Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].C(N(C(C)C)C(C)C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH3:33]>[Cl-].[Na+].O.CN(C=O)C>[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:36][CH2:35]1)[CH3:33]
Reactant: CCN1CCNCC1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCN(C(=O)c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
To a DMF solution (10 ml) of 3-nitro-benzoic acid (334 mg) and N-ethyldiisopropylamine (1 ml), HOBt (270 mg) and WSCI (575 mg) were added, followed by stirring at room temperature for 10 minutes. To this, 1-ethyl-piperazine (305 μl) was added, followed by stirring at room temperature for 22 hours. Brine (30 ml) was added, followed by extraction with ethyl acetate (30 ml×2), and the organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=100/1 to 20/1), to obtain the desired compound (365.3 mg, 69%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:23]([OH:25])=O)[C:18](=[O:22])[O:19]2)=[CH:14][CH:13]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12>CN(C)C=O>[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH:65][C:23]([C:17]3[C:18](=[O:22])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[C:12]([O:11][CH3:10])[CH:21]=4)=[O:25])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: COc1ccc2cc(C(=O)O)c(=O)oc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)c(=O)oc2c1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
DIEA (0.027 mL, 0.16 mmol) was added to 7-methoxy-3-carboxy-coumarin (0.031 g, 0.14 mmol) and HATU (0.060 g, 0.16 mmol) in 2 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (0.030 g, 0.14 mmol) was added and allowed to react for approximately 30 minutes, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.051 g of 1541C in an 86% yield: 1H NMR (400 MHz, CD3OD/CDCl3) δ 10.95 (s, 1H), 8.96 (s, 1H), 8.23 (dd, J=1.8, 1.9 Hz, 1H), 8.20 (d, J=7.1 Hz, 1H), 7.99 (s, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.63 (d, J=9.1 Hz, 1H), 7.48 (dd, J=7.9, 8.0 Hz, 1H), 7.25 (dd, J=5.5, 6.8 Hz, 1H), 7.01 (dd, J=2.4, 8.8 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 6.85 (dd, J=7.0, 7.3 Hz, 1H), 3.96 (s, 3H); LCMS (ESI) m/z 412 (MH+).
Reaction SMILES: CON(C)[C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[CH3:12].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Br:11][C:9]1[CH:8]=[CH:7][C:6]([CH3:12])=[C:5]([CH:10]=1)[CH:4]=[O:13]
Reactant: CON(C)C(=O)c1cc(Br)ccc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
Methyl 5-bromo-2-methylbenzoate (see Japanese Unexamined Patent Publication No. 9-263549) (16.12 g) was dissolved in methanol (100 ml), and thereto was added 10% aqueous sodium hydroxide solution (50 ml). The mixture was stirred at 50° C. for 40 minutes. Under ice-cooling, the mixture was adjusted to pH 1 by addition of 10% aqueous hydrochloric acid solution, and diluted with water. Precipitated powder was collected by filtration, and dried to give 5-bromo-2-methylbenzoic acid (14.1 g). ESI-Mass m/Z 213/215 (M−H). (2) The above 5-bromo-2-methylbenzoic acid (10.0 g) was suspended in dichloromethane (100 ml), and thereto were added oxalyl chloride (8.1 ml) and N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure to give 5-bromo-2-methylbenzoyl chloride. This benzoyl chloride was dissolved in dichloromethane (200 ml), and thereto was added N,O-dimethylhydroxylamine hydrochloride (12.3 g). To the mixture was added dropwise triethylamine (20 ml) at 0° C., and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate, and washed successively with water, 10% aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, and brine. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.25 g) as oil. APCI-Mass m/Z 258/260 (M+H). (3) A solution of the above N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.2 g) in tetrahydrofuran (100 ml) was cooled to −78° C. under argon atmosphere. To the mixture was added dropwise diisobutyl aluminum hydride (1.0 M toluene solution, 75 ml), and the mixture was stirred at the same temperature for one hour. 10% aqueous hydrochloric acid solution (50 ml) was added thereto, and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate twice, and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was solidified to give 5-bromo-2-methylbenzaldehyde (8.73 g). APCI-Mass m/Z 213/215 (M+H+MeOH—H2O).
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][C:11](O)=[O:12])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:46]1[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[N:48]=[C:47]1[C:55]1[C:56]([NH2:67])=[N:57][CH:58]=[C:59]([C:61]2[CH2:62][CH2:63][NH:64][CH2:65][CH:66]=2)[N:60]=1>CS(C)=O>[NH2:67][C:56]1[N:57]=[CH:58][C:59]([C:61]2[CH2:62][CH2:63][N:64]([C:11](=[O:12])[CH2:10][CH2:9][NH:8][CH3:6])[CH2:65][CH:66]=2)=[N:60][C:55]=1[C:47]1[NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[N:46]=1
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccc2[nH]1
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CNCCC(=O)N1CC=C(c2cnc(N)c(-c3nc4ccccc4[nH]3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.6 %

Procedure:
To a solution of 3-[tert-butoxycarbonyl(methyl)amino]propanoic acid (14 mg, 0.07 mmol) in DMSO (445 μL) was added HATU (26 mg, 0.07 mmol) followed by the addition of triethylamine (28 mg, 38 μL, 0.27 mmol) and 3-(1H-benzimidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (20 mg, 0.07 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, dried (Na2SO4), filtered and concentrated. To the crude material was added 1:1 DCM:TFA (3 ml) and it was stirred for 1 h. The solvents were evaporated under reduced pressure and the crude material obtained was dissolved in DMSO and purified by reverse phase chromatography using 1-99% MeOH in H2O (0.05% HCl modifier) to obtain 1-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-3-(methylamino)propan-1-one (2 mg, 7%). 1H NMR (400 MHz, MeOD) δ 8.31 (d, J=15.9 Hz, 1H), 7.81 (dd, J=6.1, 3.1 Hz, 2H), 7.52 (dd, J=6.0, 3.1 Hz, 2H), 6.88 (d, J=20.4 Hz, 1H), 4.33 (dd, J=13.5, 2.6 Hz, 2H), 3.85 (dt, J=39.3, 5.6 Hz, 2H), 2.95 (dt, J=24.1, 6.0 Hz, 2H), 2.82 (s, 1H), 2.75 (s, 4H). LC/MS m/z 378.0 [M+H]+.
Reaction SMILES: [C:1]([S:5]([N:7]=[C:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9]1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Al](C)C.[Li]C>C1(C)C=CC=CC=1>[CH3:2][C:1]([CH3:4])([S:5]([NH:7][C:8]1([CH3:20])[CH2:11][CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9]1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC(=NS(=O)C(C)(C)C)C1
Reactant: C[Al](C)C
Agent: [Li]C
Solvent: Cc1ccccc1
Product: CC1(NS(=O)C(C)(C)C)CC(NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
To a stirred solution of tert-butyl 3-(tert-butylsulfinylimino)cyclobutylcarbamate (0.8 g, 2.8 mmol) in 60 mL of toluene at −78° C. was added Me3Al (3.1 mL, 6.2 mmol, 2M in toluene). After stirred 20 minutes at −78° C., MeLi (4.1 mL, 12.3 mmol, 3M in dimethoxymethane) was added slowly. The reaction mixture was stirred at −78° C. for additional 4 hours, and was then quenched by adding 3 mL of water. The solvent was removed under reduced pressure and the residue was passed through a pad of silica gel (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1, v/v) to give tert-butyl 3-(1,1-dimethylethylsulfinamido)-3-methylcyclobutylcarbamate (0.45 g, 53%) as a crude oil which was used for the next step without further purification. MS: (M+H)+=305.2.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH2:36])(=[O:35])=[O:34]>C1C=CC=CC=1>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:35])(=[O:34])[NH2:36])=[O:15])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CC(C)(C)c1ccc(COc2cccc(C(=O)O)c2)cc1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
A benzene (30 ml) solution containing 4.00 g (14.0 mmol) of 3-(4-t-butylbenzyloxy)benzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.42 g (14.0 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were recrystallized from an ether-hexane mixed solvent to obtain 4.2 g (yield: 68.0%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5][NH2:6].[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH2:28][CH3:29])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1.ClC1C=CC(CN=C=O)=CC=1Cl>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])[CH2:5][NH:6][C:25](=[O:26])[CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[CH:17]=[CH:16][N:15]=[CH:14]2)[CH2:28][CH3:29]
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Reactant: CCC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Agent: O=C=NCc1ccc(Cl)c(Cl)c1
Product: CCC(C(=O)NCc1ccc(C(F)(F)F)c(F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3-fluoro-4-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)butanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 391 (M+H)+; MS (ESI−) m/z 389 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 0.91 (t, J 7.5, 3H), 1.81 (m, 1H), 2.17 (m, 1H), 4.35 (m, 2H), 7.17 (m, 2H), 7.69 (t, J 7.8, 1H), 7.86 (t, J 7.8, 1H), 8.04 (d, J 7.1, 1H), 8.23 (d, J 8.1, 1H), 8.65 (d, J 6.8, 1H), 8.83 (t, J 6.8, 1H), 9.60 (s, 1H); Anal. Calcd for C21H18F4N2O+1 HCl: C, 54.77; H, 3.80; N, 5.55. Found: C, 54.62; H, 3.57; N, 5.50.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1Cl)[N:16]=[C:15]([CH3:21])[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:29](O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(C)C=C2)CO)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:29])[N:16]=[C:15]([CH3:21])[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(Cl)cc2n1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1

Procedure:
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)acetic acid (2K) was prepared following the procedure used to prepare compound 1L of Example 1, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)ethanol (2J) was used instead of compound 1K. 1H-NMR 300 MHz, (CD3OD) δ 8.31 (d, 1H), 7.97 (s, 1H), 7.73 (d, 1H), 7.70-7.60 (m, 3H), 7.42-7.38 (m, 1H), 5.25 (s, 1H), 2.96 (s, 3H), 2.78 (s, 3H), 0.98 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C23H25ClNO3: 398.9. Found: 398.2, 400.1.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.C1([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[CH2:16]2)C=CC=CC=1.IC>C1COCC1>[CH3:2][CH:16]1[CH2:15][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:24]
Reactant: O=C1CC(c2ccccc2)c2ccccc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1Cc2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A 2 M solution of LDA (21 mL, 1.05 eq, from Aldrich) was added dropwise to 3-phenyl-1-indanone (8.33 g, 40.0 mmol) in THF (300 mL) at −78° C. After 1 h at this temperature, iodomethane (3.00 mL, 1.2 eq) was added. The mixture was stirred at −78° C. for 2 h, at 0° C. for 30 min and quenched with sat NH4Cl (100 mL). After evaporation of THF in vacuo, the aqueous residue was extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (20 mL), dried (MgSO4) and concentrated. Silica gel chromatography (EtOAc-Hex, 5:95 then 7:93 then 10:90) gave the 2-methylindanone (1.93 g, 22%). MS Found: (M+H)+=223.
Reaction SMILES: [NH2:1][C:2]1([CH2:19][CH2:20][OH:21])[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[C:11]([F:17])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:18])=[CH:6][CH:7]=2.C([O-])(=O)C.[Na+].[N:27]#[C:28]Br>CCO>[Br:18][C:5]1[CH:4]=[C:3]2[C:2]3([CH2:19][CH2:20][O:21][C:28]([NH2:27])=[N:1]3)[C:15]3[CH:14]=[C:13]([Cl:16])[N:12]=[C:11]([F:17])[C:10]=3[O:9][C:8]2=[CH:7][CH:6]=1
Reactant: NC1(CCO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: NC1=NC2(CCO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 44.7 %

Procedure:
To a solution of 2-(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol (13 g, 34.8 mmol) in EtOH (50 mL) was added sodium acetate (5.71 g, 69.6 mmol) followed by the dropwise addition of cyanogen bromide (3.0M solution in DCM; 13.92 ml, 41.8 mmol). The resulting mixture was stirred at RT for 5 days. The reaction mixture was concentrated under reduced pressure, washed with water and extracted with DCM. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and azeotropically dried with toluene. The obtained residue was dissolved in DCM and TFA (40 mL) was added to the solution. The resulting mixture was stirred at RT for 30 min. The mixture was carefully quenched with aqueous, saturated NaHCO3 solution and extracted with DCM. The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by chromatography (0-3% MeOH/DCM) to afford 7-bromo-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-2′-amine (6.2 g, 15.55 mmol, 44.7% yield) as a light yellow solid.
Reaction SMILES: [Na+].[Cl-].[OH:3][CH2:4][C:5]([C@H:7]([C@@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])O)O)=O.C(C1C=CC=CC=1O)(CC)C>>[OH:3][CH2:4][C:5]1[O:12][C:11]([CH:13]=[O:14])=[CH:9][CH:7]=1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCC(C)c1ccccc1O
Agent: [Cl-]
Agent: [Na+]
Product: O=Cc1ccc(CO)o1
Reaction time: 0.08 h
Yield: 74 %

Procedure:
Dehydration of fructose in aqueous solutions to obtain 5-hydroxymethylfurfural (HMF) is carried out using mineral acids, such as HCl. An organic extracting solvent, 2-sec-butylphenol (SBP), is used to extract HMF continuously to separate it from fructose and the mineral acid and to inhibit further degradation. The experiments were carried out in 10 mL glass reactors at 170° C. in a pre-heated oil bath using magnetic stifling. In a typical experiment, an aqueous fructose solution with a desired weight percentage was prepared to obtain a 0.1 M HCl and saturated with NaCl. The aqueous fructose solution and SBP were added into the glass reactor to reach the desired mass ratio (aqueous layer (g)/SBP (g)). To end the reactions, the glass reactors were taken out from the oil bath and cooled in an ethylene glycol/dry ice bath. The two phases were then separated and analyzed to quantify HMF and fructose using HPLC. Using 1.5 g of aqueous solution (7.8% fructose) and 3 g of SBP, at 170° C., in 5 min, 74% yield of HMF was obtained with complete conversion of fructose. 97% of HMF was retained in SBP. Short residences times are used to minimize the conversion of HMF to LA in this step.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:13]([N:17]=[C:18]=[S:19])([CH3:16])([CH3:15])[CH3:14]>C(O)C.O>[C:13]([NH:17][C:18]([NH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4])=[S:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc(C(N)CO)cc1
Reactant: CC(C)(C)N=C=S
Solvent: O
Solvent: CCO
Product: COc1ccc(C(CO)NC(=S)NC(C)(C)C)cc1

Procedure:
The process is performed under the conditions of Example 1, starting with 1.3 g of 2-amino-2-(4-methoxyphenyl)-1-ethanol and 1.46 cm3 of tert-butyl isothiocyanate in 12 cm3 of absolute ethanol for 21 hours at a temperature in the region of 20° C. After concentration of the reaction mass under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained is taken up in 10 cm3 of water. A crystalline precipitate forms, which is filtered off, washed with 3 times 5 cm3 of diethyl ether and dried under reduced pressure (10 Pa) at a temperature in the region of 40° C. 1.32 g of N-(tert-butyl)-N′-[1-(4-methoxyphenyl)-2-hydroxyethyl]thiourea are obtained in the form of a white solid melting at 127° C.
Reaction SMILES: [CH2:1]([C@H:8]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C@@H:9]([O:36][Si](C(C)(C)C)(C)C)[CH2:10][C@@H:11]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([C@H:8]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[C@@H:9]([OH:36])[CH2:10][C@@H:11]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(-c2ccncc2)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccncc2)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
To the product from Example 150A (0.422 g, 0.60 mmol) was added tetrabutyl ammonium fluoride solution in tetrahydrofuran (2.3 mL, 1N) and the mixture was stirred at room temperature for 18 hours. The tetrahydrofuran was evaporated and the mixture was partitioned between ethyl acetate and water. The organic was washed with brined, dried over MgSO4 filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with chloroform and ending with 80% ethyl acetate in chloroform to give the title compound (0.242 g, 58% over two steps).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[CH:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:5]1([NH:8][C:14]2[CH:15]=[CH:16][C:11]([NH2:17])=[CH:12][CH:13]=2)[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NC1CCCCC1
Product: Nc1ccc(NC2CCCCC2)cc1

Procedure:
Prepared from 1-fluoro-4-nitrobenzene and cyclohexylamine
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[C:18](OCC)(=[O:23])[CH2:19][C:20]([CH3:22])=O.N#N>>[CH2:1]([N:3]1[C:20]([CH3:22])=[CH:19][C:18](=[O:23])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]1[C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCNC(=CC(=O)OCC)c1ccc(Cl)cc1
Agent: N#N
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)n(CC)c(C)cc1=O
Yield: 33.3 %

Procedure:
6 gms of ethyl beta-ethylamino-4-chlorocinnamate and 12 gms of ethyl acetoacetate is mixed in a 50 ml 3-neck flask fitted with a N2 -inlet, magnetic stirring bar, thermometer and a short-path distillation head (with receiver). The reaction mixture is heated (170°) for 10 hours. Ethanol and water is collected in the distillation receiver. The reaction mixture is cooled and triturated with ethyl acetate/ether to yield 2.52 gms of ethyl 1-ethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinate.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Br:22][C:23]1[N:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[Br:22][C:23]1[N:24]=[C:25]([CH2:28][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)[S:26][CH:27]=1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1nc(Br)cs1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(Br)cs4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (4-bromo-1,3-thiazol-2-yl)methanol (69 mg) and triphenylphosphine (140 mg) in THF (6 ml) was added bis(2-methoxyethyl) azodicarboxylate (125 mg), and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (37.9 mg) as a white solid.