Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH2:12][CH:13]=[CH2:14])[C:6]=1[O:15][CH3:16])([O-])=O.[Sn].[OH-].[Na+]>>[NH2:2][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH2:12][CH:13]=[CH2:14])[C:6]=1[O:15][CH3:16]
Reactant: C=CCc1cc(Cl)cc([N+](=O)[O-])c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc(Cl)cc(N)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Concentrated HCl (25 ml) was added to a mixture of 2-nitro-4-chloro-6-allylanisole (11.25 g) and granulated tin (9.02 g). The resulting mixture was stirred for 1 hour with heating at a boiling water bath temperature. The reaction mixture was then cooled to 0° C. and was made basic by addition of 10 N NaOH. The resulting mixture was extracted with dichloromethane. The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo to give crude 2-amino-4-chloro-6-allylanisole (9.34 g, 95%) which was used in the next step without purification. 1H NMR (300 MHz, CDCl3) δ6.61 (d, J=2.5 Hz, 1 H), 6.55 (d, J=2.5 Hz, 1 H), 5.98-5.89 (m, 1 H), 5.13-5.06 (m, 2 H), 3.72 (s, 3 H), 3.36 (d, J=6.5 Hz, 2 H).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.[CH2:45]([NH2:47])[CH3:46].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.CO>[CH2:45]([NH:47][CH:18]1[CH2:19][CH2:20][N:15]([C:13]2[N:14]=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:10]=[C:11]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)=[O:30])=[CH:26][CH:27]=3)[N:12]=2)[CH2:16][CH2:17]1)[CH3:46]
Reactant: CCN
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg) in tetrahydrofuran (5 mL) was treated with ethylamine (2.0 M solution in tetrahydrofuran, 0.16 mL), followed by glacial acetic acid (0.009 mL) and sodium triacetoxyborohydride (51 mg). After completion of the reaction, methanol was added and mixture was concentrated to dryness. The residue was purified by HPLC to give the title compound as its di-TFA salt; MS (ES+) 530.3 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:27])[C:20]([OH:26])=[CH:21][CH:22]=3)[C:17]2=[O:28])=[C:13]([CH3:29])[CH:12]=[C:11]([CH3:30])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Br[C:34](P(=O)(OCC)OCC)([F:36])[F:35]>CC#N.O.CCOC(C)=O.O>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:27])[C:20]([O:26][CH:34]([F:36])[F:35])=[CH:21][CH:22]=3)[C:17]2=[O:28])=[C:13]([CH3:29])[CH:12]=[C:11]([CH3:30])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(CN2CCc3ccc(O)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CN2CCc3ccc(OC(F)F)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
To a solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (1h, 0.1 g, 0.237 mmol) and KOH (0.265 g, 4.74 mmol) in CH3CN/H2O (10 mL/1 mL) was added diethyl [bromo(difluoro)methyl]phosphonate (0.126 g, 0.474 mmol) at −78° C. under N2 atmosphere. The resulting mixture was allowed to warm to room temperature and stirred for 30 minutes. The mixture was diluted with EtOAc (20 mL) and H2O (5 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep. TLC (petroleum ether/EtOAc, 4:1) to obtain 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-(difluoromethoxy)-3,4-dihydroisoquinolin-1(2H)-one (1i, 0.08 g, 72%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2].Cl.[CH3:27][NH:28][CH3:29].[OH-].[K+].C(OCC)(=O)C>CS(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([N:28]([CH3:29])[CH3:27])[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(Br)c1)N2
Agent: [Cu]I
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(N(C)C)c1)N2
Temperature: 120 °C
Yield: 29.7 %

Procedure:
A mixture of 2-(3-bromo-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.41 g, 1.0 mmol), dimethylamine hydrochloride (0.41 g, 5 mmol), copper (I) iodide (0.12 g, 0.6 mmol) and potassium hydroxide (0.34, 6.0 mmol) in DMSO (5 mL) was heated for 3 hours at 120° C. After cooling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) to afford 2-(3-dimethylamino-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.11 g, 30%) as a white solid: LC/MS m/e calcd for C22H27FN2O2 (M+H)+: 371.47, observed: 371.3.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([C:17]([OH:19])=O)[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([C:17]([Cl:22])=[O:19])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc2sc3cccc(C(=O)O)c3c(=O)c2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1ccc2sc3cccc(C(=O)Cl)c3c(=O)c2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
0.21 g (0.78 mmoles) of 7-methyl-9-oxo-9H-thioxanthene-1-carboxylic acid are suspended in 30 ml of toluene containing 2 drops of DMF and 0.35 g of thionyl chloride. After stirring for 1 hour at 80° C. the mass is cooled to room temperature obtaining a yellow solution of 7-methyl-9-oxo-9H-thioxanthene-1-carbonyl chloride.
Reaction SMILES: [N+]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1)([O-])=O.[Br:20]Br.[N+](C1C=CC=CC=1)([O-])=O>CO>[Br:20][C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2cc([N+](=O)[O-])ccc21
Reactant: BrBr
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CO
Product: O=C1c2ccccc2C(=O)c2cc(Br)ccc21
Temperature: 50 °C
Yield: 97 %

Procedure:
1265 parts by weight of 2-nitroanthraquinone are reacted at 270° C. with elemental bromine in the presence of 60 parts by weight of nitrobenzene in a laboratory apparatus as described in Example 1. When the reaction is complete, the melt is discharged into 2,000 parts by weight of vigorously stirred methanol at 200° C. The suspension so obtained is refluxed for 1 hour, cooled to 50° C., filtered and dried, affording 1390 g of 2-bromoanthraquinone (97% yield) in 98% purity.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([CH3:27])=[C:14]([C:23](OC)=[O:24])[C:15]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([CH3:27])=[C:14]([CH2:23][OH:24])[C:15]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)cc2)c1-c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2c(CO)c(C)nc3c2ccn3Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
An ice cold solution of methyl 1-(4-fluorobenzyl)-6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.2236 g, 5.72 mmol) in tetrahydrofuran (THF) (48.7 ml) was treated slowly with LAH (1M in THF) (17.17 ml, 17.17 mmol), and then warmed to rt overnight. The reaction was cooled to 0° C., treated slowly with 652 uL H2O, followed by 652 uL 20% aq. NaOH and 3×652 uL H2O. The mixture was stirred at rt for 1 hour, filtered, washed with Et2O and EtOAc, and then concentrated to give crude (1-(4-fluorobenzyl)-6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (2.1421 g) as light yellow solid. The intermediate was suspended in dichloromethane (DCM) (48.7 ml), treated with PCC (1.851 g, 8.59 mmol), and stirred at rt for 18 hours. The mixture was filtered through Celite™, washed with DCM and EtOAc, and then concentrated. Purification with column chromatography (0-40% EtOAc/Hexane) afforded 1-(4-fluorobenzyl)-6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1.68 g, 4.70 mmol, 82% yield) as off white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.08 (s, 1 H), 7.38-7.29 (m, 4 H), 7.30-7.23 (m, 2 H), 7.10 (d, J=3.6 Hz, 1 H), 7.04-6.97 (m, 2 H), 6.35 (d, J=3.6 Hz, 1 H), 5.49 (s, 2 H), 2.96 (s, 3 H), 2.46 (s, 3 H); LCMS (m/z) ES+=359 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C([O:25][C:26](=O)[C:27]1[C:32]([F:33])=[CH:31][CH:30]=[C:29]([N:34]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:28]=1[F:49])C1C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1>[CH2:42]([N:34]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:29]1[C:28]([F:49])=[C:27]([C:26](=[O:25])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:32]([F:33])=[CH:31][CH:30]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: Cc1ccncc1
Reactant: O=C(OCc1ccccc1)c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
To 4-methyl-pyridine (806 μL, 8.33 mmol) in anhydrous tetrahydrofuran (35 mL) was added at 0° C. sodium hexamethyldisilazide 1 M in tetrahydrofuran (16.66 mL, 16.66 mmol) and the reaction was stirred for 20 minutes. 3-Dibenzylamino-2,6-difluoro-benzoic acid benzyl ester (3.691 g, 8.33 mmol) was dissolved in tetrahydrofuran (5 mL) and added dropwise to the solution with 4-methyl-pyridine, the reaction was stirred at 0° C. for one hour. The reaction was poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtrate and concentrated under reduced pressure. The crude was purified by silica gel column chromatography eluting with ethyl acetate 30% in hexane to give the title compound (1.775 g, 50%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].Cl.Cl.[OH:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:30]4[CH2:31][CH2:32][N:27]([OH:26])[CH2:28][CH2:29]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: ON1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCN(O)CC4)c(F)cc3cc2c1=O
Yield: 86.1 %

Procedure:
3-Ethoxycarbonyl-7-fluoro-8-(4-hydroxy-1-piperazinyl)-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8 ]naphthyridine (3 g), 1-hydroxypiperazine dihydrochloride (1.97 g) and sodium carbonate (1.99 g). 3-Ethoxycarbonyl-7-fluoro-8-(4-hydroxy-1-piperazinyl)-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (3.25 g) is obtained in the form of a yellow solid, m.p. 258°-260° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH3:12][O:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:23]=[CH:22][CH:21]=[C:20]2Cl)=[O:16].O>CS(C)=O.C(OCC)(=O)C.CCCCCC>[CH3:12][O:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:23]=[CH:22][CH:21]=[C:20]2[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([Cl:9])[CH:4]=1)=[O:16]
Reactant: Nc1ccc(O)cc1Cl
Reactant: CONC(=O)c1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CONC(=O)c1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
After dissolving 4-amino-3-chlorophenol (408 mg, 2.84 mmol) in dimethylsulfoxide (10 ml), sodium hydride (114 mg, 2.84 mmol) was gradually added at room temperature and the mixture was stirred for 30 minutes. N6-Methoxy-7-benzyloxy-4-chloro-6-quinolinecarboxamide (388 mg, 1.14 mmol) was added, and the mixture was heated at 100° C. for 18 hours while stirring. Upon cooling to room temperature, the reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, it was subjected to silica gel column chromatography, the target fraction was concentrated under reduced pressure, the obtained crude product was suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (81.0 mg, 0.180 mmol, 16%) as light red crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[CH:4][N:3]=1.O>C(O)CO.Cl>[N+:20]([C:5]1[CH:6]=[C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[NH:1][C:2]2=[N:3][CH:4]=1)([O-:22])=[O:21]
Reactant: Nc1ncc([N+](=O)[O-])cc1NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: OCCO
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)cc1
Temperature: 160 °C
Yield: 92.1 %

Procedure:
To a stirred suspension of N-(2-Amino-5-nitropyridin-3-yl)-4-nitrobenzamide (6) (1.15 g, 3.8 mmol) in ethylene glycol (75 mL) was added HCl (Conc., 3 drops) and the mixture heated at 160° C. for 6 h. The solution was cooled to room temperature and poured into H2O (200 mL) and the resulting solid collected by filtration, rinsed with H2O, and dried in vacuo at 80° C. to give 4 as a pale yellow solid (1 g, 3.5 mmol, 92%). 1H NMR (500 MHz, DMSO-d6) δ14.58 (br s, 1H), 9.28 (apparent d, 1H), 8.88 (br s, 1H), 8.51 (d, J=8.39 Hz, 2H), 8.45 (d, J=8.28 Hz, 2H). EIMS M−1 284.3. Rf=0.55 (silica, 19:1 DCM/MeOH)
Reaction SMILES: [O:1]1[C@H:3]([CH2:4][O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2]1.[CH2:13](OC1C=CC(O)=CC=1)[C:14]1C=CC=C[CH:15]=1.[OH-].[Na+].O>CS(C)=O>[CH2:6]([O:5][C:4]1[CH:15]=[CH:14][CH:13]=[CH:2][C:3]=1[OH:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccccc1OCc1ccccc1

Procedure:
A solution of 8.3 g (36.1 mmol) of (2S):1-chloro-2-hydroxy-3-N-mesylisopropylaminopropane and 8.69 g (43.4 mmol) of p-benzyloxyphenol in 75 ml DMSO was treated with 10.86 ml 4 N NaOH (43.4 mmol) and the mixture was heated at 100° for 5 hours. To the cooled reaction mixture 40 ml 1 N NaOH and 60 ml H2O were added with stirring and the resulting solid was collected by filtration and was washed well with H2O. The dried crude product was recrystallized from EtOAc-hexane to yield the end product as white needles, mp 93°-94°.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(=O)C.[NH4+].[N+:15]([CH3:18])([O-:17])=[O:16]>C(O)(=O)C.O>[CH3:9][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:18][N+:15]([O-:17])=[O:16]
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccccc1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccccc1C=C[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
Ortho-tolualdehyde (10.00 g, 83.23 mmol) was dissolved in acetic acid (50 ml), ammonium acetate (6.93 g, 89.89 mmol) and nitromethane (7 ml, 129 mmol) were added, and the mixture was stirred at 110° C. for 8 hr and stood at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (12.71 g, yield 94%) as a bistered oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](N)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].Cl.N([O-])=O.[Na+].[I-:17].[K+].S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([I:17])[CH:3]=1
Reactant: [I-]
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(F)cc1I

Procedure:
A mixture of 4.4 g. of 4-fluoroanthranilic acid in 35 ml. of water and 7 ml. of hyrochloric acid is diazotized with 2.0 g. of sodium nitrite in 6 ml. of water at 0°-5° C. The resulting cold solution is added dropwise to a mixture of 7.1 g. of potassium iodide, 2 ml. of sulfuric acid and 10 ml. of water. The mixture is heated for 2 hours to 100° C. and steam distilled. The cooled residue gives 4-fluoro-2-iodobenzoic acid, m.p. 140°-147° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][C:15]2[N:26]([CH3:29])[N:27]=[CH:28][C:14]1=2.C(Cl)Cl.O.NN>C(O)C>[NH2:3][O:12][CH:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][C:15]2[N:26]([CH3:29])[N:27]=[CH:28][C:14]1=2
Reactant: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2ON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2ON
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a mixture of tert-butyl 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]-1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate 136 (2.50 g, 6.27 mmol) in a solution of DCM (20 mL) and ethanol (4 mL) was added hydrazine hydrate (0.360 mL, 6.27 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was washed with ether and methanol to give 137 (1.06 g, 62%) as a white foam.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.[F:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1>O1CCCC1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:47][C:46]2[CH:48]=[CH:49][C:43]([F:42])=[CH:44][CH:45]=2)=[O:10])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Temperature: 23 °C
Reaction time: 48 h

Procedure:
A mixture containing 4-acetyl-benzoic acid (4 g, 0.0243 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.13 g, 0.02673 mol), triethylamine (3.7 ml, 0.02673 mol), 1-hydroxybenzotriazole (3.62 g, 0.02673 mol) and 4-fluoroaniline (2.81 ml; 0.02916 mol) in 60 ml of tetrahydrofuran is stirred for 48 hours at 23° C. The reaction medium is filtered on frit and evaporated to dryness. The residue is taken up in a mixture of solvents : ethyl acetate-water: 50-50. The precipitate is filtered on frit, washed with isopropyl ether then isopentane. After drying, a white-coloured powder is obtained.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[C@@H:23]([CH2:24][OH:25])[CH2:22][O:21][CH2:20][C@@H:19]1[CH2:26][CH:27]=[CH2:28])=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[C@H:23]([CH:24]=[O:25])[CH2:22][O:21][CH2:20][C@@H:19]1[CH2:26][CH:27]=[CH2:28])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C=CC[C@H]1COC[C@H](CO)N1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=CC[C@H]1COC[C@@H](C=O)N1C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 111.8 %

Procedure:
Dimethyl sulfoxide (498 mg, 6.38 mmol) was added at −70° C. to a solution of oxalyl chloride (405 mg, 3.19 mmol) in DCM (5 mL), then after 15 min a solution of (3S,5S)-3-allyl-5-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (547 mg, 2.13 mmol) in DCM (3 mL) was added. The reaction mixture was stirred at −70° C. for 30 min, then treated with Et3N (1.29 g, 12.8 mmol), then after 20 min the ice bath was removed. After 30 min the reaction mixture was washed with sat. aq. sodium hydrogencarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to afford the title compound (608 mg) as a light yellow gum, which was directly used in the next step.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]=[O:19])=[C:12]([F:20])[C:11]=1[F:21])[CH3:8].C(OCC)(=O)C.N>C1COCC1>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][OH:19])=[C:12]([F:20])[C:11]=1[F:21])[CH3:8]
Reactant: CCOc1ccc(CCC=O)c(F)c1F
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc(CCCO)c(F)c1F
Reaction time: 2 h
Yield: 97 %

Procedure:
Lithium aluminum hydride (1.7 g) was suspended in THF (100 ml). 3-(4-Ethoxy-2,3-difluorophenyl)propanal (s13) (9.6 g) was added dropwise to the suspension in the temperature range of −20° C. to −10° C., and the mixture was stirred at the same temperature range for 2 hours. After the completion of reaction had been confirmed by means of GC analysis, ethyl acetate and a saturated aqueous solution of ammonia were added successively to the reaction mixture under ice-cooling, and the deposits were removed by filtration through Celite. The filtrate was extracted with ethyl acetate. The combined organic layers were washed successively with water and brine, and then dried over anhydrous magnesium sulfate. The products were purified by recrystallization from heptane to give 3-(4-ethoxy-2,3-difluorophenyl)propanol (s21) (9.4 g). The yield based on the compound (s13) was 97.0%.