Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.F[C:3]1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:87]=[CH:88][CH:89]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[N:67][C:68]([N:71]5[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]5)=[CH:69][CH:70]=4)[CH:63]=3)[N:58]([S:77]([C:80]3[CH:86]=[CH:85][C:83]([CH3:84])=[CH:82][CH:81]=3)(=[O:79])=[O:78])[CH:57]=2)[CH:53]=[N:52]1.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:46][C:47]1[CH:48]=[C:49]([CH:87]=[CH:88][CH:89]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[N:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH3:3])[CH2:73][CH2:72]5)=[CH:69][CH:70]=4)[CH:63]=3)[N:58]([S:77]([C:80]3[CH:86]=[CH:85][C:83]([CH3:84])=[CH:82][CH:81]=3)(=[O:79])=[O:78])[CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C)CC5)nc4)cnc32)cc1
Yield: 88.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-133, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.164 mmol) was methylated using paraformaldehyde (15 mg, 0.494 mmol) and Na(OAc)3BH (105 mg, 0.494 mmol) in dichloroethane (5 mL) to afford 90 mg (88.2% yield) of the titled compound after purification by column (Silica gel 60/120) using 5% methanol in dichloromethane as eluent. MS: m/z=622.1 (M+1).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[CH:10]=O)=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[NH2:21].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1/[CH:10]=[N:21]/[C:14]1[C:13]([Cl:12])=[CH:18][C:17]([F:19])=[CH:16][C:15]=1[Cl:20])=[N+:2]=[N-:3]
Reactant: Nc1c(Cl)cc(F)cc1Cl
Reactant: [N-]=[N+]=Nc1ccncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1ccncc1/C=N/c1c(Cl)cc(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
Titanium tetrachloride (1M, 4.0 mL, 4.15 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (1.0 g, 6.75 mmol), 2,6-dichloro-4-fluorophenylamine (1.22 g, 6.75 mmol) and triethylamine (2.8 mL, 20.3 mmol) in DCM (24 mL), under nitrogen. The reaction was stirred for 30 minutes at 0° C., warmed to room temperature, stirred for an additional 2 h, and concentrated under reduced pressure. The residue was dissolved in toluene and filtered though a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid (2.09 g, quant.). This crude material was employed in the next step without further purification or analysis.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:15]([CH3:14])(=[O:17])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of N-benzylpiperazine (8.8 g), methanesulphonyl chloride (4.3 ml), anhydrous potassium carbonate (20 g) in dry acetonitrile (100 ml) was stirred at ambient temperature for five hours to give N-benzyl-N'-methanesulphonylpiperazine (m.p. 115°-116° C.).
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][N:14]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C@H:13]([C:22]([O:24]C(C)(C)C)=[O:23])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][N:14]([C:16](=[O:21])[C:17]([F:19])([F:20])[F:18])[C@H:13]([C:22]([OH:24])=[O:23])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A solution of (2S,5R)-tert-Butyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (1.50 g, 3.73 mmol) in methylene chloride (5.0 mL) was ice-cooled, and trifluoroacetic acid (5.0 mL) was added, and reacted at the same temperature for 30 min. and then at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, then water and 6.5% sodium bicarbonate aqueous solution was added to the residue. After pH was adjusted to ca. pH 8, aqueous layer was washed with ethyl acetate. To this aqueous layer was added 5% potassium hydrogen sulfate aqueous solution. After pH was adjusted to ca. pH 5.6, the aqueous layer was extracted with ethyl acetate. After the organic layer was washed with saturated brine, dehydrated over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to afford 0.913 g of the title compound (yield 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)([O-:10])=[O:9].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO.C1(C)C=CC=CC=1>[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(CNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
Combined aniline (6.16 g, 66.2 mmol) and 4-nitrobenzaldehyde (10.0 g, 66.2 mmol) in MeOH (165 mL) and toluene (165 mL), and heated to 60° C. for 3 h. Cooled the mixture to room temperature, added sodium borohydride (5.01 g, 132 mmol) portionwise, and then stirred at room temperature for 1 h. Added sat NaHCO3 and stirred for 1 h. Added water and extracted with EtOAc. Combined extracts were washed with brine, dried (MgSO4) filtered, and evaporated to an amber oil that was purified by chromatography on silica gel, eluting with CH2Cl2 to give the title compound (9.0 g, 59.6% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[C:9]([N+:13]([O-])=O)[CH:8]=[CH:7][CH:6]=2>[Pd]>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH2:13])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cnc2cccc([N+](=O)[O-])c2c1Cl
Agent: [Pd]
Product: Cc1cnc2cccc(N)c2c1

Procedure:
3-Methyl-4-chloro-5-nitroquinoline was hydrogenated using Pd/C to give 3-methyl-5-aminoquinoline. This material was coupled with 2-(4-(1-methylpropyl)phenoxy) nonanoic acid according to the procedure outlined in Example 25 to give the title compound.
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][CH2:29][O:30][CH3:31]>CN(C=O)C>[C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:6])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCBr
Reactant: CC(C)(C)S(=O)(=O)c1cc2c(Cl)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCOc1cc2nccc(Cl)c2cc1S(=O)(=O)C(C)(C)C
Yield: 94.4 %

Procedure:
6-(tert-Butylsulfonyl)-4-chloroquinolin-7-ol (60 mg, 0.196 mmol), K2CO3 (55 mg, 0.392 mmol) and 1-bromo-3-methoxypropane (0.088 ml, 0.785 mmol) in DMF (1 ml) were heated to 70° C. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc twice and the combined EtOAc layers were dried over Na2SO4, filtered, and concentrated. The residue was purified via Biotage (SNAP Cartridge KP Sil 10 g, 30-75% EtOAc/Hexane) to yield 6-(tert-butylsulfonyl)-4-chloro-7-(3-methoxypropoxy)quinoline (0.071 g, 0.185 mmol, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 1.99-2.08 (m, 2H) 3.27 (s, 3H) 3.58 (t, J=6.19 Hz, 2H) 4.32 (t, J=6.19 Hz, 2H) 7.73 (s, 1H) 7.76 (d, J=4.80 Hz, 1H) 8.65 (s, 1H) 8.94 (d, J=4.55 Hz, 1H), MS: m/z: 372.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([O:20]C)[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([OH:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1C#N
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1O

Procedure:
5.0 g of 3-chloro-2-(4-cyano-3-methoxyphenyl)-5-trifluoromethylpyridine and 5.5 g of pyridine hydrochloride were stirred for 2 hours at 200° C. After cooling, the reaction mixture was thoroughly stirred with 100 ml of water. The solid portion was then separated off and purified by means of column chromatography on silica gel (cyclohexane/methyl tert-butyl ether (2:1) as eluent). Yield: 3.4 g (71%) of white crystals having a melting point of 155°-157° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[C:25]([O:29][C:30](=[O:40])[NH:31][C:32]1[CH:37]=[CH:36][C:35](CO)=[CH:34][N:33]=1)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([O:29][C:30](=[O:40])[NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:20][Br:24])=[CH:34][N:33]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Temperature: -20 °C
Reaction time: 5 h
Yield: 66.5 %

Procedure:
Triphenylphosphine (8.70 g, 33.1 mmol) and carbontetrabromide (17.0 g, 51.2 mmol) were added to a suspension of (5-hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (7.00 g 31.2 mmol) in CH2Cl2 (200 mL) at room temperature. Stirring was continued for 5 h followed by evaporation of the solvent. Acetonitrile (200 mL) was added and the mixture was cooled to −20° C. for 2 h. The mixture was then filtered and the crystalline residue washed with cold acetonitrile (2×10 mL), to give (5-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (5.96 g, 67%).
Reaction SMILES: [CH2:1]([N:8]([C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[C:9](=[O:18])[CH2:10][CH:11]([CH3:17])[CH2:12][C:13]([O:15]C)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([N:8]([C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[C:9](=[O:18])[CH2:10][CH:11]([CH3:17])[CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(C)CC(=O)N(Cc1ccccc1)c1ccc(C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(CC(=O)O)CC(=O)N(Cc1ccccc1)c1ccc(C#N)cc1
Yield: 96.1 %

Procedure:
A solution of the compound obtained in Step 2 (80.0 mg, 0.23 mmol) and 1N aqueous sodium hydroxide solution (1 mL, 1.00 mmol) in methanol (2 mL) and THF (2 mL) was stirred at room temperature for 14 hr. The reaction solution was neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure to give crude 5-(benzyl(4-cyanophenyl)amino)-3-methyl-5-oxopentanoic acid (74.2 mg, 0.221 mmol, 97%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:18]3[CH2:21][CH:20]([NH:22][C:23](=[O:24])[CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:37])[F:35])[CH:29]=4)[CH2:19]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C2CCC(=O)CC2)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: COC(=O)c1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(4-oxo-cyclohexyl)-benzoic acid methyl ester (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C1COCC1.C(N(C(C)C)CC)(C)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(OCC)(=O)C>[C:25]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: OCCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(CCO)CC1

Procedure:
To a stirred solution of 4-piperidineethanol 8 (15 g, 0.12 mol), THF (500 mL), and diisopropylethylamine (40.5 mL, 0.23 mol) at 0° C. was added benzyl chloroformate (16.5 mL, 0.12 mmol). After 1 h at 0° C. the reaction mixture was diluted with ethyl acetate and then washed with H2O (2×), 10% KHSO4, and brine, dried (MgSO4), and concentrated to give 112 as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9](O)=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+].Cl>O1CCCC1.CC(C)=O.O>[F:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1ncc(F)cc1F
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: OCc1ncc(F)cc1F
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 42.4 %

Procedure:
3,5-difluoro-2-pyridinecarboxylic acid (ALFAAESAR, 300 mg, 1.886 mmol) was dissolved in tetrahydrofuran (THF) (10 mL). N,N-diethylethanamine (FLUKA, 0.549 mL, 3.96 mmol) was added and mixture was cooled to −10° C. (ice in acetone). Isobutyl chloroformate (0.269 mL, 2.074 mmol, FLUKA) was added dropwise. Reaction was stirred 20 min at −10° C. Mixture was filtered into a previously prepared solution of sodium borohydride (ALDRICH, 214 mg, 5.66 mmol) in 2 mL of water at 0° C. and was stirred at 0° C. for 45 min. HCl (1N, aq) was added slowly until neutral pH. Aqueous mixture was partitioned with DCM (3×15 ml). Organic layer was dried over Na2SO4 (anh), filtered and concentrated. Residue was purified by silica gel chromatography using a linear gradient of DCM/MeOH to yield title compound (3,5-difluoro-2-pyridinyl)methanol (116 mg, 0.799 mmol, 42.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.44-8.45 (s, 1H), 7.88-7.93 (m, 1H), 5.35 (t, 1H), 4.56-4.58 (m, 2H). [ES+MS] m/z 146 (MH+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:7]=[C:6]([CH2:8][OH:9])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:4]=1.I([O-])(=O)(=O)=[O:21].[Na+]>C(#N)C.O.[Ru](Cl)(Cl)Cl>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:7]=[C:6]([C:8]([OH:21])=[O:9])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:4]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2CO)cc1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-n2nc(C(F)(F)F)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To the solution of 3-trifluoromethyl-5-hydroxymethyl-1 -(4-methoxyphenyl)-1H-pyrazole (4.4007 mmol, 1.198 g) in acetonitrile (20 mL) and water (20 mL) was added sodium periodate (1.977, 2.1 eq.) and several crystals of ruthenium(III) chloride at 0° C. This reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was filtered through Celite to remove white solid impurity and the filter cake washed with 1:1 acetonitrile: water. The filtrate was evaporated in vacuo and the residue was taken up in water. The aqueous was made acidic (pH 3) by the dropwise addition of conc. HCl at 0° C. then extracted with ethyl acetate (3×); the ethyl acetate extracts were washed with brine, dried (MgSO4), and evaporated to gave 1.13 g of pure product (90%).
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([C:8]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([C:18]([F:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:13][C:12]=2[CH2:28][CH3:29])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:38][OH:39]>C(O)C.O>[CH2:28]([C:12]1[CH:13]=[C:14]([C:18]([F:27])([C:19]([F:22])([F:20])[F:21])[C:23]([F:25])([F:24])[F:26])[CH:15]=[C:16]([CH3:17])[C:11]=1[NH:10][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([C:1](=[N:38][OH:39])[CH3:2])=[CH:31][CH:30]=1)[CH3:29]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C(C)=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C(C)=NO)cc1
Yield: 104.8 %

Procedure:
4-Acetyl-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-benzamide (2.2 g) was dissolved in ethanol (15 ml) and water (15 ml). To the solution, sodium acetate (0.6 g) and hydroxylamine hydrochloride (0.30 g) were added and the mixture was refluxed under heating for 4 hours. The reaction solution was extracted twice with ethyl acetate. The organic phases were combined, washed with water and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-4-[N-hydroxyethaneimidoyl]benzamide (2.1 g, yield 96%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C([Sn](CCCC)(CCCC)[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:13]1[CH2:14][CH2:15][CH:10]([CH2:9][O:8][C:7]2[N:6]=[CH:5][C:4]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:3][C:2]=2[C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH2:11][CH2:12]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: NS(=O)(=O)c1cnc(OCC2CCOCC2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cnc(OCC2CCOCC2)c(-c2nccs2)c1

Procedure:
A mixture of EXAMPLE 329B (0.070 g), 2-(tributylstannyl)thiazole (0.090 g), and tetrakis(triphenylphosphine)palladium(0) (0.069 g) in dioxane (2 mL) was heated at 90° C. for 4 hours. After cooling, the mixture was loaded onto a silica gel column and eluting with 1:3 ethyl acetate:hexanes to give the title compound.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)(=O)C(Cl)=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.CN(C)C=O>[C:12]1([C:11]2[O:9][C:1](=[O:10])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[N:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=c1oc(-c2ccccc2)nc2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Anthranilic acid (1.0 g, 7.29 mmol) was dissolved in pyridine (10 mL), benzoyl chloride (1.13 g, 8.02 mmol) was slowly added on an ice bath, and stirred at 50° C. overnight. The solvent was distilled off under reduced pressure, the residue was dissolved in dry methylene chloride (20 mL), oxalyl chloride (925 mg, 7.29 mmol) and a catalytic amount of dimethylformamide were added on an ice bath, and stirred at room temperature for 4 hours. Saturated sodium hydrogen carbonate aqueous solution was added, the mixture was extracted with methylene chloride, and the organic phase was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was washed by diethyl ether/heptane, and the target substance (1.13 g, 69%) was obtained as a light yellow solid.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH3:16][CH:17]([CH3:30])[CH2:18][CH2:19][C:20](=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCCCCC.O.C1COCC1>[OH:4][C:3]1[CH2:5][C:20]([CH2:19][CH2:18][CH:17]([CH3:30])[CH3:16])([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:29][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)CCC(=O)CCc1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)CCC1(CCc2ccccc2)CC(O)=CC(=O)O1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
The title compound was prepared as described in General Method 5 using 2.56 g (22 mmol) of methyl acetoacetate, 0.97 g (24.2 mmol) of NaH 60% dispersion in oil, 14.4 mL (23.1 mmol) of 1.6 M n-butyl lithium in hexane, 4.5 g (22.0 mmol) of 6-methyl-1-phenyl-heptan-3-one (A. Katritzky, et al., J. Org. Chem., 1995, 60 (23), 7605) and 60 mL of THF. After addition of the ketone, the reaction was stirred for 90 minutes at 0° C. and then for 30 minutes at room temperature. Water (400 mL) was slowly added with vigorous stirring, and the reaction was allowed to stir overnight. The reaction was worked up as in General Method 6. The product was triturated from ether to afford a solid, m.p. 99-100.5° C. 1H NMR (CDCl3) δ 0.89-0.92 (d,d, 6 H), 1.24-1.32 (m, 2 H), 1.48-1.57 (m, 1 H), 1.64-1.83 (m, 2 H), 1.94-2.03 (m, 2 H), 2.68-2.77 (m, s, 4 H), 3.42 (s, 2 H), 7.16-7.32 (m, 5 H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([NH:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:6]2.[BrH:19]>>[BrH:19].[N:16]1[CH:15]=[CH:14][C:13]([NH:12][N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[C:3]([OH:2])[CH:4]=3)[CH2:8]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)CN(Nc1ccncc1)C2
Agent: Br
Product: Oc1ccc2c(c1)CN(Nc1ccncc1)C2
Temperature: 10 °C
Yield: 72 %

Procedure:
A solution of 2,3-dihydro-5-methoxy-N-(4-pyridinyl)-1 H-isoindol-2-amine (5.25 g) in 48% hydrobromic acid (35 ml) was heated under reflux for 5 hrs, with stirring. The reaction mixture was cooled to about 10° C. and filtered. The filter cake was washed with cold water and dried under vacuum in an oven at 80° C. to give 4.8 g (72%) of product. The product was recrystallized from water and dried under vacuum at 80° C. to give 3.1 g (46%) of the analytical sample, mp 261-264° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21][C:22]#[N:23])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.C1COCC1>C1COCC1>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: B
Solvent: C1CCOC1
Product: NCCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Yield: 25.4 %

Procedure:
A solution of 3-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionitrile (0.740 g, 2.27 mmol was dissolved in dry THF, and the reaction mixture was stirred under argon at room temperature. BH3.THF (6 mL) was added dropwise, and the reaction mixture was allowed to stir for 15 hours. The reaction mixture was quenched by careful addition of 10% aqueous HCl, followed by stirring for 10 minutes. The reaction mixture was placed under reduced pressure to remove THF. The resulting aqueous solution was diluted with 10 mL of EtOH, made basic by addition of 0.5 M NaOH solution, and warmed to 75° C. for 15 minutes. The solution was cooled and extracted three times with 150 mL of EtOAc. The combined organic layers were washed with water, saturated brine, and dried (MgSO4). Evaporation of the solvent under reduced pressure gave an oil that was purified by elution on silica gel (MeOH:CHCl3 5:95). Removal of the solvent yielded 0.190 g (0.577 mmol, 25.4%) of 3-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propylamine as an oil, which was recrystallized from EtOH/EtOAc as an oxalate salt (0.140 g, 0.334 mmol, 14.7% overall yield). MS: 330 (M+H)+.