Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.[NH2:26][C@@H:27]([C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([Br:50])[CH:44]=1)[CH2:28][N:29]([CH3:42])S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:26][C@@H:27]([C:43]3[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([Br:50])[CH:44]=3)[CH2:28][NH:29][CH3:42])=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CN(C[C@@H](N)c1cc(F)cc(Br)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ncc([C@H]2CC[C@H](O)[C@@H](F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC[C@@H](NC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (156 mg, 0.403 mmol) in DMF (1.28 mL) was added (S)—N-(2-amino-2-(3-bromo-5-fluorophenyl)ethyl)-N-methyl-2-nitrobenzenesulfonamide (180 mg, 0.384 mmol), HOAt (105 mg, 0.768 mmol), DIEA (402 μl, 2.8 mmol), and EDC.HCl (147 mg, 0.768 mmol). The reaction mixture was stirred at room temperature for 15 h, LCMS indicated the product. The mixture was diluted with EtOAc and washed with water and once with saturated Na2CO3 and the organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo providing 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide. The crude product was purified by ISCO column chromatography (0-100% EtOAc in heptane) leading to 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(N-methyl-2-nitrophenylsulfonamido)ethyl)-2-fluorobenzamide (99%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:12].[Li]CCCC.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28](=[O:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1>C1COCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][C:9]=3[F:11])[N:6]([CH3:12])[N:5]=[CH:4]4)([OH:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1
Reactant: Cn1ncc2c(F)cc(F)cc21
Reactant: CC(=O)c1cnc2ccc(Cl)nn12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ncc2c(F)c(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of 4,6-difluoro-1-methyl-1H-indazole (intermediate P) (600 mg, 3.57 mmol) in anhydrous THF (20 mL) at −78° C. was added n-BuLi (1.6M solution in hexane, 2.56 mL, 4.1 mmol). The solution was stirred at this temperature for 1 h and then a solution of 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethanone (intermediate M) (698 mg, 3.57 mmol) in anhydrous THF (10 mL) was added dropwise. The resulting solution was stirred at this temperature for 3 h and allowed to warm to it slowly and stirred overnight. The reaction mixture was quenched with water, extracted with EtOAc three times. The organic layers were combined and washed with brine, dried over Na2SO4. The crude was purified by flash chromatography (DCM: MeOH=95:5) to give 530 mg (41%) of the title compound as yellow oil. 1H-NMR (400 MHz, CDCl3) δ ppm 8.05 (d, 1H), 8.0 (s, 1H), 7.85 (s, 1H), 7.1 (d, 1H), 6.85 (d, 1H), 4.0 (s, 3H), 2.3 (s, 3H). LCMS (method B): [MH]+=363.9, tR=2.15 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][N:16]=1>>[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=3)[CH:7]=2)=[CH:17][N:16]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: O=Cc1cnc2ccc(Br)cn12
Product: COc1ncc(-c2ccc3ncc(C=O)n3c2)cn1
Yield: 55.55 %

Procedure:
The title compound was prepared by following the procedure as described for Intermediate 1 using 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and 2-methoxypyrimidin-5-ylboronic acid. Yield: 55.55%; 1H NMR (DMSO-d6; 300 MHz): δ 10.01 (s, 1H), 9.62 (s, 1H), 9.00 (s, 2H), 8.59 (s, 1H), 8.04-8.05 (m, 2H), 3.99 (s, 3H); MS: m/z 254 (M+1)+.
Reaction SMILES: [Mg].II.C(Br)C.[C:7]([C:11]#[CH:12])([CH3:10])([CH3:9])[CH3:8].CC.[CH:15]([CH:17]=[CH2:18])=[O:16]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:8][C:7]([CH3:10])([CH3:9])[C:11]#[C:12][CH:15]([OH:16])[CH:17]=[CH2:18]
Reactant: C#CC(C)(C)C
Reactant: C=CC=O
Agent: CC
Agent: II
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCBr
Solvent: C1CCOC1
Product: C=CC(O)C#CC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.5 %

Procedure:
At dry and inert atmosphere, magnesium (6.4 gr., 0.26 mole) was heated with a trace of iodine until brown vapors evolved (−60° C). It was cooled down to room temperature and toluene (300 ml) and tetrahydrofuran (30 ml) were added. The mixture was heated to 450-50° C. and a mixture of ethyl bromide (30 gr., 0.26 mole) and toluene (30 ml) was added dropwise. The mixture was stirred at 50° C. until all the magnesium had practically been consumed. The mixture was cooled and a mixture of t-butylacetylene (20 gr., 0.24 mole) mixed with toluene (20 ml) was added gradually. The mixture was stirred at 30°-40° C. for 4-6 hours. Progress of the reaction could be monitored by the evolution of ethane. The reaction mixture was cooled to 0° C.-5° C. and a mixture of acrolein (stabilized by hydroquinone) (14 gr., 0.25 mole) diluted with toluene (20 ml) was added gradually during 1 hour. The mixture was heated to room temperature and stirred for 4 hours. The reaction mixture was quenched with ammonium chloride solution. The phases were separated. The organic phase was extracted with toluene (3×50 ml). The combined organic phases were washed with water to neutrality. The solution was dried and the solvent stripped. The crude product was obtained (20.2 gr., 65% yield). The crude product was distilled (boiling point 68° C.-69.5° C. at 12 mbar) to give pure 6,6-dimethylhept-1-en-4-yn-3-ol (16.1 gr., 48%).
Reaction SMILES: O.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:13])[C:10]([OH:12])=[O:11]>[Ir].C(O)=O>[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:9]([OH:13])[C:10]([OH:12])=[O:11]
Reactant: Cc1ccccc1C(=O)C(=O)O
Agent: [Ir]
Solvent: O=CO
Solvent: O
Product: Cc1ccccc1[C@@H](O)C(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixed solvent (volume ratio=1:1, 5 mL) of water and formic acid and a chiral iridium aqua complex represented by the formula (12-R) (0.5 mol % relative to 2-methylphenylglyoxylic acid) were mixed, and 2-methylphenylglyoxylic acid (1 mmol) was added to the obtained solution at room temperature. The obtained mixture was stirred at room temperature to carry out asymmetric transfer hydrogenation. After confirming the disappearance of 2-methylphenylglyoxylic acid by thin layer chromatography, the reaction was quenched with brine (20 mL). The reaction mixture was subjected to extraction treatment (three times) with ethyl acetate (20 mL), and the obtained organic layers were combined. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=20:1) to give the corresponding (R)-2-(2-methylphenyl)-2-hydroxyacetic acid. Yield 95%, optical purity 83% e.e.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:17][CH:18]([CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=[O:24])[C:19]([OH:21])=[O:20]>CS(C)=O>[C:12]([C:11]1[C:2]([NH:17][CH:18]([CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([OH:25])=[O:24])[C:19]([OH:21])=[O:20])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:15])=[CH:6][C:5]=2[Cl:16])([OH:14])=[O:13]
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Reactant: NC(C(=O)O)C(C(=O)O)c1ccccc1
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1NC(C(=O)O)C(C(=O)O)c1ccccc1

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-phenyl-succinic acid [J. Med. Chem. 1973, 16, 1277-1280.] in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH3:1][SiH:2]([C:22]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25]([O:32][Si](C)(C)C)=[C:24]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:23]=1)[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([O:13][Si](C)(C)C)=[C:5]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:4]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[CH3:1][SiH:2]([C:3]1[CH:4]=[C:5]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]([OH:13])=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1)[C:22]1[CH:23]=[C:24]([C:37]([CH3:40])([CH3:38])[CH3:39])[C:25]([OH:32])=[C:26]([C:28]([CH3:30])([CH3:31])[CH3:29])[CH:27]=1
Reactant: C[SiH](c1cc(C(C)(C)C)c(O[Si](C)(C)C)c(C(C)(C)C)c1)c1cc(C(C)(C)C)c(O[Si](C)(C)C)c(C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C[SiH](c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.4 %

Procedure:
To a solution of 6.0 g (10 mmol) of methylbis (3,5-di-tert-butyl-4-trimethylsilyloxyphenyl)silane in 30 ml of tetrahydrofuran is added dropwise a solution of 6.3 g (20 mmol) of tetrabutylammonium fluoride trihydrate in 35 ml of tetrahydrofuran. A vigorous evolution of gas is witnessed during the addition and the reaction mixture becomes green in color. The reaction mixture is stirred for 5 minutes at room temperature and to it is added dropwise a solution of 1.9 g (52 mmol) of concentrated hydrochloric acid in 10 ml of tetrahydrofuran. The solvent is removed in vacuo and the residue is recrystallized from n-propyl alcohol to give 2.7 grams of white solid which is a mixture of two products. The product mixture is separated by preparative HPLC (silica gel, 99:1, heptane, ethyl acetate) to give 0.4 g (9%) of the desired product as white crystals; mp. 191°-193.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:33])[CH3:32]>CN1C(=O)CCC1>[CH:31]([N:34]1[CH2:39][CH2:38][N:37]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)[CH2:36][CH2:35]1)([CH3:33])[CH3:32]
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC(C)N1CCNCC1
Solvent: CN1CCCC1=O
Product: CC(C)N1CCN(c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
Trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 40 mg, 0.0921 mmol) was dissolved in NMP (1 ml) and added with 1-isopropylpiperazine (236 mg, 20 eq.). The mixture was stirred at 120° C. for 3 hr. After cooling to room temperature, purification was carried out by HPLC to obtain the target compound (white powder, 12.8 mg, 34%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C@H:28]1[NH:33][CH2:32][CH2:31][N:30]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:29]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:33]2[CH2:32][CH2:31][N:30]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH2:29][C@H:28]2[CH3:27])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: C[C@@H]1CN(c2ccc3ccccc3n2)CCN1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@@H]1CN(c2ccc3ccccc3n2)CCN1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[(R)-3-methyl-piperazin-1-yl]-quinoline
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:23]1[CH2:33][CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24]1>CC(C)=O>[CH2:29]([O:28][C:26](=[O:27])[CH:25]1[CH2:31][CH2:32][CH2:33][N:23]([CH2:2][CH2:3][CH:4]=[C:5]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:24]1)[CH3:30]
Reactant: CCOC(=O)C1CCCNC1
Reactant: BrCCC=C(c1ccccc1)c1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CCCN(CCC=C(c2ccccc2)c2ccco2)C1
Temperature: 25 °C
Reaction time: 216 h
Yield: 47.7 %

Procedure:
1-Bromo-4-(2-furanyl)-4-phenylbut-3-ene (0.23 g, 0.83 mmol) was dissolved in anhydrous acetone (10 ml) and dried potassium carbonate (0.46 g, 3.32 mmol) was added, followed by ethyl nipecotate (0.16 g, 1 mmol). The suspension was stirred at room temperature for 9 days, filtered and evaporated to a residue. The residue was purified by column chromatography on silica gel (Merck Art 9385), eluting with heptane/tetrahydrofuran (7:3), to provide the title ester (140 mg, 47%) as an oil. T.l.c. rf=0.36 (SiO2, heptane/THF (7:3)).
Reaction SMILES: [CH:1]1[C:18]2[C:5](=[C:6]([CH:19]=O)[C:7]3[C:16]([CH:17]=2)=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH2:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24]>CCO.CCOCC>[CH:1]1[C:18]2[C:5](=[C:6]([CH2:19][NH:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24])[C:7]3[C:16]([CH:17]=2)=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1c2ccccc2cc2cc3ccccc3cc12
Reactant: CC(N)(CO)CO
Solvent: CCO
Solvent: CCOCC
Product: CC(CO)(CO)NCc1c2ccccc2cc2cc3ccccc3cc12
Yield: 50.1 %

Procedure:
Using the reductive amination procedure described in Example 1, naphthacene-5-carbaldehyde (3A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 50.1% yield of 2-[(5-naphthacenylmethyl)amino]-2-methyl-1,3-propanediol methanesulfonte, mp 197.5°-199°, (EtOH/Et2O), (C, H, N, S).
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].CC1C=CC=C(C)[N+]=1[O-:23].C(OO)(=O)C>C(OCCCC)(=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:23]
Reactant: CC(C)Cc1ccc(C(C)C=O)cc1
Reactant: Cc1cccc(C)[n+]1[O-]
Agent: CC(=O)OO
Solvent: CCOC(C)=O
Solvent: CCCCOC(C)=O
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 94.9 %

Procedure:
To a stirred solution of 10.0 g (52.6 mmol) of 2-(4-isobutylphenyl)propionaldehyde (ibuprofen aldehyde)in n-butyl acetate (53 mL) cooled in a wet-ice bath (ca. 2° C.) was added 6.5 g (52.6 mmol) of 2,6-dimethylpyridine N-oxide (2,6-lutidine N-oxide). To this solution was then added slowly dropwise 29 mL (78.8 mmol) of a 20.0 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 10° C. (ca. 25 minutes). After the initial exotherm, the temperature returned to 2° C., and the reaction was maintained at this temperature for an additional 4 hours. The cold reaction solution was then transferred into a separatory funnel, was diluted with n-butyl acetate (100 mL), and was washed with a 1% aqueous solution of sodium thiosulfate (Na2S2 O3, 100 mL). The butyl acetate layer was further washed with two portions of water (100 mL each), and the combined water washes were back-extracted with n-butyl acetate (100 mL). The combined butyl acetate layers were extracted with two portions of a 5% aqueous solution of sodium hydroxide (NaOH, 100 mL each). The combined NaOH solutions were acidified to pH=1 with a 10% aqueous solution of hydrochloric acid. The resulting solution was extracted with two portions of dichloromethane (100 mL each), and the extract was dried over anhydrous Na2SO4. The extract was filtered and concentrated in vacuo to give 10.3 g (94.6%) of ibuprofen as an off-white solid.
Reaction SMILES: C([C@H]1CC[C@H](OC2C(C(F)(F)F)=C3C(=CC=2)C=C(C([N+]([O-])=O)CCC(O)=O)C=C3)CC1)(C)(C)C.[C:35]([C@H:39]1[CH2:44][CH2:43][C@H:42]([O:45][C:46]2[CH:47]=[C:48]3[C:53](=[CH:54][CH:55]=2)[CH:52]=[C:51]([C:56]([N+:64]([O-:66])=[O:65])([CH3:63])[CH2:57][CH2:58][C:59]([O:61]C)=[O:60])[CH:50]=[CH:49]3)[CH2:41][CH2:40]1)([CH3:38])([CH3:37])[CH3:36]>>[C:35]([C@H:39]1[CH2:40][CH2:41][C@H:42]([O:45][C:46]2[CH:47]=[C:48]3[C:53](=[CH:54][CH:55]=2)[CH:52]=[C:51]([C:56]([N+:64]([O-:66])=[O:65])([CH3:63])[CH2:57][CH2:58][C:59]([OH:61])=[O:60])[CH:50]=[CH:49]3)[CH2:43][CH2:44]1)([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)CCC(C)(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C(CCC(=O)O)[N+](=O)[O-])ccc3c2C(F)(F)F)CC1
Product: CC(CCC(=O)O)(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]

Procedure:
4-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-4-nitropentanoic acid was synthesized as per 4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-nitrobutanoic acid (Example 202) in 96% yield using methyl 4-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-4-nitropentanoate as starting material.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][CH:11]=1)([O-:3])=[O:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:19][CH2:18][C:13](=[O:14])[CH2:12][CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnccc1C1=CCC2(CC1)OCCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC=C(c2ccncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of 3-nitro-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine (1.0 equiv.) in 20% TFA in CH2Cl2 (0.2 M) was stirred at room temperature overnight. The solvents were removed under reduced pressure. The residue was dissolved with ethyl acetate (200 mL), and washed with sat NaHCO3 (30 mL), and sat NaCl (30 mL). The organic was dried with MgSO4, filtered and concentrated to give 4-(3-nitropyridin-4-yl)cyclohex-3-enone (85%). The crude product was used to next step without further purification. LC/MS (m/z): MH+=218.9, Rt=0.60
Reaction SMILES: [BrH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C:13]#[CH:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:3]>>[Br:1][C:13]([C:7]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH2:2][CH3:3])[CH:6]=1)=[CH2:14]
Reactant: Br
Reactant: C#Cc1ccc(OC)c(OCC)c1
Product: C=C(Br)c1ccc(OC)c(OCC)c1
Yield: 93.3 %

Procedure:
According to the General Procedure D, HBr (33% in acetic acid, 1.22 ml, 0.51 g, 6.25 mmol) and 3-Ethoxy-4-methoxyphenylacetylene (1.10 g, 6.25 mmol) are converted to give after workup and chromatography (SiO2 PE/EE 5:1, Rf=0.35) the title compound (1.53 g, 5.83 mmol) as a brown oil; C11H13BrO2 (257.13).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Brc1cnc2ccccc2c1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cnc2ccccc2c1

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), and 3-bromoquinoline (purchased from the Aldrich Chemical Co.) were coupled according to the procedure described in Example 1A to provide the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[C:6]2[C:7](=[O:18])[NH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)=[CH:10][N:5]2[N:4]=1>C(O)(=O)C.[Zn]>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[NH:8][C:7](=[O:18])[C:6]3[N:5]([N:4]=[C:3]([CH3:2])[CH:19]=3)[CH:10]=2)=[CH:16][CH:15]=1
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)cn2nc(CBr)cc12
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1cc2c(=O)[nH]c(-c3ccc(Br)cc3)cn2n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 64.4 mg (0.168 mmol) bromomethyl-6-(4-bromo-phenyl)-5H-pyrazolo[1,5-a]pyrazin-4-one in 2.5 ml acetic acid are added 55 mg (0.84 mmol) activated zinc powder. The reaction mixture is stirred at 100° C. for 18 hours. The reaction mixture is allowed to cool to room temperature and partitioned between water and ethylacetate. The organic phase is washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated to afford 6-(4-bromo-phenyl)-2-methyl-5H-pyrazolo[1,5-a]pyrazin-4-one as white solid;
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]3[O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:23]=3[CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:22]1[C:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][C:24]=2[C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[CH:18][CH:17]=2)=[CH:20][CH:21]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc(-c2cccc3c2oc2ccccc23)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 100 °C

Procedure:
A solution of 4-formylphenylboronic acid (0.9 g, 5.64 mmol) in ethanol (10 mL) was added to a stirred solution of the crude 4-(4-bromophenyl)-dibenzofuran (from the previous reaction) in toluene (40 mL). Tetrakis-(Triphenylphosphine)-palladium(0) (270 mg, 5 mol %) and 2 N sodium carbonate (4.7 mL, 9.4 mmol) were added and then the reaction was heated to 100° C. (oil bath temp.) for 2-3 h until complete (TLC control). The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The phases were separated, the aqueous phase being further extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with 0.5 N hydrochloric acid, water and sat'd aq NaCl and then dried over anhyd MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (10-20% ethyl acetate in heptane) afforded the title compound has a white solid (1.51 g).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[NH:9][CH3:10].[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([O:21][CH3:22])[CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=2[NH:9][CH3:10])=[C:14]([O:21][CH3:22])[CH:13]=1
Reactant: CNc1cnc(C)cc1I
Reactant: COc1cc(F)ccc1B(O)O
Product: CNc1cnc(C)cc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-6-methyl-pyridin-3-yl)-methyl-amine and 4-fluoro-2-methoxyphenylboronic acid after a reaction time of 14.5 hours at reflux. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown solid (84%). MS (ESI): m/z=247.12 [M+H]+.