Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH2:19][CH3:20])=[C:16]([Cl:18])[N:17]=2)=[O:12])[CH2:8][CH2:7][N:6]([C:21]2[S:22][C:23]3[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][C@H:4]1[C@@H:9]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH2:19][CH3:20])=[C:16]([Cl:18])[N:17]=2)=[O:12])[CH2:8][CH2:7][N:6]([C:21]2[S:22][C:23]3[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:5]1
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N=[N+]=[N-])C3)sc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Yield: 73.5 %

Procedure:
Ethyl cis(±)-2-(3-azido-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained in Example (81d) (84 mg, 0.17 mmol) was dissolved in THF (3 mL). Triphenylphosphine (63 mg, 0.24 mmol) and distilled water (0.2 mL) were added, and the mixture was heated under reflux for 15 hours. The reaction solution was concentrated under reduced pressure and the precipitated solid was collected by filtration, to obtain 59.6 mg of the title compound as a white solid (75%).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+].O>CO.C(O)(=O)C>[C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([NH2:20])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCN(c2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: NC1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-Phenylpiperidin-4-one (3.0 g, 17.1 mmol) was dissolved in methanol (250 mL) and acetic acid (147 mL), and ammonium acetate (67 g, 870 mmol) was added portionwise. The mixture was stirred for 4 hrs at room temperature, then cooled to 0° C. (ice-water) and sodium cyanoborohydride (1.6 g, 25 mmol) was added, then the reaction mixture was stirred at room temperature for 18 hrs. Water (20 mL) was added, and the mixture was concentrated under reduced pressure. The residue was adjusted to pH 12 with 15% aqueous NaOH and the resulting mixture was extracted with dichloromethane (3×100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with dichloromethane--3% methanol--0.3% NH4OH to give the product as a pale solid.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[CH2:10][C:9]3([CH2:19][C:18](=[O:20])[C:17]4[C:12](=[CH:13][CH:14]=[C:15](/[CH:21]=[CH:22]/[C:23]([NH:25][O:26]C5CCCCO5)=[O:24])[CH:16]=4)[O:11]3)[CH2:8]2)=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:10][C:9]3([CH2:19][C:18](=[O:20])[C:17]4[C:12](=[CH:13][CH:14]=[C:15](/[CH:21]=[CH:22]/[C:23]([NH:25][OH:26])=[O:24])[CH:16]=4)[O:11]3)[CH2:8]2)=[CH:33][CH:34]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccc(F)cc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccc(F)cc3)C1)O2)NO
Yield: 66.8 %

Procedure:
(E)-3-[1′-(4-Fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (260 mg, 0.56 mmol) in DCM (10 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving (E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide (143 mg, hydrochloride salt) as as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C(O[CH:12]=[C:13]([C:19]#[N:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[C:19]([C:13](=[CH:12][NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:20]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Cc1ccc(N)nc1
Product: CCOC(=O)C(C#N)=CNc1ccc(C)cn1
Yield: 50.5 %

Procedure:
A mixture of 2-amino-5-methylpyridine (5.0 g., 46.2 mmoles) and ethyl ethoxymethylenecyanoacetate (7.82 g., 46.2 mmoles) was heated by means of an oil bath maintained at 100° for 15 minutes. The mixture was cooled and the resultant solid recrystallized from acetonitrile to give the title compound (5.4 g., 50.5%), m.p. 170°-171.5°.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:14][C:15](=[O:18])[NH:16][NH2:17])([CH3:13])([CH3:12])[CH3:11]>C(O)C>[C:10]([O:14][C:15]([NH:16][N:17]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)=[O:18])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=Cc1ccc(O)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NN=Cc1ccc(O)cc1

Procedure:
Analogously to Example 4a, 14 g (106 mmol) of 4-hydroxybenzaldehyde and 14 g (117 mmol) of tert-butylcarbazate in 125 ml of ethanol are reacted to form 4-hydroxybenzaldehyde-tert-butoxycarbonylhydrazone. (19.8 g, 80%). 9.73 g thereof are hydrogenated in 200 ml of THF in the presence of 0.6 g of 5% palladium on carbon at 1 atm hydrogen pressure to yield the title compound, which is crystallised from hot methanol. 1H-NMR (200 MHz, CD3OD): 7.18 (d, J=8 Hz, 2H), 6.73 (d, J=8 Hz, 2H), 3.80 (s, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[OH:13]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[OH:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc(N)c1O
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of 2-hydroxy-3-nitrobenzoic acid methyl ester (5 g, 25.4 mmol) in ethanol (40 mL) was added 10% palladium on carbon (0.5 g), and the mixture was hydrogenated for 2 h. The catalyst was removed via filtration and the solvent was removed via evaporation, yielding 4.17 g (88%) of title compound 3-amino-2-hydroxybenzoic acid methyl ester, 1l.
Reaction SMILES: [N:1]1([C:6]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:16]1[S:17][C:18]([Br:21])=[CH:19][N:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:21][C:18]1[S:17][C:16]([N:9]2[CH2:8][CH2:7][C:6]([CH2:12][CH2:13][OH:14])([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:11][CH2:10]2)=[N:20][CH:19]=1
Reactant: OCCC1(N2CCCC2)CCNCC1
Reactant: Brc1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCC1(N2CCCC2)CCN(c2ncc(Br)s2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
A mixture of 2-(4-pyrrolidine-1-ylpiperidine-4-yl)ethanol (4.11 g), 2,5-dibromothiazole (5.03 g), potassium carbonate (3.43 g) and dimethylformamide (75 mL) was stirred at 60° C. for 16 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and washed with magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (3.88 g). Yield: 52%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17](Br)=[C:16]([CH3:21])[N:15]([C@@H:22]([CH3:26])[CH2:23][O:24][CH3:25])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:29][CH:30]([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:30]([F:40])[F:29])[CH:36]=3)=[C:16]([CH3:21])[N:15]([C@@H:22]([CH3:26])[CH2:23][O:24][CH3:25])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COC[C@H](C)n1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c(Br)c1C
Reactant: OB(O)c1cccc(C(F)F)c1
Product: COC[C@H](C)n1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c(-c2cccc(C(F)F)c2)c1C

Procedure:
Example 42 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 41c and replacing 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid. ESI mass spectrum: [M+H]+=519; Retention time HPLC: 0.97 min (Z018_S04).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1
Yield: 27.2 %

Procedure:
The title compound (0.1 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 1 mmol) using 4-methoxybenzyl chloride (1.5 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C21H22ClN3O, 367.15. found, m/z 368.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.41-7.39 (m, 2H), 7.31 (d, J=7.7 Hz, 2H), 6.70 (d, J=7.7 Hz, 2H), 5.36 (s, 2H), 3.60 (s, 3H), 3.33-3.31 (br m, 2H), 3.21-3.19 (br m, 2H), 3.18-3.16 (br m, 2H), 2.96-2.94 (br m, 2H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:27]=1[C:28]([OH:30])=O.CCN(C(C)C)C(C)C.[Cl:46][C:47]1[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=1[C:54]1[CH:59]=[CH:58][C:57]([NH2:60])=[CH:56][CH:55]=1>CN(C=O)C>[Br:25][C:26]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:27]=1[C:28]([NH:60][C:57]1[CH:56]=[CH:55][C:54]([C:48]2[CH:49]=[CH:50][C:51]([Cl:53])=[CH:52][C:47]=2[Cl:46])=[CH:59][CH:58]=1)=[O:30]
Reactant: Nc1ccc(-c2ccc(Cl)cc2Cl)cc1
Reactant: O=C(O)c1cc(F)c(F)cc1Br
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: O=C(Nc1ccc(-c2ccc(Cl)cc2Cl)cc1)c1cc(F)c(F)cc1Br
Temperature: 25 °C

Procedure:
Solid HATU (501 mg, 1.3 mmol) was added to a DMF solution (1 mL) of 2-bromo-4,5-difluorobenzoic acid (250 mg, 1.1 mmol), i-Pr2NEt (0.5 mL, 3.2 mmol), and 2′,4′-dichloro-[1,1′-biphenyl]-4-amine (251 mg, 1.1 mmol) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture was directly purified via column chromatography to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH2:24][CH3:25])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([CH2:24][CH3:25])[CH:17]=1
Reactant: CCc1cc(Cl)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CCc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-ethylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=7.6 Hz), 2.70 (2H, q, J=7.6 Hz), 5.20 (2H, s), 5.78 (1H, d, J=2.0 Hz), 7.20 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.25 (1H, d, J=1.6 Hz), 7.36 (1H, d, J=8.4 Hz), 7.39 (1H, dd, J=1.6 Hz, 5.2 Hz), 7.59 (1H, d, J=2.0 Hz), 7.99 (1H, s), 8.67 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H15ClN4O, 339. Found, 339.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].FC(F)(F)C(=O)CC(O)=O.[CH:23](OCC)(OCC)[O:24][CH2:25][CH3:26].C(OC(=O)C)(=O)C>>[CH2:25]([O:24][CH:23]=[C:5]([C:6](=[O:11])[C:7]([F:10])([F:8])[F:9])[C:4]([O:3][CH2:1][CH3:2])=[O:12])[CH3:26]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=C(O)CC(=O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Temperature: 120 °C
Yield: 89.9 %

Procedure:
In a 500 ml four-necked flask with stirrer, 78.3 g (0.425 mol) of trifluoroacetoacetate ethyl-(4,4,4-trifluoro)-3-oxobutyrate, 103.3 g (0.638 mol) of triethyl orthoformate and 130.0 g (1.275 mol) of acetic anhydride were mixed and heated at 120° C. for 6 hours. Then, at atmospheric pressure, initially the low-boiling components were removed and the product was then distilled under reduced pressure over a column. This gave 91.8 g (yield 90%) of the title compound as a colorless liquid of a purity>98%.
Reaction SMILES: [CH2:1]([C:3]([OH:35])([CH2:33][CH3:34])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:30][CH3:31])([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:32])[CH3:2].[CH2:36]([O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][C:44](Cl)=[CH:45][CH:46]=1)[CH3:37].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH2:36]([O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][C:44]([C:18]2[CH:17]=[CH:16][C:15]([C:12]([CH2:30][CH3:31])([C:9]3[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([CH2:33][CH3:34])([OH:35])[CH2:1][CH3:2])=[C:7]([CH3:32])[CH:8]=3)[CH2:13][CH3:14])=[CH:20][CH:19]=2)=[CH:45][CH:46]=1)[CH3:37]
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C)CC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(CC)CC)c(C)c3)cc2)nc1
Temperature: 140 °C
Yield: 73.2 %

Procedure:
A solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 50.0 mg, 0.10 mmol), (6-chloro-pyridin-3-yl)acetic acid ethyl ester (31.4 mg, 0.15 mmol), tetrakistriphenylphosphine palladium (16.9 mg, 0.0146 mmol) and potassium phosphate (33.4 mg, 0.15 mmol) in N,N-dimethylformamide (0.30 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the residue was purified by silica gel chromatography (30 to 40% ethyl acetate/hexane) to give the title compound (37.6 mg, 69%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][C@H:9]([OH:11])[CH3:10])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:22][S:23]([O:11][C@H:9]([CH3:10])[CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:12])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(F)cc1C[C@@H](C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(F)cc1C[C@@H](C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (R)-1-(5-fluoro-2-methylphenyl)propan-2-ol (6.1 g, 36.3 mmol) and DIEA (12.6 mL, 72.6 mmol) in 200 mL anhydrous DCM was cooled in ice-water bath. Then methylsulfonyl chloride (3.4 mL, 43.5 mmol) was added slowly and the mixture was stirred for 30 min at rt. And then, saturated NaHCO3 solution (30 mL) was added to the solution and extracted with DCM, dried over anhydrous MgSO4, concentrated, passed through silicagel pad to give crude (R)-1-(5-fluoro-2-methylphenyl)propan-2-yl methanesulfonate (F-2).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[OH-].[NH4+:32]>>[NH2:32][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:22]([Cl:28])=[CH:23][N:24]=[CH:25][C:26]=1[Cl:27]
Reactant: [NH4+]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Agent: [OH-]
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and 28% ammonium hydroxide following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h, then second aliquot of NH4OH added, then 60° C., 24 h).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](Cl)=[O:7].C(N(CC)CC)C.Cl.[NH2:22][CH2:23][C:24]#[N:25]>C1C=CC=CC=1>[C:23]([CH2:24][NH:25][C:6](=[O:7])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1])#[N:22]
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Reactant: N#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: N#CCNC(=O)COc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 11.95 g. (0.05 mole) of 2,4 dichlorophenoxyacetyl chloride in 50 ml. of benzene was added slowly to a stirred mixture of 10.1 g. (0.10 mole) of triethylamine and 4.2 g. (0.05 mole) aminoacetonitrile hydrochloride in 200 ml. of benzene. The mixture was stirred for 2 hours at room temperature and then washed successively with water, 5% sodium hydroxide solution, water, 5% hydrochloric acid solution, and water and then dried over magnesium sulfate. The resultant filtrate was concentrated under vacuum to give a solid which was crystallized from dilute ethanol to give 8.6 g. (66% yield) of product having a melting point of 107°-108° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.O.[NH2:11][NH2:12]>>[NH:11]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1)[NH2:12]
Reactant: NN
Reactant: OCc1ccc(Cl)nc1
Solvent: O
Product: NNc1ccc(CO)cn1

Procedure:
20.0 g (139 mmol) (6-chloropyridin-3-yl)methanol are heated under reflux overnight in 400 ml of a 35% strength aqueous hydrazine hydrate solution. The mixture is concentrated, toluene is added, the mixture is concentrated again and the residue is stirred with a mixture of methylene chloride, methanol and diethyl ether. The crystalline residue (hydrazine hydrochloride) is filtered off, the filtrate is concentrated and the residue is dried in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH2:10]([O:16][C:17]1[CH:24]=[C:23]([CH2:25][OH:26])[C:22]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][C:18]=1[CH:19]=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C([O-])([O-])=O.[Na+].[Na+].CCl>C(Cl)Cl.CO>[CH3:9][C:3]1[C:2]2[N:1]=[C:19]([C:18]3[CH:21]=[C:22]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:23]([CH2:25][OH:26])=[CH:24][C:17]=3[O:16][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCOc1cc(CO)c(OCCCCCC)cc1C=O
Reactant: Cc1cccc(O)c1N
Agent: CCl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: CCCCCCOc1cc(-c2nc3c(C)cccc3o2)c(OCCCCCC)cc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Herein, the detailed synthetic procedure is described to illustrate the features related to the compound preparations, chemical synthesis, and spectroscopic properties. For the first reaction shown in Scheme 1, activated molecular sieves (5 Å) was added to 100 mL MeOH in 500 mL flask. Into this flask were charged 2-amino-m-cresol (2.39 g, 21.7 mmol) and 2,5-bis(hexyloxy)-4-(hydroxymethyl)benzaldehyde (2.54 g, 21.7 mmol). The resulting mixture solution was heated to reflux overnight. The solution was cooled to room temperature, filtered, and solvent was removed using a rotary evaporator. Then solution of DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) (4.85 g, 21.4 mmol) in 700 mL CH2Cl2 was added to the above residue. After stirring at room temperature for 2 h, the reaction mixture was treated with 400 mL saturated Na2CO3 and methyl chloride to remove the DDQH by-product, then washed with water and brine, and dried over Na2SO4. After evaporation of the solvent, the solid residues were collected and purified on a silica gel column by using an eluant (hexane:CH3COOEt=15:1). After recrystallization from methanol, the product 2-(4-methylbenzoxazolyl)-5-(hydroxylmethyl)-1,4-bis(hexyloxy)benzene was obtained as an off-white solid (7.8 g, 81.8%), which has the following spectral properties. 1H NMR (CDCl3, 300 MHz, δ): 7.58 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.32 (dd, J=8.4 Hz, J=8.1 Hz, 1H), 7.14 (d, J=7.5 Hz, 1H), 7.06 (s, 1H), 4.74 (d, J=6.6 Hz, 2H), 4.07 (tt, J=6.3 Hz, 4H), 2.68 (s, 3H), 1.83 (m, 4H), 1.58 (m, 4H), 1.34 (m, 8H), 0.89 (m, 6H). MS (EI): [M+H+]+=356.3, [M+Na+]+=462.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2(O)[C:13]1[C:14]([O:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=1)#[N:2].N1C=CC=CC=1.S(Cl)([Cl:31])=O.ClCCl.CO>ClCCl>[Cl:31][C:6]1([C:13]2[C:14]([O:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=2)[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][C:7]1=[O:12]
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Reactant: O=S(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ncccc1C1(Cl)C(=O)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
Under an atmosphere of nitrogen, 6.00 g (20.32 mmol) of the 5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one were suspended in 60 ml of anhydrous dichloromethane (dried over molecular sieve). 2.30 ml (28.45 mmol) of pyridine were then added. The reaction mixture was cooled to a temperature of 0° C., and 2.06 ml (28.45 mmol) of neat thionyl chloride were then added dropwise (exothermic reaction). The mixture was stirred at room temperature for one hour. The formation of a yellow suspension was observed. The course of the reaction was monitored by thin-layer chromatography (TLC) (silica gel, dichloromethane/methanol in a ratio of 95:5). The reaction mixture was carefully poured into ice-water. After 15 minutes of stirring, the organic phase was removed. The aqueous phase was extracted with dichloromethane (2×). All organic phases were combined, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The product gave 5.70 g (18.17 mmol, 89%) of 3-chloro-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile as an amorphous solid which was used without further purification for the next reaction.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:27][C:26]([C:28]([F:31])([F:30])[F:29])=[C:25]([C:32]([O:34]CC)=[O:33])[CH:24]=1.[OH-].[Na+]>C(O)C.O>[O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:27][C:26]([C:28]([F:31])([F:30])[F:29])=[C:25]([C:32]([OH:34])=[O:33])[CH:24]=1
Reactant: CCOC(=O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F
Yield: 84 %

Procedure:
To a solution of ethyl 5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylate (1.30 g, 2.59 mmol) in ethanol (8 mL) and water (1.7 mL) was added sodium hydroxide (0.12 g, 3.00 mmol). The reaction mixture was heated at reflux for 45 min, concentrated in vacuo to remove ethanol. To the residue was added water (15 mL) and the mixture was acidified to pH-3 by 10% hydrochloric acid at 0° C. The resulting mixture was extracted with ethyl acetate (3×50 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 5-((2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)methyl)-2-(trifluoromethyl)furan-3-carboxylic acid (1.03 g, 84%): mp 195-197° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.13-7.26 (m, 1H), 7.17-7.15 (m, 2H), 7.05-7.00 (m, 2H), 6.67 (s, 1H), 6.09 (s, 1H), 5.90-5.88 (m, 2H), 5.11-4.96 (m, 2H), 4.80-4.66 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.0, 161.9, 155.8, 152.3, 148.9, 142.2, 141.9, 141.5, 132.1, 129.3, 124.1, 123.8, 122.2, 120.6, 120.1, 117.0, 111.8, 109.7, 103.1, 101.9, 93.8, 80.1, 57.9, 36.7; MS (ES−) m/z 472.0 (M−1).