Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
A 300-ml flask was charged with 16.6 g of 4-fluorotoluene, 30.0 g of NBS, 0.5 g of benzoyl peroxide and 150 ml of carbon tetrachloride, and the mixture was refluxed for 2.0 hours. The reaction mixture was cooled to room temperature, and the formed precipitate was removed by filtration and the residual CCl4 solution was washed with dilute alkali and then with water, dried over Na2SO4, and evaporated under reduced pressure to give 28.8 g of crude 4-fluorobenzyl bromide.
Reaction SMILES: BrC[CH2:3][CH2:4][CH:5]([CH3:11])[CH:6]([CH3:10])[C:7]([OH:9])=[O:8].C(O)(=O)C(C)C.[Cl:18]CCCCl>>[Cl:18][CH2:3][CH2:4][CH:5]([CH3:11])[CH:6]([CH3:10])[C:7]([OH:9])=[O:8]
Reactant: CC(CCCBr)C(C)C(=O)O
Reactant: ClCCCCl
Solvent: CC(C)C(=O)O
Product: CC(CCCl)C(C)C(=O)O

Procedure:
The title compound was prepared as described for 6-bromo-2,3-dimethylhexanoic acid from isobutyric acid (9.67 g, 109.8 mmol), and 1,3-dichloropropane (37.2 g, 329.2 mmol). The product was purified by flash chromatography (CHCl3) to provide the acid (0.9 g, 5%) as a oil, HRMS (M+Li)+ calcd for C7H13O2ClLi 171.0764, found 171.0766.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:3]=12.[N:17]1([CH2:22][CH2:23][O:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[C:11]1([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[N:29]3[CH2:30][CH2:31][CH:26]([CH2:25][O:24][CH2:23][CH2:22][N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:27][CH2:28]3)[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ccnc2scc(-c3ccccc3)c12
Reactant: C1CCN(CCOCC2CCNCC2)C1
Product: c1ccc(-c2csc3nccc(N4CCC(COCCN5CCCC5)CC4)c23)cc1
Temperature: 170 °C
Yield: 10.8 %

Procedure:
4-Chloro-3-phenyl-thieno[2,3-b]pyridine (150 mg, 0.462 mmol) and 4-(2-pyrrolidin-1-ylethoxymethyl)piperidine (150 mg, 0.706 mmol) were combined and heated in a Reactivial at 170° C. overnight. The reaction mixture was allowed to cool to room temperature and purified by basic prep HPLC to afford 3-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-b]pyridine (21 mg). LCMS [M+H]=422.2
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][N:12]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:14]Cl.O>CC(C)=O>[CH2:1]([N:8]1[CH2:10][CH2:11][N:12]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(N(CCCl)CCCl)c1
Reactant: NCc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cccc(N2CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 41 h
Yield: 51 %

Procedure:
Benzylamine (1.2 mL, 11 mmol), 120b (1.0 g, 3.6 mmol), water (50 mL), and acetone (50 mL) were heated an reflux for 28 h, then stirred at room temperature an additional 41 h. After evaporation of the acetone, the mixture was extracted with EtOAc (2×). The organic phase was extracted further with water and brine, then dried (Na2SO4), filtered and concentrated. The product was purified by chromatography on silica gel, eluting with 30% to 50% EtOAc in hexanes, then evaporated to yield a yellow oil (0.57 g). IR(neat): cm-1 1722. 1H NMR(300 MHz, CDCl3): 7.57-7.08 (m, 9H), 3.88 (s, 3H), 3.56 (s, 2H), 3.24 (m, 4H), 2.61 (m, 4H). HR-MS: Calc'd. 311.1760, Found 311.1764.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].[S:13](Cl)([CH3:16])(=[O:15])=[O:14].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][S:13]([N:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:12][CH2:11]1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
An ice cold solution of 1-ethoxycarbonylmethylpiperazine (5 g, 29 mmol), mesyl chloride (3.37 mL, 43.5 mmol) and triethyl amine (6.05 mL, 43.5 mmol) in CH2Cl2 (150 mL) was stirred at 0° C. for 5 min then at rt for 30 min, then partitioned between CH2Cl2 and aq. sat. NH4Cl. The organics were washed with aq. NaHCO3, brine, dried (Na2SO4), filtered and concentrated to give 6.88 g of the title compound. MS (APCI) m/z 251 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[O:12]1[C@@H:14]([CH2:15][CH3:16])[CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[OH:12][C@@H:14]([CH2:15][CH3:16])[CH2:13][N:9]1[C:7](=[O:8])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]1=[O:11]
Reactant: CC[C@H]1CO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](O)CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C

Procedure:
To 1,2-Benzenedicarboximide (4.29 g) in DMF (10 ml), (S)-(−)-1,2-epoxybutane (2.1 g) was added followed by K2CO3 (4.03 g) and heated at 60° C. for 48 h. The reaction was diluted with water, extracted with EtOAc, dried and solvent removed to give the subtitle compound as a white solid, 1.8 g.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.O=C1CC2C(=CC=C(/C=C/C(O)=O)C=2)N1.[CH3:34][NH:35][CH2:36][C:37]1[O:38][C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[CH:41]=1.CC1NC2C(C=1CNC)=CC=CC=2>>[O:38]1[C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[CH:41]=[C:37]1[CH2:36][N:35]([CH3:34])[C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]1[CH:9]=[N:10][C:11]2[NH:12][C:3](=[O:2])[CH2:4][CH2:5][C:6]=2[CH:7]=1
Reactant: CNCc1cc2ccccc2o1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CNCc1c(C)[nH]c2ccccc12
Agent: Cl
Agent: O=C(O)/C=C/c1ccc2c(c1)CC(=O)N2
Product: CN(Cc1cc2ccccc2o1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 87.8 %

Procedure:
According to the procedure of Example 4, except substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt (1.60 g, 6.3 mmole) for the (E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt, and substituting 2-(methylaminomethyl)benzofuran (1.20 g, 6.9 mmole) for the 2-methyl-3-(methylaminomethyl)indole, the title compound (2.0 g, 90%) was prepared as a tan solid: MS (ES) m/e 363 (M+H)+.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.CON(C)[C:23]([C:25]1[CH:26]=[N:27][CH:28]=[N:29][CH:30]=1)=[O:24]>C1COCC1>[CH3:6][N:7]1[C:11]([C:23]([C:25]2[CH:26]=[N:27][CH:28]=[N:29][CH:30]=2)=[O:24])=[CH:10][N:9]=[CH:8]1
Reactant: CON(C)C(=O)c1cncnc1
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(=O)c1cncnc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-BuLi (1.6 M in hexane, 3.71 mL, 5.94 mmol) was added to a solution of 1-methylimidazole (0.452 mL, 5.7 mmol) in THF (10 mL) at −78° C. The mixture was stirred at −78° C. for 30 min. Chlorotriethylsilane (0.957 mL, 5.7 mmol) was added slowly. The mixture was stirred at −78° C. for 30 min. A second portion of n-BuLi (1.6 M in hexane, 3.71 mL, 5.94 mmol) was added. The mixture was stirred at −78° C. for 30 min. Crude N-methoxy-N-methylpyrimidine-5-carboxamide (794 mg, 4.75 mmol, Intermediate 28, step a) was added via cannula as a solution in THF (5 mL). The mixture was stirred at −78° C. for 5 min and was removed from the cold bath and stirred at room temperature overnight. Saturated aqueous NH4Cl was added and the phases were separated. The aqueous phase was extracted twice with DCM. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, gradient 10-100% EtOAc-heptanes, then 0-10% MeOH-EtOAc) to afford impure title compound, which was further purified by flash column chromatography (silica gel, 4-5% MeOH-DCM).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH3:13])[C:8]([CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)=[N:7][C:6]=2[N:5]([CH3:25])[C:3]1=[O:4]>CN(C=O)C.[H][H].[Pd]>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH3:13])[C:8]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)=[N:7][C:6]=2[N:5]([CH3:25])[C:3]1=[O:4]
Reactant: Cn1c(=O)c2c(nc(C=Cc3cccc([N+](=O)[O-])c3)n2C)n(C)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(CCc3cccc(N)c3)n2C)n(C)c1=O

Procedure:
Compound 54 was made from 21b with H2 /Pd 50 psi in DMF for 3 h. mp 158°-160° C. 1H NMR DMSO-d6 d 2.82 (t, 2H J=8 Hz); 2.96 (t, 2H J=8 Hz); 3.20 (s, 3H N--CH3); 3.42 (s, 3H N--CH3); 3.69 (s, 3H N7 --CH3); 4.95 (s, 2H --NH2); 6.34-6.39 (3H, H-2 H-4 H-6); 6.90 (t, 1H J=8 Hz, H-5). MS (CI/NH3) m/e 314 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.Cl.[CH3:9][O:10][CH:11]1[CH2:14][NH:13][CH2:12]1>>[CH3:9][O:10][CH:11]1[CH2:14][N:13]([CH2:6][C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:12]1
Reactant: COC1CNC1
Reactant: O=Cc1ncc[nH]1
Agent: Cl
Product: COC1CN(Cc2ncc[nH]2)C1

Procedure:
The title compound was prepared from 2-imidazolecarboxaldehyde and 3-methoxyazetidine hydrochloride using the synthetic procedure described for Intermediate 5.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])([O-])=[O:7].[K+].[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:6]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:17])([O-:9])=[O:7]
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1ccccc1[N+](=O)[O-]

Procedure:
The toluene derivative (h) is charged with concentrated sulfuric acid and potassium nitrate to obtain the 2-nitrotoluene derivative (i) (reaction 7), which is subsequently reduced (reaction 8) with hydrogen over Raney-nickel to the amine (j). In a Sandmeyer reaction (reaction 9) with amylnitrate and the halogenide (R7 -Hal) in the presence of copper, the toluene derivative (k) is obtained. The reaction with chromium(VI)oxide in acetic acid leads to the aldehyde (a).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[N:4]=1.[Br:10]N1C(=O)CCC1=O.C(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:10][C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([NH2:9])=[N:6][CH:7]=1
Reactant: COc1ccnc(N)n1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1nc(N)ncc1Br
Reaction time: 5 h
Yield: 96 %

Procedure:
To a solution of 4-methoxypyrimidine-2-ylamine (1.84 g, 14.7 mmol) in chloroform (600 mL) was added N-bromosuccinimide (2.62 g, 14.7 mmol). After stirring in the dark for 5 hours, the solution was added to CH2Cl2 (200 mL) and 1N NaOH (100 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated yielding 2.88 g (96%) of 5-bromo-4-methoxypyrimidine-2-ylamine. LCMS (m/z): 204/206 (MH+). 1H NMR (CDCl3): δ 8.10 (s, 1H), 4.93 (bs, 2H), 3.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[C:15]=3[F:22])/[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12]
Reactant: O=C1Cc2cc(F)c(Cl)cc2N1
Reactant: O=Cc1cccc(Cl)c1F
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)c(F)cc2/C1=C/c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 87 %

Procedure:
To the mixture of 6-chloro-5-fluoroindolin-2-one (Natrochem) (2.88 g, 15.5 mmol) and 3-chloro-2-fluorobenzaldehyde (3.69 g, 23.3 mmol) (Aldrich) in methanol (140 mL) was added piperidine (3.96 g, 46.6 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-5-fluoro-1,3-dihydro-indol-2-one as a yellow solid (Yield 4.4 g, 87%).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([CH:9]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)[CH3:8]>O1CCCC1.C(N(CC)CC)C.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.[Cu]I>[CH2:7]([CH:9]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:16][CH:17]=1)[CH3:8]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCC(CC)COc1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(CC)COc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 64.5 h
Yield: 0.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.52 g, 0.45 mmol) was added to a degassed suspension of trimethylsilyl acetylene (3.00 mL, 2.09 g, 21.2 mmol), 4-(2-ethylhexyloxy)iodobenzene (2) (4.27 g, 12.9mmol) and copper (I) iodide (294 mg, 1.54 mmol) in tetrahydrofuran (20 mL) and triethylamine (30 mL). The mixture was stirred under argon at room temperature for 64.5 h. The solution was filtered through a short plug of silica with dichloromethane as eluent and the solvent removed. The residue was purified by column chromatography over silica with light petroleum as eluent to leave [4-(2-ethylhexyloxy)phenylethynyl]trimethylsilane (3) (2.93 mg, 75%) as a clear, colourless oil. (Found: C, 75.35; H, 9.85. Cl9H30OSi requires C, 75.43; H, 10.0%); ν-max(film)/cm−2156 (C≡C); δH(400 MHz, CDCl3) 0.25 (9 H, s, SiMe3), 0.92 (6 H, m, CH3), 1.30-1.51 (8 H, m, CHCH2CH2CH2CH3 and CHCH2CH3) 1.72 (1 H, OCH2CR), 3.84 (2 H, d, J5, OCH2CH) and 6.82 and 7.40 (4 H, AA′BB′, phenyl H); δc(100.6 MHz, CDCl3) 0.1, 11.1, 14.1, 23.0, 23.8, 29.0, 30.4, 39.3, 70.5, 92.2, 105.3, 114.3, 114.8, 133.4 and 159.6.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[CH2:11]O.P(Br)(Br)[Br:14].O>C(OCC)C>[Br:14][CH2:11][C:3]1[S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: OCc1sc2ccccc2c1Cl
Solvent: CCOCC
Solvent: O
Product: Clc1c(CBr)sc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3-chloro-1-benzothiophen-2-yl)methanol (480 mg, 2.4 mmol) in anhydrous diethyl ether (8 mL) was added dropwise a solution of phosphorus tribromide (230 μL, 2.4 mmol) in anhydrous diethyl ether (2 mL) at 0° C. The mixture was stirred for 3 hours at room temperature. Water was added and extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, 2-(bromomethyl)-3-chloro-1-benzothiophene was obtained as a pink pale solid (537 mg, 85% yield) and used for the next step without further purification; 1H NMR (400 MHz, CDCl3): δ 4.81 (s, 2H), 7.40-7.48 (m, 2H), 7.76-7.82 (m, 2H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[CH:12]=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(O)(=[O:17])C.CC1C=CC=C(C)N=1.C(OO)(=O)C>C(OCC)(=O)C>[OH:13][C:12]([CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=1)[CH3:14])=[O:17]
Reactant: CC(C)Cc1ccc(C(C)C=O)cc1
Reactant: CC(=O)O
Agent: CC(=O)OO
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 92.2 %

Procedure:
To a stirred solution of 109 g (573 mmol) of 2-(4-isobutylphenyl)-propionaldehyde (ibuprofen aldehyde) in ethyl acetate (5 12 mL) cooled in a wet-ice bath (ca. 2° C.) was added concurrently 34.4 g (573 mmol) of glacial acetic acid and 61.4 g (573 mmol) of 2,6-dimethyl pyridine (2,6-lutidine). To this solution was then added slowly dropwise 276 mL (859 mmol) of a 23.7 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 7° C. (ca. 1 h 40 min). After the initial exotherm, the temperature returned to 2° C,, and the reaction was maintained at this temperature for an additional 2 hours. Conversion of aldehyde at this time was ca. 99%, as monitored by GC (DB-1 column). The cold reaction solution was then transferred into a separatory funnel, was diluted with ethyl acetate (650 mL), and was washed with a 7% aqueous solution of sodium thiosulfate (Na2S2O3, 500 mL). The ethyl acetate layer was further washed with two portions of water (750 mL each), and the combined water washes were back-extracted with ethyl acetate (300 mL). The combined ethyl acetate layers were extracted with three portions of a 5% aqueous solution of sodium hydroxide (NaOH, 750 mL twice, then 500 mL). The combined NaOH solutions were acidified to pH=1 with a 10% aqueous solution of hydrochloric acid. The resulting solution was extracted with three portions of dichloromethane (500 mL twice, then 300 mL), and the extract was dried over anhydrous Na2SO4. The extract was filtered and concentrated in vacuo to give 109 g (92.2%) of ibuprofen as an off-white solid. HPLC analysis of this material indicated an `S` acid content of 83%, the same as the starting aldehyde as measured following KMnO4 oxidation.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[CH:9][CH:8]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: NCCCO
Product: OCCCNCc1ccc(F)cc1
Yield: 63.9 %

Procedure:
In a similar manner to Reference Example 23, 3-amino-1-propanol (52.0 g) was reacted with 4-fluorobenzylchloride (10.0 g) to obtain 3-(4-fluorobenzylamino)-1-propanol (8.10 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: Cc1ccc(CBr)cc1
Product: Cc1ccc(COc2ccc(Cl)c([N+](=O)[O-])c2)cc1

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-4-methyl-benzene using the conditions described in Example 10C to provide 1-Chloro-4-(4-methyl-benzyloxy)-2-nitro-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]2[C:10]=1[C:9](=[O:11])[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[N:6]=2.[O:18]1[CH:22]=[CH:21][CH2:20][CH2:19]1.B(F)(F)F.CCOCC>CN(C=O)C>[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[N:4]1[C:5]2=[N:6][C:7]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:8][C:9](=[O:11])[C:10]2=[C:2]([CH3:1])[NH:3]1
Reactant: C1=COCC1
Reactant: CC1=C2C(=O)N=C(c3ccncc3)N=C2N=N1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1[nH]n(C2CCCO2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 108 h
Yield: 37 %

Procedure:
A solution of 3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-one (2.3 g, 0.01 mol), DMF (50 ml) and 2,3-dihydrofuran (14.0 g, 0.20 mol) was stirred at 0° C. for 10 minutes and BF3. Et2O (1.5 ml, 0.012 mol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 108 hours. The reaction was quenched with concentrated ammonium hydroxide until pH of 7.5 and the resulting precipitate was collected by filtration. The solid residue was taken up in isopropanol (200 ml), heated to reflux and filtered to remove insoluble material. Concentration of the filtrate to 75 ml and cooling caused precipitation of the product. The product was collected by filtration and washed with ether to afford 1.1 g (37%) of 1-(2-tetrahydrofuranyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as a white powder, m.p. 268°-9° C. when dried at 70° C. in high vacuum.
Reaction SMILES: CS(N)(=O)=O.[N:6]1([S:10]([NH2:13])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:41]1([C:44]2[C:45]([O:54][CH2:55][C:56]3([F:62])[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)=[CH:46][C:47]([F:53])=[C:48]([CH:52]=2)[C:49](O)=[O:50])[CH2:43][CH2:42]1>>[N:6]1([S:10]([NH:13][C:49](=[O:50])[C:48]2[CH:52]=[C:44]([CH:41]3[CH2:42][CH2:43]3)[C:45]([O:54][CH2:55][C:56]3([F:62])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]3)=[CH:46][C:47]=2[F:53])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2(F)CCCCC2)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2(F)CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methane sulfonamide with azetidine-1-sulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-2-fluoro-4-((1-fluorocyclohexyl)methoxy)benzoic acid, the title compound was obtained following purification by reverse-phase HPLC as a colorless powder (0.037 g, 37%): 1H NMR (300 MHz, DMSO-d6) 11.64 (br s, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 4.16 (d, J=8.3 Hz, 2H), 4.05 (dd, J=8.3, 4H), 2.25-1.82 (m, 5H), 1.78-1.45 (m, 7H), 1.41-1.21 (m, 1H), 0.96-0.86 (m, 2H), 0.75-0.63 (m, 2H); MS (ES+) m/z 429.1 (M+1)
Reaction SMILES: [SH2:1].[C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[CH:18]3)=[N:8][CH:9]=1)#[N:3].C(NCC)C>CN(C=O)C>[NH2:3][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[CH:18]3)=[N:8][CH:9]=1)=[S:1]
Reactant: S
Reactant: COC(=O)C(C)n1ccc2cc(OCCCOc3ccc(C#N)cn3)ccc21
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COC(=O)C(C)n1ccc2cc(OCCCOc3ccc(C(N)=S)cn3)ccc21
Temperature: 60 °C
Yield: 90 %

Procedure:
H2S gas was passed slowly through a solution of methyl 2-(5-{3-[(5-cyano-2-pyridinyl)oxy]propoxy}-1H-indol-1-yl)propanoate (Example 67, 0.50 g, 1.32 mmol) in DMF (7.80 mL) for 20 minutes at rt. Diethylamine (0.21 mL, 2.37 mmol) was added in one portion, and the resultant light green solution was heated at 60° C. for 3 h. The reaction mixture was purged with a stream of argon, and then concentrated under reduced pressure. The desired compound (0.49 g, 90%) was isolated by column chromatography (50% hexanes in EtOAc) as a bright yellow solid. 1H NMR (400 MHz, CD2Cl2) δ 8.63 (dd, 1H), 8.16 (dd, 1H), 7.25-7.08 (m, 3H), 6.86-6.74 (m, 2H), 6.46 (d, 1H), 5.16 (qt, 1H), 4.59 (t, 2H), 4.17 (t, 2H), 3.71 (s, 3H), 2.35-2.25 (m, 2H), 1.82 (d, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:2]=1.S(=O)(=O)(O)O.Cl[C:22]1C(CSCCNC2NC(=S)C(CC3C=NC=CC=3)=CN=2)=NC=C[CH:27]=1.C(O)C.O>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][C:13]([O:15][CH2:22][CH3:27])=[O:14])[CH:2]=1
Reactant: O=C(O)C=Cc1cnc2ccccc2c1
Reactant: S=c1[nH]c(NCCSCc2ncccc2Cl)ncc1Cc1cccnc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C=Cc1cnc2ccccc2c1

Procedure:
A solution of 3-quinolineacrylic acid (63.71 g) and concentrated sulphuric acid (25 ml) in ethanol (350 ml) was refluxed for 18 hours. The product was obtained according to the procedure of Example 8 (i), giving ethyl 3-quinolineacrylate, m.p. 86.5°-88° (Ex ethanol-water).
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([CH3:10])[S:8][CH:9]=1)[CH2:3][NH2:4].Cl[CH2:12][C:13](OCC)=[O:14]>C(OCC)(=O)C.CO>[CH3:10][C:7]1[S:8][CH:9]=[C:5]([CH:2]2[O:1][CH2:12][C:13](=[O:14])[NH:4][CH2:3]2)[N:6]=1
Reactant: CCOC(=O)CCl
Reactant: Cc1nc(C(O)CN)cs1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc(C2CNC(=O)CO2)cs1

Procedure:
Prepared analogously to Example S by reaction of 2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with ethyl chloroacetate and purification on a silica gel column using ethyl acetate/methanol=19:1 as eluant.