Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[CH:4][CH:3]=1.[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([OH:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.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>[C:20]([CH2:19][NH:18][C:16]([C:13]1[C:14](=[O:15])[N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:34]=[CH:35][C:30]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)=[CH:3][CH:4]=2)[N:10]=[C:11]([CH:24]([CH3:26])[CH3:25])[C:12]=1[OH:23])=[O:17])([OH:22])=[O:21]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nn(Cc2ccc(-c3ccc(C(=O)O)cc3)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 36.2 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 61, 40 mg, 0.094 mmol), 4-carboxybenzeneboronic acid (19 mg, 0.10 mmol), potassium carbonate (40 mg, 0.290 mmol), and tetrakis(triphenylphosphine)palladium (0) (6 mg, 5 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes, diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was washed with brine, dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water (0.1% TFA)) to afford the title compound (16.0 mg, 0.034 mmol, 36% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.89 (s, 1H), 12.99 (br. s., 1H), 10.19 (t, J=5.68 Hz, 1H), 8.01 (m, 2H), 7.78 (m, 2H), 7.72 (d, J=8.34 Hz, 2H), 7.42 (d, J=8.59 Hz, 2 H), 5.31 (s, 2H), 4.10 (d, J=5.56 Hz, 2H), 3.20 (qq, J=6.85, 6.69 Hz, 1H), 1.22 (d, J=6.82 Hz, 6 H). MS (ES+) m/e 466 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[S:9][CH:10]=1)C.[OH-].[Na+]>C1COCC1>[O:30]=[C:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:31])=[O:3])[N:7]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC/C=C/CCCCCCCC(=O)Nc1nc(CC(=O)OCC)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCC/C=C/CCCCCCCC(=O)Nc1nc(CC(=O)O)cs1
Temperature: 0 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
A mixture of the above ester (7.4 g, 16.5 mmol) and sodium hydroxide (1.44 g, 36.1 mmol) was combined in THF (150 mL) and cooled in ice under N2 atmosphere. Enough distilled water was added portionwise until the hydroxide was dissolved (˜15 mL) and the mixture was maintained at 0° C. for 2 h, then allowed to warm to ambient temperatures with stirring for 15 h. The reaction mixture was evaporated in vacuo, the residue cooled in ice and treated with 2M aqueous HCl solution with stirring. The white precipitate was collected by vacuum filtration, washed with water and air dried. This material was crystallized from boiling heptane, filtered hot, and dried overnight on an abderhalden apparatus (refluxing acetone) to give 4.6 g of the title compound as a white powder, mp 116-118° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:18]12CC[CH:21]([CH2:22][CH2:23]1)[C@@H:20](O)[CH2:19]2.[H-].[Na+]>C1(C)C=CC=CC=1>[N:18]12[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19]1)[C@@H:1]([O:3][C:4]([C:6]1([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH2:2]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CCOC(=O)C1(c2cccs2)CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C1(c2cccs2)CCCCCC1
Yield: 86 %

Procedure:
1-Thiophen-2-yl-cycloheptanecarboxylic acid ethyl ester (Example 5c) (2.5 g) and (R) -quinuclidin-3-ol (2.08 g) were dissolved in toluene (350 mL) and sodium hydride (0.1 g) added under nitrogen. The mixture was heated to reflux for 20 hours after which the toluene was carefully distilled off to leave ˜100 mL which was cooled and washed with water (100 mL), dried (MgSO4) and evaporated. The crude product was purified by column chromatography on silica eluting with ethyl acetate/triethylamine (99/1) to afford the sub-titled compound (2.84 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](Br)[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OCCO)C.[Cu].[Cu]I>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1Br
Reactant: Nc1ccccc1
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOCCO
Product: O=C(O)c1ccc(F)cc1Nc1ccccc1
Temperature: 138 °C
Reaction time: 70 h

Procedure:
A mixture of 4-fluoro-2-bromo-benzoic acid (25 g, 114 mmol), aniline (12.5 mL, 137 mmol), potassium carbonate (17.4 g, 126 mmol), copper powder (725 mg, 11.4 mmol), and copper (I) iodide (1.09 g, 5.71 mmol) in 2-ethoxyethanol (70 mL) was stirred at 138° C. for 70 hr. under an argon atmosphere. The reaction mixture was cooled to room temperature, then water (60 mL) was added. The mixture was filtered through celite. The filtrate was adjusted to pH<2, then an additional 200 mL of water was added. The mixture was allowed to stir for 1 hr. The precipitated solids were collected via filtrated. The solids were taken up into 5% sodium carbonate solution, then filtered. The product was dried under vacuum overnight at 85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:18]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21].CCCCCC.CCOC(C)=O>C1COCC1>[CH2:18]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([N:15]2[CH2:16][CH2:17][N:12]([C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH2:13][CH2:14]2)=[O:30])=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21]
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: CCCCc1ccc(N=C=O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1ccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and 4-(n-butyl)phenyl isocyanate (57 μL, 0.30 mmol) in THF (10 mL) are reacted according to method C yielding the title product as a colorless solid after column chromatography with hexane-EtOAc.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][N:9]([OH:12])[C:8]1=[O:13].Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[OH:12][N:9]1[CH2:10][CH2:11][N:7]([CH2:6][CH2:5][CH2:4][CH:3]=[O:2])[C:8]1=[O:13]
Reactant: COC(CCCN1CCN(O)C1=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CCCCN1CCN(O)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To a solution of 1-(4,4-Dimethoxy-butyl)-3-hydroxy-imidazolidin-2-one (0.753 g, 3.45 mmol) in THF (3 mL) was added 1.0 N HCl (18 mL) and the mixture was stirred at room temperature overnight. The mixture was saturated with solid Na2CO3 (˜2 g) and extracted with CH2Cl2 (5×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated and provided 0.30 g (51%) of 4-(3-Hydroxy-2-oxo-imidazolidin-1-yl)-butyraldehyde as a yellow oil. 1H NMR (CDCl3) δ 1.83-1.91 (m, 2H), 2.53 (t, 2H, J=6.9 Hz), 3.25 (t, 2H, J=6.9 Hz), 3.30 (t, 2H, J=6.9 Hz), 3.48 (t, 2H, J=6.9 Hz), 7.75 (br s, 1H), 9.70 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:9](Br)=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)[NH:25][C@H:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]#[CH:33])[C:27]1=[O:34])C1C=CC=CC=1>>[C:1]([O:5][C:6]([N:7]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:33]=[C:32]1[CH2:31][N:28]1[CH2:29][CH2:30][C@H:26]([NH2:25])[C:27]1=[O:34])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCN1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(C)(C)OC(=O)Nc1cccnc1Br
Product: CC(C)(C)OC(=O)n1c(CN2CC[C@H](N)C2=O)cc2ncccc21

Procedure:
The title compound is prepared from (2-bromo-pyridin-3-yl)-carbamic acid tert-butyl ester (1.6 g, 5.9 mmol) and (2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl carbamic acid benzyl ester (1.6 g, 5.9 mmol) according to the methods described in EXAMPLE 59, Parts C,D and E. The title compound was obtained as a white solid (0.29 g, 0.88 mmol).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([F:14])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[NH2:15].[F:16][B-:17]([F:20])([F:19])[F:18].[N:21]#[O+]>C1COCC1>[F:16][B-:17]([F:20])([F:19])[F:18].[Br:1][C:2]1[C:11]2[C:6](=[C:7]([F:14])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:15]#[N:21]
Reactant: N#[O+]
Reactant: COc1cc(F)c2ncc(N)c(Br)c2c1
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: COc1cc(F)c2ncc([N+]#N)c(Br)c2c1
Temperature: -2 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
A solution of 4-bromo-8-fluoro-6-(methoxy)-3-quinolinamine (3 g, 11.1 mmol) in anhydrous THF (40 mL) cooled down to −9° C., with an ethanol/ice bath, was treated with nitrosonium tetrafluoroborate (1.4 g, 12.2 mmol) added portionwise over 20 minutes. The reaction mixture was stirred for 30 minutes at −2° C. under argon atmosphere. A precipitate was formed which was filtered, washed with cold THF and dried in vacuo overnight to afford the product as a yellow solid (3.2 g, 79%). MS (+ve ion electrospray) m/z 370 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:11])[CH:6]=[CH:7][C:8](=[O:10])[CH:9]=1)[CH2:2][CH3:3].C[O:13][C:14]1[CH2:19][CH2:18][CH:17]=[CH:16][CH:15]=1.Cl>C1C=CC=CC=1.CO>[OH:11][C:5]1[C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][C:8]2[O:10][C@H:16]3[CH2:15][C:14](=[O:13])[CH2:19][CH2:18][C@H:17]3[C:7]=2[CH:6]=1
Reactant: CCCC1=CC(=O)C=CC1=O
Reactant: COC1=CC=CCC1
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Product: CCCc1cc2c(cc1O)[C@@H]1CCC(=O)C[C@@H]1O2
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.1 %

Procedure:
A solution of 1.08 g (7.2 mmol) of 2-propyl-1,4-benzoquinone and 2.20 g (20.0 mmol) of 1-methoxy-1,3-cylcohexadiene in 20 mL of benzene was heated at reflux for 2 h. The solution was concentrated in vacuo and the residue dried under high vacuum to afford a pale yellow oil. This material was dissolved in 20 mL of methanol and to that solution was added 1 mL of 2.0M HCl. The solution was stirred at room temperature for 6 hours, then was concentrated to about 5 mL volume. This was partitioned between ethyl acetate and water and the aqueous layer was washed with two portions of ethyl acetate. The organic extracts were sequentially washed with water and NaCl solution, combined, dried over magnesium sulfate, and concentrated. The residue was crystallized from ether-hexane to afford 0.764 g white crystals, 43%.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][S:4][C:5]1[N:10]=[C:9]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>C(Cl)(Cl)Cl>[F:23][C:2]([F:1])([F:22])[CH2:3][S:4]([C:5]1[N:10]=[C:9]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)=[O:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1c2ccccc2ncn1-c1ccnc(SCC(F)(F)F)n1
Solvent: ClC(Cl)Cl
Product: O=c1c2ccccc2ncn1-c1ccnc(S(=O)CC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
3-[2-(2,2,2-Trifluoro-ethylsulfanyl)-pyrimidin-4-yl]-3H-quinazolin-4-one (1.1 g, 3.25 mmol) was dissolved in 20 mL chloroform, and m-chloroperoxybenzoic acid (m-CPBA) (0.7 g, 3.57 mmol, 85% of purity) was added at room temperature. The reaction mixture was stirred for 3 hours at room temperature. Washing with sodium-thiosulfate solution and sodium-hydrogencarbonate, drying with Na2SO4 and the crude product was purified by prep-TLC and then prep-HPLC to give 3-[2-(2,2,2-trifluoro-ethylsulfinyl)pyrimidin-4-yl]-3H-quinazolin-4-one (0.35 g, 30.5%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].[Cl-].[Al+3].[Cl-].[Cl-].COC1C=C(C(C2C=CC(OC)=CC=2)=CC#N)C=CC=1OC>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:7])[CH:17]=[CH:16][C:15]=1[O:20][CH3:21]
Reactant: COc1ccccc1OC
Reactant: COc1cccc(C(=O)Cl)c1
Agent: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cccc(C(=O)c2ccc(OC)c(OC)c2)c1
Yield: 110 %

Procedure:
3-methoxybenzoyl chloride (2.06 ml, 14.65 mmol), 1,2-dimethoxybenzene (1.87 ml, 14.65 mmol) in anhydrous methylene chloride (25 ml), and aluminum chloride (2.15 g, 16.12 mmol) were treated in the same manner as described above for the synthesis of 3-(3,4-dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (20% EtOAc in hexane) to give (3,4-dimethoxy-phenyl)-(3-methoxy-phenyl)-methanone as a yellow oil (4.39 g, 100%); 1HNMR (CDCl3) δ 7.50 (d, J=1 Hz, 1H, Ar), 7.42-7.30 (m, 4H, Ar), 7.14-7.09 (m, 1H, Ar), 6.90 (d, J=8 Hz, 1H, Ar), 3.96 (s, 3H, OCH3), 3.95 (s, 6H, 2OCH3), 3.86 (s, 3H, OCH3); 13C NMR (CDCl3) δ 195.4, 159.6, 153.1, 149.1, 139.7, 130.3, 129.2, 125.6, 122.5, 118.3, 114.4, 112.3, 109.9, 56.2, 56.2, 55.6; Anal. Calcd. For C16H16O4: C, 70.58; H, 5.92. Found: C, 70.38; H, 5.99; N, <0.05. The product was carried over to the next step.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.C(N(CC)CC)C.[NH2:20][CH2:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=2)=[O:30])[CH2:24]1>CCO>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[NH:20][CH2:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=2)=[O:30])[CH2:24]1)[CH3:10]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1c(NCCC2CN(C(=O)OCc3cc(Cl)cc(Cl)c3)CCO2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture comprising of 3,4-diethoxycyclobut-3-ene-1,2-dione (77 mg, 0.453 mmol) and triethylamine (253 μl, 1.813 mmol) in EtOH (1511 μl) was stirred at 40° C. for 20 minutes under nitrogen. After cooling to room temperature, 3,5-dichlorobenzyl 2-(2-aminoethyl)morpholine-4-carboxylate (step 2) (151 mg, 0.453 mmol) was added dropwise and the reaction mixture was allowed to stir at room temperature for a further 30 minutes. The resulting reaction mixture was concentrated under reduced pressure and diluted with EtOAc. The organic portion was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was dried loaded using silica onto an ISCO 4 g column, eluting with 0-100% EtOAc in iso-hexane. The product fractions were concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:13](N)=[NH:14]>O>[CH3:12][O:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:14][CH:13]=[N:1]2)=[CH:7][CH:8]=1
Reactant: N=CN
Reactant: COc1ccc(C(=O)O)c(N)c1
Solvent: O
Product: COc1ccc2c(O)ncnc2c1
Temperature: 125 °C
Yield: 76.4 %

Procedure:
To a solution of 2-amino-4-methoxy benzoic acid (8.6 g, 51.4 mmol) in 2-dimethoxy ethane (100 ml) was added formamidine (10.71 g, 103 mmol). The reaction mass was heated to 125° C. 18 h. The reaction mass was diluted with cold water. The precipitated solid was filtered, washed with water to get crude compound (6.92 g, 74.8%) as pale yellow solid. 1H NMR (400 MHz, DMSO): δ ppm 12.10 (br, s, 1H), 8.06 (s, 1H), 8.03-8.01 (d, J=8 Hz, 1H), 7.11-7.09 (m, 2H), 3.89 (s, 3H);
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N[C@@](C)([C@H](O)C)CO.[CH:13]([C:16]([N+:21]([O-])=O)([CH2:19]O)[CH2:17][OH:18])([CH3:15])[CH3:14]>>[C:1]([O:4][CH2:19][C:16]([NH2:21])([CH:13]([CH3:15])[CH3:14])[CH2:17][OH:18])(=[O:3])[CH3:2]
Reactant: CC(C)C(CO)(CO)[N+](=O)[O-]
Reactant: CC(=O)O
Agent: C[C@@H](O)[C@](C)(N)CO
Product: CC(=O)OCC(N)(CO)C(C)C
Yield: 98 %

Procedure:
Using the procedure in 7E, 2-isopropyl-2-nitro-1,3-propanediol gave a 98% yield of 2-amino-2-isopropyl-1,3-propanediol acetate mp 155°-155.5°. H. S. Broadbent et al., J. Heterocyclic Chem., 13, 337 (1975) report the synthesis of this compound as the free base (mp 70°-72°)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[OH-].[K+].[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29].[Cl-]>ClCCl.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH2:14][NH:15][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: COc1ccc2ccccc2c1CCN
Reactant: CCCCC(=O)Cl
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCC(=O)NCCc1c(OC)ccc2ccccc12
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
0.59 g (2.93 mmol) of 2-(2-methoxy-1-naphthyl)ethylamine, which is solubilized in 20 cm3 of anhydrous dichloromethane, is introduced into a 100-cm3 two-necked flask under an inert atmosphere. The mixture is cooled with an ice bath and stirred, and 0.61 cm3 (4.37 mmol) of triethylamine dried over potassium hydroxide, is introduced, followed by 0.42 cm3 (3.54 mmol) of valeryl chloride. After the introduction of the reactants, the ice bath is removed and reaction is allowed no proceed at room temperature for 30 min. Hydrolysis of the excess chloride is carried out by pouring the reaction mixture into water. After extraction three times with dichloromethane, the organic phase is dried over magnesium sulfate. After evaporation of the solvent and recrystallization of the solid obtained, in the heated state, in a pentane/ethyl acetate mixture, 0.39 g (1.37 mmol) of N-[2-(2-methoxynaphthyl)ethyl]pentanamide (white solid) is obtained, equivalent to a yield after purification of 47%.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:41]=[CH:40][O:39][CH:38]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.O1CCOCC1.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:41][CH2:40][O:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccoc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCOC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a solution mixture of tert-butyl 2-(2-(benzyloxy)-5-(furan-3-yl)benzamido)-4-phenylbenzoate (0.048 g) in methanol (2 mL) and dioxane (2 mL), 10% palladium-carbon (20 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. The insoluble substrate was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 97-85% hexane/ethyl acetate] to obtain 0.027 g of tert-butyl 2-(2-hydroxy-5-(tetrahydrofuran-3-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]([CH3:23])[S:5](=[O:22])(=[O:21])[O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[CH:17]=[CH:18][C:19]#[N:20].CO.Cl>C1COCC1.O>[CH3:23][N:4]([CH3:3])[S:5](=[O:21])(=[O:22])[O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[CH2:17][CH2:18][C:19]#[N:20]
Reactant: COc1cc(C=CC#N)c(OS(=O)(=O)N(C)C)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CCC#N)c(OS(=O)(=O)N(C)C)cc1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Disperse 6.7 g (0.177 mol) of sodium borohydride in 150 ml of THF. Pour in dropwise a suspension of 18.4 g (0.059 mol) of 2-(2-cyanovinyl)-4,5-dimethoxyphenyl dimethylsulphamate in 200 ml of THF. Pour in dropwise 48 ml of methanol. Heat for 3 h at 50° C. and then cool and add 1 g (0.026 mol) of sodium borohydride. Heat the reaction mixture at 50° C. for 1 h and then stir overnight at ambient temperature. Hydrolyse by pouring into the reaction mixture 60 ml of aqueous 4N HCl solution while maintaining the temperature at approximately 20° C. Add 40 g of ice and 30 ml of water and then extract twice with 200 ml of ethyl acetate each time. The organic phase is washed with water and saturated aqueous NaCl solution and then dried over MgSO4, filtered and evaporated to dryness. 17.4 g of title product are obtained.
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]1(=[O:24])[O:23][CH2:22][CH2:21]1.Cl>[OH-].[Na+]>[O:18]=[C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH2:22][CH2:21][C:20]([OH:24])=[O:23])=[C:10]([Cl:16])[C:9]=2[Cl:17])[CH2:14][C:6]1([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH3:19]
Reactant: O=C1CCO1
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C2CCCC2)Cc2cc(OCCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
2-Cyclopentyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (15.5 g., 0.05 mole) is dissolved in a 10% sodium hydroxide solution (50 ml.). The solution is heated to reflux and beta-propiolactone (36.0 g., 0.5 mole) is added at such a rate as to keep the reaction mixture refluxing. The reaction mixture is kept basic by the addition of 10% sodium hydroxide. The reaction mixture is cooled and acidified with dilute hydrochloric acid. The product is extracted with ether and extracted from the ether solution with a 5% solution of sodium bicarbonate. Acidification affords the desired product.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:28]([CH:30]1[O:32][CH2:31]1)[Cl:29].CC(O)C>O>[Cl:29][CH2:28][CH:30]([OH:32])[CH2:31][NH:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: ClCC1CO1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NCC(O)CCl)no2)cc1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
To a flask containing (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (84 mg, 0.23 mmol) was added 2 mL of WA. The cloudy, white mixture was cooled to 0° C. and epichlorohydrin (20.7 μL, 0.26 mmol) was added and the reaction mixture stirred at room temperature overnight. The IPA was removed by concentration in vacuo and water (500 μl) and aliquots of epichlorohydrin (20.7 μL, 0.26 mmol) were added every hour (4 total) at room temperature until conversion was complete. The reaction mixture was concentrated, dissolved in DCM and purified by chromatography (MeOH/DCM) to provide 19.3 mg (18%) of 5-(3 ((1R)-1-(3-chloro-2-hydroxypropylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile INT-15 as a white solid. LCMS-ESI (m/z) calculated for C24H25ClN4O3: 452.9; found 453.1 [M+H]+, tR=2.62 min.