Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].CC(O)=O.[Br:18]Br.C([O-])([O-])=O.[Na+].[Na+]>O>[Br:18][C:10]1[C:11]([CH3:13])=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C)cc1OC
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(Br)c(C)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A 250 ml 3-neck RBF fitted with a magnetic stirring bar, a thermometer and a dropping funnel was charged with methyl 2-methoxy-4-methylbenzoate 10b (10 g, 0.056 mol) and AcOH (70 mL). To this solution bromine (3 mL, 0.06 mol) was added drop-wise while maintaining the reaction temperature below 25° C. When bromine addition was complete, the reaction mixture was stirred at RT for 2 hours, then poured into 600 mL of cold water and the pH was adjusted to 8-9 with Na2CO3. The crude product was extracted with Et2O (3×300 mL), the combined extracts washed with brine, dried over sodium sulfate and the solvent was removed under vacuum to give methyl 5-bromo-2-methoxy-4-methylbenzoate as an orange oil, which solidified on standing (14.3 g, 99% yield, >90% purity by 1H NMR).
Reaction SMILES: [CH3:1][N:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][NH:5][CH2:6][CH2:7]2.[S:11](N)([NH2:14])(=[O:13])=[O:12]>O1CCOCC1>[CH3:1][N:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][N:5]([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:6][CH2:7]2
Reactant: NS(N)(=O)=O
Reactant: CN1C2CCNCC1CC2
Solvent: C1COCCO1
Product: CN1C2CCC1CN(S(N)(=O)=O)CC2
Yield: 15.4 %

Procedure:
To a solution of 9-methyl-3,9-diazabicyclo[4.2.1]nonane (0.56 g) in 1,4-dioxane (10 ml) was added sulfamide (0.37 g) and the reaction mixture was then heated at reflux in 1,4-dioxane for 72 h. The reaction mixture was purified by loading onto SCX and eluting with 7N NH3/MeOH (200 ml). The eluent was then reduced in vacuo to yield 9-methyl-3,9-diazabicyclo[4.2.1]nonane-3-sulfonamide (0.13 g) as a yellow solid. A mixture of 9-methyl-3,9-diazabicyclo[4.2.1]nonane-3-sulfonamide (0.13 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.31 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 5 step i), 0.25 g) in 1,4-dioxane (10 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 min. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield 0.35 g
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:12][C:13](=[O:20])[CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:7][CH:8]=2)[C:3]1=[O:21].N1C(C)=CC(C)=CC=1C>O1CCCC1>[CH:15]1([CH2:14][C:13]([NH:12][C:6]2[CH:5]=[C:4]3[C:9]([CH:10]=[CH:11][CH:2]=[C:3]3[OH:21])=[CH:8][CH:7]=2)=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(CC1CCCC1)Nc1ccc2c(c1)C(=O)C(Br)CC2
Solvent: C1CCOC1
Solvent: Cc1cc(C)nc(C)c1
Product: O=C(CC1CCCC1)Nc1ccc2cccc(O)c2c1
Temperature: 160 °C

Procedure:
A mixture of 2-bromo-7-cyclopentylacetamido-1-tetralone (1.1 g) and collidine (12 ml) was heated at 160° C. for 2 h. After cooling, the reaction mixture was diluted with 1:9 tetrahydrofuran:ethyl acetate, washed (1N HCl (4 times), brine), dried (MgSO4) and evaporated to give 7-cyclopentylacetamido-1-napthol (quantitative) as a brown glassy solid which was used without further purification.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([N:10]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:13][C:12]([C:26]2[CH:27]=[C:28]([C:32]3([NH:36]S(C(C)(C)C)=O)[CH2:35][O:34][CH2:33]3)[CH:29]=[CH:30][CH:31]=2)=[N:11]1)[CH3:9]>CO>[CH2:8]([N:10]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=2)=[CH:13][C:12]([C:26]2[CH:27]=[C:28]([C:32]3([NH2:36])[CH2:35][O:34][CH2:33]3)[CH:29]=[CH:30][CH:31]=2)=[N:11]1)[CH3:9]
Reactant: CCn1nc(-c2cccc(C3(NS(=O)C(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCn1nc(-c2cccc(C3(N)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reaction time: 0.25 h

Procedure:
A solution of hydrochloric acid in dioxane (4 M, 1.55 mL, 6.2 mmol, 4.0 equiv) was added to a solution of N-[3-(3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (785 mg, 1.55 mmol, 1 equiv) in methanol (3.5 mL) at 22° C. The reaction mixture was stirred for 15 minutes, then was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to afford 3-(3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)oxetan-3-amine, which was used in the next step without further purification. Calc'd (M+1)+: 404.2. Found: 404.1.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([OH:22])[C@:20]([CH3:24])([OH:23])[C@@H:19]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:42]>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][C:41]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:42])[C@:20]([CH3:24])([OH:23])[C@@H:19]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:16])([CH3:15])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](OCC[Si](C)(C)C)[C@H](OCc2ccccc2)[C@@H](O)[C@]1(C)O
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](OCC[Si](C)(C)C)[C@H](OCc2ccccc2)[C@@H](OC(=O)Oc2ccccc2)[C@]1(C)O
Reaction time: 0.33 h
Yield: 100 %

Procedure:
Compound 5.09 (4.0 g, 8.0 mmol) was dissolved in CH2Cl2 (80 mL) and pyridine (2.6 mL, 32 mmol) then chilled to 0° C. Phenyl chloroformate (1.1 mL, 8.8 mmol) was added and the reaction was stirred for 20 min then quenched with 20 mL MeOH and concentrated in vacuo. The residue was dissolved in CH2Cl2 then washed with H2O and brine. The organic layer was concentrated in vacuo and the residue was purified by silica gel chromatography (10% EtOAc/petroleum ether) to afford the title compound (5.0 g, 8.0 mmol, 100%). 1H NMR (500 MHz, CDCl3): δ ppm 7.36-7.25 (m, 7H, PhH), 7.22 (t, J=7.3 Hz, 1H, PhH), 7.10 (d, J=8.8 Hz, 2H, PhH), 4.97 (d, J=10.3 Hz, 1H, H-3), 4.95, 4.67 (ABq, J=11.2 Hz, OCH2Ph1H each,), 4.53 (d, J=7.8 Hz, 1H, H-1), 4.04-3.96 (m, 1H, OCHHCH2SiMe3), 3.89 (d, J=7.3 Hz, 2H, H-6), 3.64 (s, 1H, OH), 3.63-3.58 (m, 1H, OCHHCH2SiMe3), 3.54 (t, J=7.1 Hz, 1H, H-5), 3.38 (dd, J=10.3, 7.8 Hz, 1H, H-2), 1.36 (s, 3H, Me), 1.04 (t, J=8.8 Hz, 2H, OCH2CH2SiMe3), 0.91 (s, 9H, SiCMe3), 0.13, 0.12 (s, 3H each, SiMe2), 0.04 (s, 9H, SiMe3); 13C NMR (125 MHz, CDCl3): δ ppm 153.72, 151.34, 138.51, 129.43, 128.44, 127.66, 127.64, 125.97, 121.18, 103.63, 83.26, 79.14, 75.22, 74.80, 73.57, 68.06, 62.56, 25.94, 18.69, 18.26, 16.13, −1.29, −5.38, −5.55; HRMS calcd for C32H54NO8Si2 [M+NH4]+: 618.3044. found 618.9056.
Reaction SMILES: [N:1]1[N:2]=[N:3][C:4](=[O:6])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[O:13]1[CH:15]([CH3:16])[CH2:14]1>CN(C=O)C>[OH:13][CH2:14][CH2:15][CH2:16][C:5]1[C:4](=[O:6])[N:3]=[N:2][N:1]=1
Reactant: O=C1C=NN=N1
Reactant: CC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N=NN=C1CCCO
Temperature: 60 °C
Yield: 283.4 %

Procedure:
To a mixture of triazolone 35 (248 mg, 0.5 mmol) and potassium carbonate (138 mg, 1 mmol) in DMF (6 ml), 1,2-epoxypropane (870 mg, 15 mmol) was added. The reaction mixture was heated at 60° C. for 18 h and concentrated in vacuo. The residue was treated with crushed ice, extracted with ethyl acetate (3×30 ml). The combined extract was washed with brine, dried (Na2SO4) and the solvent was removed under reduced pressure. The resulting crude product was purified on a column of silica gel (EtOAc/MeOH, 9:1) to give the hydoxypropyltriazolone 42 as a colorless solid (200 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:18])[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([NH2:16])[CH:13]=[C:12]([CH3:17])[N:11]=1.C([O-])(O)=O.[Na+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[Cl:18][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([NH:16][C:24](=[O:26])[CH3:25])[CH:13]=[C:12]([CH3:17])[N:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)nc(SCc2c(Cl)cncc2Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Nc1cc(C)nc(SCc2c(Cl)cncc2Cl)n1
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-amine (500 mg, 1.7 mmol) in acetic anhydride (10 mL) was stirred at reflux overnight. After cooling to room temperature, the mixture was neutralized slowly with a saturated solution of NaHCO3 (aq.) until pH 7-8 was reached. The mixture was extracted with ethyl acetate (2×25 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-3% MeOH/CH2Cl2), affording the title compound (136 mg, 23% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.11 (s, 3H), 2.51 (s, 3H), 4.70 (s, 2H), 7.70 (s, 1H), 8.67 (s, 2H), 10.87 (s (br), 1H); M+ 287.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.CS(C)=O.[H-].[Na+]>O>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCC(CO)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
A mixture of 1-chloro-4-nitrobenzene (23) (2.37 g, 15.0 mmol), alcohol 22 (1.94 g, 15.0 mmol), and DMSO (25 mL) was treated portionwise with NaH (60% in mineral oil, 660 mg, 16.5 mmol) at 40° C. The mixture was stirred at 70° C. for 3 h, poured into water (150 mL), and extracted with Et2O (5×100 mL). The combined organic fractions were washed with water (250 mL) and brine (250 mL), dried (MgSO4), and the solvent was removed in vacuo. The resulting solid was recrystallized from Et2O to give 24 (3.12 g, 83%) as yellow needles. 1H NMR (300 MHz, CDCl3): δ=1.36-1.56 (m, 2 H, 3-Hax, 5-Hax), 1.75-1.91 (m, 3 H, 3-Heq, 4-H, 5-Heq), 1.98 (dt, J=11.9, 1.9 Hz, 2 H, 2-Hax, 6-Hax), 2.30 (s, 3 H, NMe), 2.85-2.98 (m, 2 H, 2-Heq, 6-Heq), 3.90 (d, J=5.8 Hz, 2 H, OCH2), 6.94 (mc, 2 H, 2′-H, 6′-H), 8.19 (mc, 2 H, 3′-H, 5′-H) ppm. —13C NMR (50.3 MHz, CDCl3): δ=28.9 (C-3, C-5), 35.1 (C-4), 46.4 (NMe), 55.3 (C-2, C-6), 73.3 (OCH2), 114.3 (C-2′, C-6′), 125.8 (C-3′, C-5′), 141.3 (C-4′), 164.1 (C-1′) ppm. −MS (70 eV, EI): m/z (%)=250 (79) [M]+, 249 (100) [M−H]+. —C13H18N2O3 (250.29): calcd. C, 62.38; H, 7.25; found C, 62.25; H, 7.40.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[C:11](SC)=[N:12][CH2:13][CH2:14][C:9]=3[C:8]([CH2:17][CH3:18])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([NH:27][NH2:28])(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>N1C=CC=CC=1>[CH:1]1([N:6]2[C:10]3[C:11]4[N:12]([C:19]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[N:27][N:28]=4)[CH2:13][CH2:14][C:9]=3[C:8]([CH2:17][CH3:18])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NNC(=O)c1cccnc1
Reactant: CCc1nn(C2CCCC2)c2c1CCN=C2SC
Solvent: c1ccncc1
Product: CCc1nn(C2CCCC2)c2c1CCn1c(-c3cccnc3)nnc1-2
Temperature: 135 °C

Procedure:
1-Cyclopentyl-4,5-dihydro-3-ethyl-7-methylthio-1H-pyrazolo[3,4-c]pyridine (0.036 grams, 0.14 mmoles) and nicotinic acid hydrazide (0.021 grams, 0.15 mmoles) was dissolved in anhydrous pyridine (5 ml) in a flame dried flask. An oven-dried condenser was added, which was septa sealed and had an outlet to a bubbler. A long stainless steel needle was pierced through the septa and condenser center into the magnetically stirred solution. Nitrogen was bubbled through the long needle. The flask was heated to 135° C. for 4 hours. The pyridine was then removed under nitrogen purge. The resulting oil was heated to 150° C. for 4 hours. The flask was cooled to ambient temperature and contained 0.045 grams of the crude title compound as a white solid. The crude product did not contain any impurities measurable by thin layer chromatography. The product can be purified by either column chromatography on a silica gel column using a gradient mixture of ethyl acetate/hexane as eluent or by recrystallization from a mixture of ethyl acetate in hexane. Melting Point 140-5° C. (crude); 1H NMR (300 MHz, CDCl3) δ 1.24 (t, J=7.6 Hz, 3H), 1.72 (m, 2H), 1.94 (m, 2H) 2.16 (m, 4H), 2.66 (q, J=7.6 Hz, 2H), 2.98 (t, J=7.0 Hz, 2H), 4.25 (t, J=7.0 Hz, 2H), 5.60 (quintet, J=7.7 Hz, 1H), 7.48 (dd, J=4.9 and 7.8 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 8.75 (dd, J=1.4 and 4.9 Hz, 1H), 8.9 (d, J=1.7 Hz, 1H); Anal. calcd. for C19H22N6 : C, 68.23; H, 6.63; N, 25.13. Found: C, 67.39; H, 6.87; N, 24.00.
Reaction SMILES: [CH:1]([N:4]([CH2:8][C:9]1[O:18][C:12]([CH2:13][NH:14][CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].CS[C:21](=[C:24]([C:27]#[N:28])[C:25]#[N:26])[NH:22][CH3:23]>>[CH:1]([N:4]([CH2:8][C:9]1[O:18][C:12]([CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:21](=[C:24]([C:27]#[N:28])[C:25]#[N:26])[NH:22][CH3:23])=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CNC(SC)=C(C#N)C#N
Reactant: CC(C)N(Cc1ccc(CNCCN)o1)C(C)C
Product: CNC(NCCNCc1ccc(CN(C(C)C)C(C)C)o1)=C(C#N)C#N

Procedure:
Using Compound g and [(methylthio)(methylamino)methylene]propanedinitrile, the corresponding procedure of Example 1 was followed to give Compound 12 as light yellow crystals.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][N:7]1[CH2:11][C@H:10]2[C@H:12]([NH:15][C:16](=[O:23])[C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18])[CH2:13][CH2:14][C@H:9]2[CH2:8]1.[N:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[C:30]=[O:31]>ClCCl>[C:32]([NH:29][C:30]([NH:18][C@H:17]([C:16]([NH:15][C@H:12]1[C@H:10]2[C@H:9]([CH2:8][N:7]([CH2:6][C:5]3[CH:24]=[CH:25][CH:26]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:4]=3)[CH2:11]2)[CH2:14][CH2:13]1)=[O:23])[CH2:19][CH:20]([CH3:21])[CH3:22])=[O:31])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)NC(C)(C)C)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N1-{(3aS,4R,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide (113 mg, 0.284 mmol) from Example 170 Step B in dichloromethane (0.5 mL) was added 2-isocyanato-2-methylpropane (35.1 μL, 0.313 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-12). The title compound was eluted with a gradient of 0% to 10% methanol (2 N ammonia)/dichloromethane over 20 minutes: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.74 (d, J=8.3, 1H), 7.73 (s, 1H), 7.57 (d, J=9.5, 2H), 7.44 (t, J=7.7, 1H), 6.56 (d, J=8.6, 1H), 6.33 (s, 1H), 4.88 (td, J=5.6, 8.9, 1H), 4.41-4.33 (m, 1H), 3.56 (d, J=13.5, 1H), 3.41 (d, J=13.6, 1H), 2.71 (dd, J=1.7, 9.2, 1H), 2.55-2.45 (m, 2H), 2.35 (dd, J=6.9, 8.9, 1H), 2.29-2.20 (m, 2H), 2.11 (dq, J=6.1, 12.1, 1H), 1.92-1.77 (m, 3H), 1.73-1.64 (m, 2H), 1.44 (s, 9H), 1.43-1.35 (m, 1H), 0.85 (d, J=3.3, 3H), 0.84 (d, J=3.2, 3H); MS (ESI+) m/z 497 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[Na+].[Na+].F[C:20]1[CH:21]=[N+:22]([O-:29])[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:20]1[CH:21]=[N+:22]([O-:29])[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Oc1ccc2cc(Br)ccc2c1
Reaction time: 0.17 h
Yield: 227.1 %

Procedure:
To 6-bromo-2-naphthol (8.43 g) in 80 ml DMF at room temperature was added sodium carbonate (8.0 g) portionwise, and after the addition was complete, the mixture was stirred for 10 minutes, and then a solution of 3-fluoro-4-nitropyridine-N-oxide (6.0 g) in 40 ml DMF was added dropwise. The reaction mixture was then stirred for six hours at room temperature. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with sat. NaCl solution and dried over Na2SO4. The filtrate was concentrated to yield a solid (31 g). This material was triturated with methanol to yield a solid, 10.0 g, m.p. 175°-177° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=1.Br[CH:18]([CH2:20][CH3:21])[CH3:19]>CN(C=O)C.O>[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[CH:9][N:10]([CH:18]([CH2:20][CH3:21])[CH3:19])[C:11]=2[CH:12]=1
Reactant: CCC(C)Br
Reactant: COC(=O)c1cc(Br)cc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)n1ccc2c(C(=O)OC)cc(Br)cc21
Reaction time: 0.33 h
Yield: 38.2 %

Procedure:
To a stirred suspension of sodium hydride (5.66 g, 141.7 mmol) in DMF (100 mL) was added a solution of methyl 6-bromo-1H-indole-4-carboxylate (4) (30 g, 118.1 mmol) in DMF (50 mL) at 0° C. and stirred for 20 min. Then 2-Bromo butane (29.1 g, 212.5 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with cold water and extracted with ethyl acetate (4×150 mL). The combined organic layer was washed with cold water (150 mL), brine (100 mL) and dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude, which was purified by column chromatography over silica gel (60-120 mesh) using 5% EtOAc: Pet ether as eluent to afford the title compound methyl 6-bromo-1-sec-butyl-1H-indole-4-carboxylate, (14 g, 40.1%) as pale yellow solid. 1H NMR (CDCl3, 400 MHz) δ 0.843-0.870 (m, 3H), 1.512 (d, J=6.4 Hz, 3H), 1.844-1.926 (m, 2H), 3.976 (s, 3H), 4.333-4.385 (m, 1H), 7.132 (d, J=3.2 Hz, 1H), 7.302 (d, J=3.6 Hz, 1H), 7.707 (s, 1H), 7.984 (d, J=1.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[C:9](Cl)(=[O:11])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:8][C:3]1[CH:4]=[C:5]([C:9]([CH3:10])=[O:11])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Cc1ccccc1F
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(F)c(C)c1
Yield: 98.2 %

Procedure:
A mixture of 50 grams (454 millimoles) of ortho-fluorotoluene and 42.8 grams (545 millimoles) of acetyl chloride was dissolved in 250 milliliters of methylene chloride, and then 72.7 grams (545 millimoles) of anhydrous aluminum chloride was gradually added thereto while cooling with ice and stirring. The resulting mixture was further stirred for 2 hours while cooling with ice. Then the reaction mixture was added to 1,200 milliliters of 5% hydrochloric acid, which was then allowed to separate into aqueous and organic layers. The organic layer thus obtained was washed with a 5% aqueous solution of sodium carbonate and dried over anhydrous sodium sulfate and, thereafter, the methylene chloride was distilled away under reduced pressure. Thus, as a product, 67.9 grams (446 millimoles) of 3-methyl-4-fluoroacetophenone was obtained (yield, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.[CH3:32][O:33][C:34]1[C:35](=O)[C:36](=[O:40])[C:37]=1[O:38]C>CO>[CH3:32][O:33][C:34]1[C:37](=[O:38])[C:36](=[O:40])[C:35]=1[NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:11]=1
Reactant: COc1ccc(C(NCC(c2ccccc2)c2ccccc2)c2cccc(N)c2)cc1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CO
Product: COc1ccc(C(NCC(c2ccccc2)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Yield: 52.6 %

Procedure:
In a similar manner to that described in Example (1c), a solution of 3-[(4-methoxyphenyl)-(2,2-diphenylethylamino)methyl]phenylamine (2.02 g) [prepared as described in step (b) above] in methanol (40 ml) and 3,4-dimethoxy-3-cyclobutene-1,2-dione (731 mg) were reacted, to afford the title compound (1.35 g) as a white foamy solid.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]1[O:16][C:15]2[CH:14]=[CH:13][C:9]([CH2:10][CH2:11]O)=[CH:8][C:7]=2[O:6]1>C(Cl)(Cl)(Cl)Cl>[CH2:5]1[O:16][C:15]2[CH:14]=[CH:13][C:9]([CH2:10][CH2:11][Br:2])=[CH:8][C:7]=2[O:6]1
Reactant: BrP(Br)Br
Reactant: OCCc1ccc2c(c1)OCO2
Solvent: ClC(Cl)(Cl)Cl
Product: BrCCc1ccc2c(c1)OCO2
Yield: 121.1 %

Procedure:
A solution of phosphorus tribromide (8.1 g) in carbon tetrachloride (50 ml) was added dropwise over 30 minutes to a stirred solution of 3,4-methylenedioxyphenethyl alcohol (15.0 g). (see Preparation 19) in carbon tetrachloride (200 ml) and the mixture was heated under reflux for 3 hours, washed sequentially with water (twice), 5M aqueous sodium hydroxide solution and water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica (100 g) using carbon tetrachloride as the eluent. Appropriate fractions were combined and evaporated to give the title compound as a pale yellow oil (8.3 g, 40%), which was characterised by its 1H,-n.m.r. spectrum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Cl[CH2:17][CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17]/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: Fc1ccc(C=CCCl)cc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OC/C=C/c2ccc(F)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with 1-(3-chloro-1-propenyl)-4-fluorobenzene (0.85 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. Crystallization from diethyl ether-hexane provided 0.9 g of (E)-4-[[3-(4-fluorophenyl)-2-propenyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 84°-85° C.