Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[C:10]([OH:16])[CH:9]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C=CC=CC=1.C1COCC1>[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:1][CH3:2])=[C:10]([OH:16])[CH:9]=1
Reactant: O=Cc1ccc(Br)cc1O
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC=Cc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of ethyltriphenylphosphonium bromide (8.44 g, 22 mmol, 2.2 eq.) in toluene (60 mL), a solution of potassium tert-butoxide (2.60 g, 22 mmol, 2.2 eq.) in THF (15 mL) was added dropwise. The resulting red mixture was stirred at r.t. for 4 hours. The mixture was then cooled to −78° C. and a solution of 4-bromo-2-hydroxybenzaldehyde (2.12 mg, 10 mmol, 1.0 eq.) in toluene (10 mL) was added dropwise. The resulting solution was allowed to slowly warm to r.t. and further stirred at r.t. for 20 hours. The reaction was quenched with sat. aq. NH4Cl soln. (30 mL). The mixture was diluted with water (30 mL). The layers were separated and the aq. phase was extracted with Et2O (3×30 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, Heptane to Heptane/AcOEt 8:2) to yield 5-bromo-2-(propenyl)-phenol as a yellow oil as an unseparable mixture of E- and Z-isomer (ca. 85:15).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])[C@@H:3]1[O:5][C@H:4]1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1.[OH-].[K+].[Cl-].[Ca+2:39].[Cl-]>C(O)C>[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[Ca+2:39]
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Product: C/C(=C\C(=O)OCCCCCCCCC(=O)[O-])C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Reaction time: 1 h

Procedure:
Pseudomonic acid (5.00 g, 10 mmole) was dissolved in ethanol (20 ml), ethanolic solution of potassium hydroxide (0.56 g, 10 mmole potassium hydroxide and 10 ml ethanol) and ethanolic solution of calcium chloride (0.56 g, 5.0 mmole calcium chloride and 10 ml ethanol) were added to the mixture. The mixture was stirred for 1 hour and the solution was filtered to remove potassium chloride (0.51 g). The ethanol was subsequently evaporated at reduced pressure to give a solid, white foam. The product was dried for 12 hours at 45° C. under vacuum. The product had a mass of 4.38 grams. Assay: 99.1%, water: 2.36% [total impurity: 2.44%, highest impurity: 1.10% different method than the assay].
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:4]1[CH:3]=[C:2]([NH:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncnc1
Reactant: N#Cc1cccc(N)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1cccc(Nc2cncnc2)c1
Temperature: 100 °C
Yield: 93.4 %

Procedure:
5-Bromopyrimidine (1 g, 6 mmol, 1 eq), 3-aminobenzonitrile (0.892 mg, 7.55 mol, 1.20 eq), Cs2CO3 (2.87 g, 8.81 mmol, 1.40 eq), Pd2(dba)3 (347 mg, 0.603 mmol, 0.080 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (437 mg, 0.755 mmol, 0.120 eq) and dioxane (15 mL) were added to a microwave vial. The vial was purged with argon, capped and heated at 100° C. for 18 h. After cooling the reaction was filtered over a plug of celite and the plug was washed with 5% MeOH/CH2Cl2. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 1.1 g (89%) of the title compound as an orange solid: 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.73 (s, 1H), 8.63 (s, 2H), 7.49-7.43 (m, 2H), 7.43-7.39 (m, 1H), 7.32 (dt, J=7.2, 1.4 Hz, 1H); [M+1]+: 197.2.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13](C4C=CC(C=O)=CC=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(Cl)Cl.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH:35]1[CH3:40])[CH3:33].[BH4-].[Na+]>CC(O)=O>[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:10]2[C:11]3[C:2](=[O:1])[NH:3][N:4]=[C:5]4[CH:14]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH2:13][NH:12][C:7]([C:6]=34)=[CH:8][CH:9]=2)[CH2:36][CH:35]1[CH3:40])[CH3:33]
Reactant: CCN1CCNCC1C
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1CCN(Cc2ccccc2-c2ccc3c4c(n[nH]c(=O)c24)C(c2ccccc2)CN3)CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 163.2 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (86 mg, 0.23 mmol) in dryness DCM (15 mL) was added HOAc followed by 1-ethyl-2-methylpiperazine (90 mg, 0.7 mmol), after the addition the mixture was stirred at room temperature overnight. Then the mixture was cooled to 0° C. Sodium borohydride (85 mg, 1.4 mmol) was added. After the addition, the mixture was stirred at this temperature for 12 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC to give the title compound as white solid (90 mg, yield 71%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.30 (t, 3H), 1.42 (m, 3H), 3.23 (s, 1H), 3.47-3.56 (m, 6H), 3.80 (t, 2H), 4.46 (m, 3H) 4.91 (m, 10H), 7.20-7.29 (m, 3H), 7.30-7.32 (m, 3H), 7.46-7.48 (m, 3H), 7.59 (m, 1H), 7.69 (t, 1H). LC-MS (ESI) 552 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[OH-].[NH4+].[CH3:17][N:18](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([C:17]#[N:18])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Br)c2ncccc12
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [C-]#N
Agent: [NH4+]
Product: N#Cc1ccc([N+](=O)[O-])c2cccnc12
Temperature: 100 °C
Yield: 51 %

Procedure:
Compound 464A (15.0 g, 59.3 mmol) was dissolved in DMF (120 mL) and zinc cyanide (4.20 g, 35.9 mmol) was added. Bis(diphenylphosphino)ferrocene (3.00 g, 5.40 mmol) and tris(benzylidineacetone)dipalladium (3.00 g, 3.30 mmol) were then added and the reaction was heated to 100° C. for 1.5 h. The reaction was cooled to 22° C. and then poured into concentrated ammonium hydroxide (900 mL) resulting in an orange precipitate which was filtered and rinsed with cold water (1 L). The resulting precipitate was dissolved in methylene chloride, washed with brine (1×300 mL) and then dried over anhydrous sodium sulfate. Concentration in vacuo gave the crude material as an orange solid which was purified by flash chromatography on silica gel eluting with methylene chloride to give 6.01 g (51%) of compound 464B as a yellow solid. HPLC: 99% at 1.900 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 ml-min, monitoring at 220 nm).
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.[O:18]=[C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][N:20]1[CH:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:14]([NH:13][C:11](=[O:12])[NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([F:17])[C:2]([C:23]3[CH:22]=[CH:21][N:20]([CH:34]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[CH2:35]4)[C:19](=[O:18])[CH:24]=3)=[CH:16][C:6]=2[N:7]=1)[CH3:15]
Reactant: CCNC(=O)Nc1nc2cc(Br)c(F)cc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(B3OC(C)(C)C(C)(C)O3)cc2=O)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3ccn(C4CCN(C(=O)OC(C)(C)C)C4)c(=O)c3)c(F)cc2s1
Temperature: 80 °C
Yield: 36 %

Procedure:
A solution of 1-(5-bromo-6-fluoro-benzothiazol-2-yl)-3-ethyl-urea (0.07 g, 0.31 mmol), tert-butyl 3-(2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)pyrrolidine-1-carboxylate (0.24 g, 0.62 mmol) and K3PO4 (0.13 g, 0.62 mmol) in DMF-H2O (5.0 mL, 3:2) was degassed by flushing with nitrogen for 15 min. Dichlorobis(triphenylphosphine)-palladium(II) (0.022 g, 0.03 mmol) was then added to the reaction mixture followed by degassing with nitrogen for another 15 min. The resulting reaction mixture was then heated to 80° C. for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to room temperature and poured onto ice-cold water followed by extraction with EtOAc (3×50 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was then purified over silica gel (100-200 M, 1.50% MeOH-DCM) to obtain the desired product (0.056 g, 36%). MS: 502.20 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(#N)C>[Si:13]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][Cl:1])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCOCCCl
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCOCCCl
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of ethylene glycol mono-2-chloroethyl ether (6.2 g, 50 mmol) in acetonitrile (150 mg) were added imidazole (6.77 g, 99.54 mmol) and t-butyldimethylsilyl chloride (11.25 g, 74.65 mmol) at room temperature. The reaction mixture was stirred overnight at the same temperature. After the reaction was completed, the mixture was filtered through a filter paper, and concentrated under reduced pressure. Then, the concentrate was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=9:1) to give the title compound (11.0 g, yield 92%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[C:4]2[C:22]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].[C:30](OC(=O)C)(=[O:32])[CH3:31].C(=O)(O)[O-].[Na+].Cl>N1C=CC=CC=1.O1CCCC1.O.CO>[C:30]([N:19]1[CH2:20][CH2:21][C:22]2[C:4]3[C:5]([S:16][C:17]=2[CH2:18]1)=[N:6][C:7]([CH2:8][N:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]1=[O:14])=[C:2]([Cl:1])[C:3]=3[C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCC(=O)N1Cc1nc2sc3c(c2c(-c2ccc(O)cc2)c1Cl)CCNC3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CCc2c(sc3nc(CN4C(=O)CCC4=O)c(Cl)c(-c4ccc(O)cc4)c23)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.8 %

Procedure:
To a solution of the compound obtained in Example 15 (640 mg) in pyridine (30 ml) was added acetic anhydride (336 mg) while cooling with ice. After stirring for 14 hours at room temperature, the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (25 ml), washed with water, dried (MgSO4), and then the solvent was distilled off. The residue was subjected to column chromatography on silica gel. The fraction eluted with hexane-ethyl acetate (5:1, v/v) was collected and the solvent was distilled off. The residue thus obtained, which was combined with saturated aqueous sodium bicarbonate (15 ml), methanol (30 ml), water (15 ml) and tetrahydrofurane (30 ml), was stirred for 3 hours at room temperature, and then neutralized with 1N hydrochloric acid. The crystal precipitated was isolated by filtration, and washed with methanol to obtain the title compound (406 mg, 58%). The product was recrystallized from tetrahydrofuran-methanol. A colorless prism crystal. M.p. 300° C. or higher.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([N:18]=[CH:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO>[Cl:1][C:2]1[C:3]2[N:4]([N:18]=[CH:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([CH:8]([NH2:27])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)c2ccnn2c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1cc(Cl)c2ccnn2c1-c1cccc(F)c1
Temperature: 65 °C
Reaction time: 18 h
Yield: 88.8 %

Procedure:
The mixture of 1-[4-chloro-7-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-6-yl]ethanone (0.2 g, 0.7 mmol) in methanol (7.0 mL) and the ammonium acetate (0.5340 g, 6.928 mmol) was heated at 65° C. for 1 hour, all solids dissolved. The sodium cyanoborohydride (0.1306 g, 2.078 mmol) was added and the solution was heated at 65° C. overnight. The reaction was incomplete, additional ammonium acetate and sodium cyanoborohydride were added and the reaction was stirred for another 18 hours. This was allowed to cool to room temperature, concentrated in vacuo, taken up in ethyl acetate and washed with a small amount of water, brine, dried over magnesium sulfate and concentrated to give 1-[4-chloro-7-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-6-yl]ethanamine (0.18 g, 90%) as a viscous oil. LCMS calculated for C15H14ClFN3 (M+H)+: m/z=290.1. found: 289.9.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:22]([O:26][C:27]([N:29]1[CH2:47][CH2:46][N:32]2[C:33](=[O:45])[C:34]3[C:39]([C@@H:31]2[CH2:30]1)=[CH:38][C:37](Br)=[CH:36][C:35]=3[C:41]([F:44])([F:43])[F:42])=[O:28])([CH3:25])([CH3:24])[CH3:23].[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:22]([O:26][C:27]([N:29]1[CH2:47][CH2:46][N:32]2[C:33](=[O:45])[C:34]3[C:39]([C@@H:31]2[CH2:30]1)=[CH:38][C:37]([NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[CH:36][C:35]=3[C:41]([F:44])([F:43])[F:42])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Br)cc3C(F)(F)F)[C@@H]2C1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Nc4ccccc4)cc3C(F)(F)F)[C@@H]2C1
Yield: 54.4 %

Procedure:
To a degassed solution of tris(dibenzylideneacetone) dipalladium(0) (7 mg, 0.007 mmol) and 2-(di-tert-butylphosphino)biphenyl (6 mg, 0.021 mmol) in toluene (2 mL) was added N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (50 mg, 0.115 mmol). The mixture was degassed (alternating vacuum and argon) and aniline (0.031 mL, 0.345 mmol) and sodium tert-butoxide (33 mg, 0.345 mmol) were added. The mixture was degassed a final time and then subjected to microwave conditions (150° C., 1800 sec). The mixture was diluted with saturated aqueous sodium chloride and ethyl acetate, and the layers were separated. The aqueous layer washed with ethyl acetate (×2) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by radial chromatography (10-20% ethyl acetate in hexanes) to give 28 mg (55%) of a pale yellow residue. MS (ESI) 448 (M+H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([F:11])[CH:3]=1.[Mg].[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(OCC)C.O1CCCC1.ClCCl>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([C:2]2[C:10]3[O:9][CH:8]=[CH:7][C:6]=3[CH:5]=[C:4]([F:11])[CH:3]=2)[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: Fc1cc(Br)c2occc2c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC1CN(Cc2ccccc2)CCC1(O)c1cc(F)cc2ccoc12
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A mixture of 6.0 gm (27.9 mMol) 7-bromo-5-fluorobenzofuran and 0.70 gm (28.8 mMol) magnesium in 75 mL diethyl ether was heated at reflux for 30 minutes. To this mixture was then added a solution of 6.3 gm (31 mMol) 1-benzyl-3-methyl-4-oxopiperidine in 30 mL tetrahydrofuran dropwise over 15 minutes. The resulting mixture was heated at reflux for about 24 hours. The reaction mixture was cooled to room temperature and poured into 100 mL water. The resulting emulsion was diluted with 500 mL dichloromethane and then filtered through a bed of celite. The filter cake was washed with 2×200 mL dichloromethane. The filtrate aqueous phase was washed with 2×200 mL dichloromethane. All organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure The residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0-50% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 7.3 gm (77%) of the desired compound.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH3:19])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]([CH3:16])[C:4]1=[O:17])[CH3:2].[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[CH2:18]([C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([N+:20]([O-:22])=[O:21])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]([CH3:16])[C:4]1=[O:17])[CH3:19]
Reactant: O=[N+]([O-])O
Reactant: CCC1(CC)C(=O)N(C)c2ccc(NC(C)=O)cc21
Solvent: CC(=O)O
Product: CCC1(CC)C(=O)N(C)c2cc([N+](=O)[O-])c(NC(C)=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-(3,3-diethyl-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.2 g) in acetic acid (5 ml) at 0° C. is added nitric acid (fuming, 0.5 ml) drop-wise. The mixture is stirred at RT for 30 min and then poured into ice-water. The precipitate is collected by filtration and washed with water to give N-(3,3-diethyl-1-methyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1,38 g).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:21]=[CH:20][C:8]2[CH:9]=[C:10]([C:17]([OH:19])=[O:18])[CH:11]([C:13]([F:16])([F:15])[F:14])[O:12][C:7]=2[CH:6]=1)([CH3:4])[CH3:3].[Br:22]Br>[Fe].C(Cl)(Cl)Cl>[Br:22][C:21]1[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:6][C:7]2[O:12][CH:11]([C:13]([F:14])([F:15])[F:16])[C:10]([C:17]([OH:19])=[O:18])=[CH:9][C:8]=2[CH:20]=1
Reactant: CC(C)(C)c1ccc2c(c1)OC(C(F)(F)F)C(C(=O)O)=C2
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc2c(cc1Br)C=C(C(=O)O)C(C(F)(F)F)O2

Procedure:
7-(1,1-Dimethylethyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example 12)(0.6 g, 2 mmol), chloroform (50 mL), iron filings (0.01 g, 0.2 mmol), and bromine (0.48 g, 3.00 mmol) were stirred at reflux for 16 h. The mixture was allowed to cool and was washed with brine (2×50 mL). After drying over MgSO4, the mixture was filtered, concentrated in vacuo, and the residue crystallized from ether-hexanes yielding the title compound as a white solid (0.5 g, 66%): ° p 198.6-199.9° C. 1H NMR (acetone-d6/3(d MHz) 7.85 (s, 1H), 7.72 (s, 1H), 7.13 (H, 1H) 5.83 (q, 1H, J=7.2 Hz), 1.5(s, 9H). Anal. Calc'd for C15H14O3F3Br: C, 47.52; H, 3.72; N, 21.07. Found: C, 47.42; H. 3.68; N. 21.15.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][C:17]=1[F:31].[Cl-].[NH4+]>O1CCCC1.O>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:19]1[CH:18]=[C:17]([F:31])[C:16]([CH2:15][CH:3]([C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])=[C:21]([F:22])[CH:20]=1)#[N:30]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: N#Cc1ccccc1-c1cc(F)c(CBr)c(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)C(Cc1c(F)cc(-c2ccccc2C#N)cc1F)C(=O)OC
Reaction time: 1 h

Procedure:
To a solution of methyl 3-oxoheptanoate (6.82 g) in tetrahydrofuran (75 mL) was added 60% sodium hydride (1.29 g), and the mixture was stirred for 1 hr. A solution of 4′-(bromomethyl)-3′,5′-difluorobiphenyl-2-carbonitrile (6.65 g) in tetrahydrofuran (25 mL), and the mixture was stirred for 15 hr. Ammonium chloride and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (7.93 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:25](=[O:26])[CH2:24][Cl:23])=[CH:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2ccc3cc[nH]c3c2)cc1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C(CCl)c1c[nH]c2cc(-c3ccc(F)cc3)ccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution under N2 of 6-(4-fluorophenyl)indole (10.0 g, 47.4 mmol) in dioxane (36 mL) was added pyridine (5.80 mL, 71.8 mmol) and the solution was heated to 60° C. A solution of chloroacetyl chloride (5.66 mL, 71.1 mmol) in dioxane (12.5 mL) was added over one hour. The reaction mixture was stirred for one hour at 60° C., then was cooled to ambient temperature and partitioned between H2O and ether. The resulting orange precipitate was filtered off, recrystallized from ethanol, and rinsed with cold ether to give 6-(4-fluorophenyl)-3-chloroacetylindole (2.78 g, 20% as an orange solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH2:14][O:13][CH2:12][CH2:11][C:10]=2[CH2:15]O)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Br:17]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:15][C:10]1[CH2:11][CH2:12][O:13][CH2:14][C:9]=1[C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)n1nccc1C1=C(CO)CCOC1
Solvent: ClCCl
Product: CC(C)n1nccc1C1=C(CBr)CCOC1
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a solution of (5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-yl)methanol (300 mg, 1.35 mmol) in DCM (5 mL) was added dibromotriphenylphosphorane (630 mg, 1.35 mmol) at room temperature, after stirring for 30 min, it was diluted with DCM, organic layer was washed with Sat. NaHCO3, brine, dried and concentrated to give crude product, which was purified by column(Hexanes/EtOAc=4:1) to give 5-(4-(bromomethyl)-5,6-dihydro-2H-pyran-3-yl)-1-isopropyl-1H-pyrazole (360 mg).