Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.O[N:27]1[C:31]2[CH:32]=CC=C[C:30]=2N=N1.C(N(C(C)C)C(C)C)C.C(N)(C)C.[Cl-].[Na+]>CN(C=O)C>[CH:31]([NH:27][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22])([CH3:32])[CH3:30]
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)n(C)n1
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NC(C)C)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.9 %

Procedure:
To a solution of 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid (0.3 mmol) in DMF (7 mL) was added 1-hydroxybenzotriazole hydrate (0.45 mmol), N-ethyldiisopropylamine (1.2 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (0.45 mmol) and isopropylamine (0.45 mmol) and the resulting mixture stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by preparative HPLC afforded the title compound (6.5 mg, 11%) as a white solid. MS: m/e=369.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24]O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].P(Br)(Br)[Br:28]>COCCOC>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][Br:28])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CO)c1
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (2′-hydroxymethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (2.30 mmol) in DME was added phosphorus tribromide (0.26 mL, 2.76 mmol), and the reaction was stirred for 3 hours at room temperature. The mixture was cooled to 0° C., quenched with saturated aqueous NaHCO3, and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:23][CH:22]([OH:24])[CH2:21][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:42]1[CH:41]=[C:40]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([C:11]4[N:16]=[C:15]([N:17]5[CH2:23][CH:22]([OH:24])[CH2:21][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]5)[CH:14]=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)[CH:44]=[N:43]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC(O)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC(O)C1
Temperature: 100 °C
Yield: 35 %

Procedure:
A suspension of tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)Pyridine-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (160 mg, 0.36 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (140 mg, 0.72 mmo), Pd(dppf)Cl2 (147 mg, 0.18 mmol), and aq. Na2CO3 (2.0 M, 1 mL) in 1,4-dioxane (10 mL) under nitrogen was heated at 100° C. for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc as eluting solvent to afford tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate as a yellow solid (60 mg, 35%). MS (ESI) m/z: 477 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][C@@H:13]([NH2:16])[CH2:14][OH:15])C.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(#N)C>[OH:15][CH2:14][C@@H:13]1[NH:16][C:4](=[O:3])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH:11]=[CH:12]1
Reactant: CCOC(=O)c1ccccc1C=C[C@@H](N)CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C1N[C@@H](CO)C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-((R)-3-amino-4-hydroxy-but-1-enyl)-benzoic acid ethyl ester (1.8 g, 7.65 mmol) in 1:1 toluene/acetonitrile (4 mL) is added DBU (1 mL, 6.45 mmol) and stirred at RT for 18 h. The white precipitate is filtered to give the title compound: (M+1)+=190.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].S(Cl)(Cl)=O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 4-bromo-3-fluorobenzoic acid (1.0 g, 0.0046 mol), thionyl chloride (0.65 mL, 0.0089 mol) and a drop of DMF and the reaction was refluxed for 2 h. The thionyl chloride was then distilled off and benzene (20 mL, 0.2 mol) and aluminum trichloride (0.576 g, 0.00432 mol) was added to the reaction mixture and the reaction was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc. HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=7.45-7.55 (m, 3H), 7.58 (dd, J=8.84, 1.77 Hz, 1H), 7.60-7.66 (m, 1H), 7.70 (dd, J=8.21, 6.69 Hz, 1H), 7.75-7.82 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(O)(=O)C.[F:12][C:13]1[CH:28]=[CH:27][C:16]([C:17]([N:19]([CH3:26])[C@@H:20]([CH:23]([CH3:25])[CH3:24])[CH:21]=O)=[O:18])=[CH:15][C:14]=1[CH3:29].[Na].[OH-].[Na+]>C(Cl)Cl>[F:12][C:13]1[CH:28]=[CH:27][C:16]([C:17]([N:19]([C@@H:20]([CH:23]([CH3:24])[CH3:25])[CH2:21][N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)[CH3:26])=[O:18])=[CH:15][C:14]=1[CH3:29]
Reactant: Cc1cc(C(=O)N(C)[C@H](C=O)C(C)C)ccc1F
Reactant: OC1CCNCC1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C(=O)N(C)[C@H](CN2CCC(O)CC2)C(C)C)ccc1F
Reaction time: 3 h
Yield: 21.5 %

Procedure:
Piperidin-4-ol (0.048 g, 0.48 mmol) and acetic acid (0.032 mL, 0.56 mmol) was added to (S)-4-fluoro-N,3-dimethyl-N-(3-methyl-1-oxobutan-2-yl)benzamide (Compound A2.1) (0.1 g, 0.40 mmol) in DCM (3 mL). The resultant mixture was stirred at rt for 30 min before sodium triacetoxyhydroborate (0.101 g, 0.48 mmol) was added. The stirring was continued at rt for 3 h. NaOH (1 N aq.) was added to the mixture. The organic phase was filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC. The product containing fractions was concentrated and the residue was purified a second time by preparative HPLC using Chiralpak AD 5 μm 20×250 mm column and Heptan/EtOH/TEA 80/20/0.1, as mobile phase to give the title compound (29 mg, 22%). Enantiomeric excess: 99.9%. Mixture of rotamers: (600 MHz, CD3OD) δ 0.82-1.08, 1.43-1.63, 1.71-2.06, 2.12-2.51, 2.54-2.81, 2.89, 2.97-3.09, 3.27-3.46, 3.51-3.65, 4.40-4.59, 7.06-7.14, 7.22-7.37. Total no of protons: 28. HRMS (M+H)+: calculated 337.2291. found 337.2268.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:18](CC)CC.ClC(OCC)=O.N>C(Cl)(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([NH2:18])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(COCc1ccccc1)C(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: CC(C)(COCc1ccccc1)C(N)=O
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
To a 0° C. solution of 2.4 g (11.4 mmol) of 3-benzyloxy-2,2-dimethyl-propionic acid and 1.65 ml (11.5 mmol) of Et3N in 80 mL of chloroform was added 1.04 mL (11.5 mmol) of ethyl chloroformate. After stirring for 15 min, NH3 gas was passed through the solution for 5 minutes. The resulting suspension was removed from the ice bath and allowed to stir overnight. The suspension was filtered and the filtrate was concentrated to near dryness. The resulting residue was crystallized from benzene/hexanes (16 mL/40 mL) mixture to provide 2.3 g of 3-benzyloxy-2,2-dimethyl-propionamide.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[CH:16]=[C:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[S:18][CH:19]=1>[Cu]I>[N:23]1[CH:22]=[CH:21][C:20]([C:17]2[S:18][CH:19]=[C:15]([N:3]3[CH2:4][C@:5]4([CH:10]5[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]5)[CH2:6]4)[O:1][C:2]3=[O:13])[CH:16]=2)=[CH:25][CH:24]=1
Reactant: Brc1csc(-c2ccncc2)c1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Agent: [Cu]I
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1csc(-c2ccncc2)c1

Procedure:
The title compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 4-bromo-2-(4-pyridyl)thiophene using 2 equivalents of copper (I) iodide. The title compound (1.70 g) was obtained as a pale-yellow solid, m/z 342 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH2:7][N:6]([CH3:8])[S:5](=[O:10])(=[O:9])[N:4]([CH3:11])[C:3]=1[C:12]([O:14]C)=O.[NH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1>>[OH:1][C:2]1[CH2:7][N:6]([CH3:8])[S:5](=[O:9])(=[O:10])[N:4]([CH3:11])[C:3]=1[C:12]([NH:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1)=[O:14]
Reactant: COC(=O)C1=C(O)CN(C)S(=O)(=O)N1C
Reactant: Cc1cc(N)no1
Product: Cc1cc(NC(=O)C2=C(O)CN(C)S(=O)(=O)N2C)no1
Yield: 49 %

Procedure:
The synthesis was effected analogously to Example 1 using in each case 1.0 equivalent of methyl 5,6-dihydro-4-hydroxy-2,6-dimethyl-1,1-dioxo-2H-1,2,6-thiadiazine-3-carboxylate and 3-amino-5-methylisoxazole. Recrystallisation from a diisopropyl ether/tetrahydrofuran mixture gives the title compound in a yield of 49%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([OH:84])([CH2:82][CH3:83])[CH2:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]([CH2:79][CH3:80])([C:64]2[CH:69]=[CH:68][C:67](B3OC(C)(C)C(C)(C)O3)=[CH:66][CH:65]=2)[CH2:62][CH3:63])=[CH:57][C:56]=1[CH3:81])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:67]2[CH:66]=[CH:65][C:64]([C:61]([CH2:79][CH3:80])([C:58]3[CH:59]=[CH:60][C:55]([CH2:54][CH2:53][C:52]([CH2:82][CH3:83])([OH:84])[CH2:50][CH3:51])=[C:56]([CH3:81])[CH:57]=3)[CH2:62][CH3:63])=[CH:69][CH:68]=2)[CH:10]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)cc2)cc1C
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 76.8 %

Procedure:
(5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 35.2 mg, 0.153 mmol), palladium acetate (2.2 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.2 mg, 0.020 mmol), potassium phosphate (65 mg, 0.306 mmol) and water (0.2 mL) were added to a solution of 3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-pentan-3-ol (Example 145-(1); 48.8 mg, 0.102 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (39.3 mg, 77%).
Reaction SMILES: [CH2:1]([C:5]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl.FC(F)(F)C(O)=O>[OH-].[Na+].CCOCC>[CH2:1]([C:5]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn2ccccc2c1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nn2ccccc2c1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1 g of the product of Example 6, 20 ml of methylene chloride and 4 ml of trifluoroacetic acid was stirred at room temperature for 4 hours and the solvent and the reagent were eliminated at 30° C. under reduced pressure. The residue was taken up in a mixture of 40 ml of 1N sodium hydroxide and 20 ml of ether and extracted with 1N sodium hydroxide. The aqueous phase was acidified with concentrated hydrochloric acid and extracted with ether after saturation with sodium chloride. After drying and filtering, the solvent was eliminated at 50° C. under reduced pressure.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.B1C2CCCC1CCC2.Br[C:29]1[CH:40]=[CH:39][C:32]2[O:33][CH:34]([CH3:38])[C:35](=[O:37])[NH:36][C:31]=2[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C1COCC1>[CH3:38][CH:34]1[O:33][C:32]2[CH:39]=[CH:40][C:29]([CH2:1][CH:2]3[CH2:7][CH2:6][N:5]([C:8]4[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=4)[CH2:4][CH2:3]3)=[CH:30][C:31]=2[NH:36][C:35]1=[O:37]
Reactant: C=C1CCN(c2ccc(C(=O)OCC)cc2)CC1
Reactant: CC1Oc2ccc(Br)cc2NC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCC(Cc3ccc4c(c3)NC(=O)C(C)O4)CC2)cc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
Ethyl 4-(4-methylenepiperidin-1-yl)benzoate 390C (145.8 mg, 0.594 mmol) was taken up with 0.5M THF solution of 9-BBN (1.189 mL, 0.594 mmol) under nitrogen and stirred at 75° C. for 1 h. The reaction mixture was then added to a suspension of 6-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 19 (144 mg, 0.594 mmol), PdCl2(dppf)-CH2Cl2 adduct (14.56 mg, 0.018 mmol) and potassium carbonate (164 mg, 1.189 mmol) in DMF (2.0 mL) and water (0.2 mL) and stirred at 60° C. The reaction was pulled, cooled to RT, and diluted with water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL); the organic layer was separated and washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Flash column chromatography (10%-20%-30% EA/Hex) provided the desired product as an off-white solid (62 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.32 (m, 6H) 1.35-1.46 (m, 2H) 1.56-1.76 (m, 3H) 2.43 (d, J=6.82 Hz, 2H) 2.77 (t, J=11.75 Hz, 2H) 3.82-3.96 (m, 2H) 4.22 (q, J=7.07 Hz, 2H) 4.56-4.66 (m, 1H) 6.63-6.77 (m, 2H) 6.86 (d, J=8.08 Hz, 1H) 6.94 (d, J=9.09 Hz, 2H) 7.69-7.82 (m, 2H) 10.59 (s, 1H). ESI-MS: m/z 409.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:5]2=[N:6][CH:7]=1.[F-].[Cs+].[CH2:20](B1OC(C)(C)C(C)(C)O1)[CH:21]=[CH2:22]>C1COCC1.CCOCC.[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>[CH2:22]([C:2]1[CH:3]=[C:4]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:5]2=[N:6][CH:7]=1)[CH:21]=[CH2:20]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Br)cnc2C1
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCc1cnc2c(c1)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of tert-butyl 3-bromo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (857 mg, 2.87 mmol), cesium fluoride (1.7 g, 11.5 mmol), and tetrakis-(triphenylphosphine) palladium (0) (229 mg, 0.2 mmol) in THF (15 mL) was degassed and flushed with nitrogen. To this mixture was added allyl-boronic acid pinacol ester (820 μL, 4.3 mmol). The resulting mixture was heated to reflux and stirred at this temperature for 2.5 hr then cooled to room temperature, diluted with ether, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica chromatography (25 g silica, eluted with 5-40% ethyl acetate in hexanes) to give the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21]Br>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:21][CH2:20][CH2:19][Br:18])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: BrCCCBr
Product: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 2.1, 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-ol and 1,3-dibromopropane were converted to yield 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole as yellow oil, MS: 425 (M, 2Br).
Reaction SMILES: [C:1]12([NH:11][C:12]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(=O)C)=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+].Cl.NC1C=CC=CC=1S(NC(N)=S)(=O)=O>O>[C:1]12([NH:11][C:12]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NC(=S)NC23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Agent: NC(=S)NS(=O)(=O)c1ccccc1N
Agent: [Na+]
Solvent: O
Product: Nc1ccc(S(=O)(=O)NC(=S)NC23CC4CC(CC(C4)C2)C3)cc1

Procedure:
A suspension of 28.25 g. (0.070 mol) of 1-adamantyl-3-(4-acetamidophenylsulfonyl)thiourea and 28 g. (0.70 mol) of sodium hydroxide in 500 ml. of water was refluxed for 1 hour. On cooling, the pH of the mixture was adjusted to 1 by dropwise addition of 6 N hydrochloric acid and the precipitate was recrystallized from methanol-water to give 20.8 g. (83%) of the (aminophenylsulfonyl)thiourea, m.p. 176°-179°.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:33][C:34]1[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[C:35]=1[CH2:36][S:37]([C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][CH:41]=1)(=[O:39])=[O:38].C(O)(=O)CC>C1COCC1.O.CCCCCC.C(OCC)(=O)C.CN1C(=O)N(C)CCC1>[C:1]([NH:8][CH:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:44][C:43]2[CH:42]=[CH:41][C:40]([S:37]([CH2:36][C:35]3[C:34]([Cl:33])=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:52])(=[O:39])=[O:38])=[CH:47][CH:46]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=S(=O)(Cc1c(Cl)cccc1Cl)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Solvent: CCC(=O)O
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(S(=O)(=O)Cc3c(Cl)cccc3Cl)cc2)C(=O)O1

Procedure:
In analogy with Example 5d), 5.0 g (16.34 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one, dissolved in 24 ml of abs. THF and 2.7 ml of DMPU, are deprotonated, at -75° C., with 32.7 ml of a 1 M solution of lithium bis(trimethylsilyl)amide in THF, and alkylated, at -75° C., with 9.67 g (24.5 mmol) of p-(2,6-dichlorobenzylsulfonyl)benzyl bromide (Maybridge; Tintagel/UK) in 50 ml of abs. THF. Protonation, at -75° C., with 6.1 ml (81.7 mmol) of propionic acid and 6.1 ml of water, extraction and column chromatography (SiO2, hexane/ethyl acetate, 2:1) of the crude product, and crystallization from DIPE, affords the title compound: TLC Rf (D)=0.30; tRet (II)=17.3 min.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:11][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:2]([F:10])[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1C(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)c1ccccc1CBr
Temperature: 25 °C

Procedure:
To a solution of 1-(difluoromethyl)-2-methylbenzene (2.90 g, 20.4 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (3.63 g, 20.4 mmol) and 2,2′-azobis(2-methylpropionitrile) (0.167 g, 1.02 mmol). The mixture was heated at reflux for 16 h. Further 2,2′-azobis(2-methylpropionitrile) (0.167 g, 1.02 mmol) was added, the mixture was heated at reflux for 4 h, allowed to cool to ambient temperature, diluted with dichloromethane (175 mL) and washed with water (2×175 mL) and saturated sodium bicarbonate (150 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified by column chromatography and eluted with a 0% to 10% gradient of ethyl acetate in dichloromethane to afford 1-(bromomethyl)-2-(difluoromethyl)benzene as a yellow solid: 1H NMR (300 MHz, CDCl3) δ7.58-7.56 (m, 1H), 7.43-7.37 (m, 3H), 6.95 (t, 55.2 Hz, 1H), 4.59 (s, 2H).