccccc3)cc2)CO1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 2-amino-2-[2-(4-benzyloxy-phenyl)-ethyl]-propane-1,3-diol (31.1 g, 0.10 mol) in acetonitrile (2.381) is added triethylortho acetate (17.1 ml, 0.12 mol, 1.2 eq) and acetic acid (5.48 ml, 0.11 mol, 1.1 eq), the reaction mixture is then stirred at 80° C. for 5 hours. The reaction mixture is then concentrated under vacuum, {4-[2-(4-benzyloxy-phenyl)-ethyl]-2-methyl-4,5-dihydro-oxazol-4-yl}-methanol is isolated after crystallization with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[N:19]=[CH:20][C:21]2[N:22]([C:24]([CH3:30])=[C:25]([CH:27]3[CH2:29][CH2:28]3)[N:26]=2)[CH:23]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+].N>[Cu]I.CS(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[N:19]=[CH:20][C:21]4[N:22]([C:24]([CH3:30])=[C:25]([CH:27]5[CH2:29][CH2:28]5)[N:26]=4)[CH:23]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Reactant: Cc1c(C2CC2)nc2cnc(Br)cn12
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: Cc1c(C2CC2)nc2cnc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cn12
Temperature: 150 °C
Yield: 42.2 %

Procedure:
A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (26.2 mg), 6-bromo-2-cyclopropyl-3-methylimidazo[1,2-a]pyrazine (42.1 mg), N,N′-dimethyl-1,2-ethanediamine (19.63 mg), CuI (21.2 mg), potassium carbonate (46.2 mg) and DMSO (1 ml) was heated at 150° C. for 1 h under microwave irradiation. The mixture was poured into 28% NH3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (hexane/EtOAc) to give the title compound (19.1 mg) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH:12]1[CH2:11][O:10][NH:9]2.C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.[Zn]>[NH2:9][C:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:12]([CH2:11][OH:10])[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC2CONC2(c2ccccc2F)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(CO)C(N)(c2ccccc2F)C1
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
A mixture of tert-butyl 6a-(2-fluorophenyl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (5 g, 16.2 mmol) and zinc dust (10.6 g 0.16 mol) is treated with acetic acid (65 mL) in one portion under nitrogen at room temperature. The resulting mixture is stirred for 0.5 hour, diluted with ethyl acetate, and filtered through diatomaceous earth. The filtrate is added drop-wise to a mixture of saturated sodium bicarbonate in water containing an excess of solid sodium bicarbonate (84 g, 1 mol). The mixture is extracted with ethyl acetate, the organic phase is dried over magnesium sulfate, and the solvent removed under vacuum. The residue is purified by silica gel chromatography eluting with ethyl acetate to give the title compound (4.4 g, 87%). ES/MS (m/e): 311(M+H).
Reaction SMILES: [S:1]([O:5][CH:6]([CH2:11][C:12]#[CH:13])[C:7]([O:9]C)=[CH2:8])([CH3:4])(=[O:3])=[O:2].S(=O)(=O)(O)O>CC(C)=O>[S:1]([O:5][CH:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:9])[CH3:8])([CH3:4])(=[O:2])=[O:3]
Reactant: C#CCC(OS(C)(=O)=O)C(=C)OC
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C#CCC(OS(C)(=O)=O)C(C)=O
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To a solution of 3-mesyloxy-2-methoxy-1-hexen-5-yne (0.5 g) in acetone (1.5 ml) was added 20% sulfuric acid (1.5 ml) under ice-cooling and the mixture was stirred for 1.5 hours under the same conditions and then for 1.5 hours at room temperature. Acetone was evaporated in vacuo and the residue was extracted with methylene chloride. The extract was washed successively with water, aqueous sodium bicarbonate solution, and brine, dried over magnesium sulfate, and evaporated in vacuo to give 3-mesyloxy-5-hexyn-2-one (0.41 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8](O)=[O:9])[CH2:7][CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.ClC(OCC)=O.[BH4-].[Na+].CO>C1COCC1.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1([CH2:8][OH:9])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(=O)O)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: O
Product: COC(=O)C1(CO)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1,1-Cyclopropane dicarboxylic acid-1-methyl ester (4 g, 27.8 mmol) was mixed with DIPEA (6 ml, 34.4 mmol) in THF (50 ml) and stirred at a 0° C. for 10 min. To the reaction was slowly added ethyl chloroformate (2.7 ml, 28.1 mmol). The reaction was stirred for 1.5 hours and allowed to warm to ambient temperature. The reaction was then re-cooled to 0° C. and NaBH4 (1.6 g, 42.3 mmol) was slowly added, followed by the addition of methanol (3 ml, 74.2 mmol). The reaction was allowed to warm to ambient temperature over 2 h. Then the reaction was diluted with EtOAc and water. The aqueous layer was separated and extracted with EtOAc three times. The combined organic layers were washed with water, then brine, dried over (MgSO4), filtered, and concentrated to afford the title compound. 1H NMR (500 MHz, CDCl3): δ 3.70 (s, 3H), 3.60 (s, 2H), 1.25 (m, 2H), 0.85 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:4]=1[CH:5]=[CH:6][C:7]1[S:8][C:9]2[NH:10][CH2:11][CH2:12][CH2:13][C:14]=2[N:15]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:22]([N:10]1[CH2:11][CH2:12][CH2:13][C:14]2[N:15]=[C:7]([CH:6]=[CH:5][C:4]3[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:3]=3[O:2][CH3:1])[S:8][C:9]1=2)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(C=Cc2nc3c(s2)NCCC3)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cccc(C=Cc2nc3c(s2)N(C(C)=O)CCC3)c1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
to a solution of 2-(2,3-dimethoxystyryl)-4,5,6,7-tetrahydrothiazolo[5,4-b]pyridine (1.0 g, 3.3 mmole) in pyridine (10 ml) was added dropwise acetic anhydride (0.68 g, 6.6 mmole) with ice-cooling. The reaction mixture was heated with stirring at 80° C. for 3 hours and then a sodium bicarbonate solution was added to the mixture which was extracted with a chloroform-methanol mixed solvent. The extract was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography and then recrystallized from hexane-ethyl acetate to obtain the title compound (867 mg, yield: 76.0%).
Reaction SMILES: [NH2:1][C:2]1[N:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52][C:53](=[O:55])[CH3:54])=[C:47]([CH:51]=2)[C:48](O)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]>C(Cl)Cl>[C:7]([O:6][C:4]([C:3]1[C:2]([NH:1][C:48](=[O:49])[C:47]2[CH:51]=[C:43]([CH2:42][C:36]3[C:37](=[O:41])[C:38]([O:39][CH3:40])=[C:33]([O:32][CH3:31])[C:34](=[O:57])[C:35]=3[CH3:56])[CH:44]=[CH:45][C:46]=2[O:52][C:53](=[O:55])[CH3:54])=[N:14][CH:13]=[CH:12][CH:11]=1)=[O:5])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)c1cccnc1N
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ncccc3C(=O)OC(C)(C)C)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 53.3 %

Procedure:
tert-Butyl 2-aminonicotinate (0.311 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=15:1) to obtain the titled compound (0.157 g, 0.285 mmol, 53%).
Reaction SMILES: [C:1](=[NH:25])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][CH:19]=2)=[C:8]([F:24])[CH:7]=1)[NH2:2].FC(F)(F)C([O-])=O.[CH:33]([CH:35]([CH2:40][C:41]1[CH:42]=[N:43][C:44]([O:47][CH3:48])=[N:45][CH:46]=1)[C:36](OC)=O)=[O:34].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:12][C:10]1[CH:11]=[C:6]([CH:7]=[C:8]([F:24])[C:9]=1[O:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:21])([F:22])[F:23])=[N:16][CH:15]=1)[CH2:5][CH2:4][O:3][C:1]1[NH:2][CH:36]=[C:35]([CH2:40][C:41]2[CH:42]=[N:43][C:44]([O:47][CH3:48])=[N:45][CH:46]=2)[C:33](=[O:34])[N:25]=1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ncc(Cc2c[nH]c(OCCc3cc(F)c(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc2=O)cn1
Temperature: 80 °C
Yield: 28.8 %

Procedure:
To the solution of 3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenethyl carbamimidate, trifluoroacetate (200 mg, 0.421 mmol) and methyl 2-formyl-3-(2-methoxypyrimidin-5-yl)propanoate (113 mg, 0.505 mmol) in 1,4-dioxane (2 mL) was added K2CO3 (233 mg, 1.683 mmol). The mixture was heated with a microwave reactor at 80° C. for 0.5 h. Purification via MDAP then afforded the title compound (65 mg, 28.8% yield). LCMS: rt=3.05 min, [M+H]=537
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[NH:16][CH2:15][CH2:14]2.Br[C:23]1[S:27][C:26]([S:28]([NH:31][CH2:32][CH3:33])(=[O:30])=[O:29])=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>CCCCO.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>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:23]2[S:27][C:26]([S:28]([NH:31][CH2:32][CH3:33])(=[O:30])=[O:29])=[CH:25][CH:24]=2)=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[NH:16][CH2:15][CH2:14]2
Reactant: CCNS(=O)(=O)c1ccc(Br)s1
Reactant: Nc1ncc(B(O)O)cc1-c1ccc2c(c1)CCNC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CCNS(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)c2)s1
Temperature: 140 °C

Procedure:
A mixture of (6-amino-5-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)boronic acid (291 mg, 1.02 mmol), 5-bromo-N-ethylthiophene-2-sulfonamide (278 mg, 1.02 mmol), and PdCl2(PPh3)2 (35 mg, 0.05 mmol) in n-BuOH (3 mL) was treated with 2.0 M aq. Na2CO3 solution (1 mL) then microwave heated at 140° C. for 6 min. The reaction was then filtered, and purified by HPLC to provide 5-(6-amino-5-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)-N-ethylthiophene-2-sulfonamide as a white solid after preparatory HPLC purification. 1H NMR (300 MHz, MeOH) δ ppm 8.31 (d, J=2.3 Hz, 1H), 8.07 (d, J=8.0 Hz, 1 H), 7.72 (d, J=2.3 Hz, 1H), 7.54 (dd, J=3.8, 2.1 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.48 (s, 1 H), 7.34 (d, J=3.8 Hz, 1H), 3.57 (dd, J=13.4, 6.5 Hz, 1H), 2.93-3.15 (m, 2H), 1.85-2.03 (m, 3H), 1.13 (dd, J=14.5, 7.2 Hz, 3H); MS (EI) m/z: 429 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:5]([O:15][CH2:16][CH3:17])=[C:6]([C:12](=[O:14])[CH3:13])[CH:7]=[C:8]([Cl:11])[C:9]=1[CH3:10]>CO>[Br:3][C:4]1[C:5]([O:15][CH2:16][CH3:17])=[C:6]([CH:12]([OH:14])[CH3:13])[CH:7]=[C:8]([Cl:11])[C:9]=1[CH3:10]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1c(C(C)O)cc(Cl)c(C)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium tetrahydroborate (0.31 g, 8.1 mmol) was added to a mixture of 1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethanone (1.5 g, 5.4 mmol) in methanol (25 mL) at 0° C. and the resultant reaction mixture was stirred at room temperature for 1 hour. The solvent was removed and the resulting residue was diluted with ethyl acetate, washed with sat. NaHCO3, water, brine, then dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 30% EtOAc in hexanes (0.30 g, 90%).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[N+:15]([CH2:19][CH:20]=[CH2:21])[CH:16]=[CH:17][CH:18]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].[BH3-]C#N.[Na+]>CO>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH2:14][N:15]([CH2:19][CH:20]=[CH2:21])[CH2:16][CH2:17][CH:18]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: C=CC[n+]1cccc(-c2ccc([N+](=O)[O-])c(OC)c2)c1
Agent: [BH3-]C#N
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: C=CCN1CCC=C(c2ccc([N+](=O)[O-])c(OC)c2)C1
Temperature: 65 °C
Reaction time: 72 h
Yield: 50.1 %

Procedure:
To a solution of 3-[3-(methyloxy)-4-nitrophenyl]-1-(2-propen-1-yl)pyridinium bromide (28.2 g, 80.0 mmol) in MeOH (200 mL) was added NaBH3CN (21.1 g, 320.0 mmol). The reaction was heated to 65° C. and stirred for 72 h. The cooled solution was concentrated to remove MeOH, and to the residue was added saturated aq. NaHCO3 (100 mL). After extraction with Ethyl acetate (2×100 mL), concentration, and drying (Na2SO4), purification by silica chromatography afforded 5-[3-(methyloxy)-4-nitrophenyl]-1-(2-propen-1-yl)-1,2,3,6-tetrahydropyridine (11.0 g, 50%). ESIMS (M+H)+=275.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]([NH2:12])[CH2:9][CH2:10][CH3:11]>O>[CH2:8]([NH:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][CH3:11]
Reactant: Clc1ccncc1
Reactant: CCCCN
Solvent: O
Product: CCCCNc1ccncc1

Procedure:
A solution of 4-chloropyridine (2.0 g, 17.6 mmol), 50% butylamine in water (30 mL) was heated at 150° C. in a sealed tube for 24 h. The reaction mixture was evaporated, partitioned between 0.1 N NaOH and CH2Cl2, dried (Na2SO4) and evaporated. Crystallization in ether/petroleum ether 4:1 afforded 2.4 g of the title product 113 as a white powder (LCMS analysis).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:26]([C:28]1[CH:29]=[CH:30][C:31]([O:44][CH3:45])=[C:32]([CH:43]=1)[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:27].P([O-])([O-])([O-])=O.OO>C(Cl)Cl.O.CO>[CH2:36]([O:35][C:33]([C:32]1[CH:43]=[C:28]([CH:26]([OH:27])[CH:15]([CH2:16][CH3:17])[C:14]([N:9]2[C@@H:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12][O:11][C:10]2=[O:13])=[O:18])[CH:29]=[CH:30][C:31]=1[O:44][CH3:45])=[O:34])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: COc1ccc(C=O)cc1C(=O)OCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: OO
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CCC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(O)c1ccc(OC)c(C(=O)OCc2ccccc2)c1
Temperature: -74 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
(S)-4-benzyl-3-butyryl-2-oxazolidinone (1.65 g, 6.68 mmol) was dissolved in 22 ml of dehydrated methylene chloride, which was cooled to −74° C. under an atmosphere of argon. After triethylamine (1.11 ml, 8.02 mmol) was added, 1.0 mol/l solution of dibutylboryltrifurate in methylene chloride (7.35 ml, 7.35 mmol) was added dropwise over 15 minutes, which was stirred for 30 minutes. Next, after stirring for 50 minutes under cooling with ice, the mixture was cooled to −75° C. Following this, benzyl 5-formyl-2-methoxybenzoate (1.81 g, 6.68 mmol) dissolved into 56.5 ml of dehydrated methylene chloride was added dropwise over 20 minutes. After stirring for 1.5 hours at −75° C., the mixture was stirred for 2 hours under cooling with ice. A mixed solution comprising 30 ml of methanol, 16.7 ml of phosphate buffer and 7.3 ml of 30% aqueous hydrogen peroxide was added and the mixture was stirred further for 30 minutes at 0° C. The reaction mixture was poured into water, which was extracted with methylene chloride. The extract was washed with brine, then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=3:2 v/v) to obtain 1.36 g (39%) of (4S)-3-[3-(3-benzyloxycarbonyl-4-methoxyphenyl)-2-ethyl-3-hydroxypropionyl]-4-benzyl-2-oxazolidinone.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCCCCCCCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCON=C(C(=O)O)c1csc(N)n1
Yield: 89.7 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-n-octyloxyiminoacetate (syn isomer, 64 g.), 2 N-aqueous solution of sodium hydroxide (196 ml.), methanol (196 ml.) and tetrahydrofuran (300 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4yl)-2-n-octyloxyiminoacetic acid (syn isomer, 52.5 g.), mp. 146° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[N:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C:24]1[CH:25]=[C:26]2[C@@:37]3([CH2:41][O:40][C:39]([NH2:42])=[N:38]3)[C:36]3[C:31](=[N:32][CH:33]=[C:34]([C:43]#[C:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH:35]=3)[O:30][C:27]2=[CH:28][CH:29]=1)(=O)=O.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>[NH2:42][C:39]1[O:40][CH2:41][C@:37]2([C:36]3[C:31](=[N:32][CH:33]=[C:34]([C:43]#[C:44][C:45]([CH3:46])([CH3:47])[CH3:48])[CH:35]=3)[O:30][C:27]3[C:26]2=[CH:25][C:24]([C:5]2[CH:6]=[N:7][CH:8]=[C:3]([CH:4]=2)[C:1]#[N:2])=[CH:29][CH:28]=3)[N:38]=1
Reactant: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1O2
Reactant: N#Cc1cncc(B(O)O)c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncc(C#N)c3)ccc1O2
Temperature: 80 °C

Procedure:
A vial charged with 5-cyanopyridin-3-ylboronic acid (0.030 g, 0.206 mmol), palladiumtetrakis (10.80 mg, 9.35 μmol), potassium carbonate (0.129 g, 0.935 mmol), and (S)-2′-amino-3-(3,3-dimethylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (0.090 g, 0.187 mmol) was treated with 1 mL of dioxane followed by 0.4 mL water. The vial was flushed with argon and was heated to 80° C. for 4 hours. The reaction mixture was diluted with EtOAc and dried over MgSO4. The organics were then concentrated, and the crude residue was purified by column chromatography yielding (S)-5-(2′-amino-3-(3,3-dimethylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl)nicotinonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[CH2:27]Cl.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:27][C:26]3[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:24]([O:23][CH3:22])[CH:25]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: COc1cc(CCl)cc(OC)c1
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1cc(CN2N=C(c3ccc(OC)c(OC)c3)[C@@H]3CCCC[C@@H]3C2=O)cc(OC)c1

Procedure:
Prepared from compound 1 and 3,5-dimethoxybenzylchloride as described for compound 78. Purified by chromatography (dichloromethane). Crystallized from methanol. M.p. 114°-117° C.