Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Br:15]Br.[OH-].[Na+].[Al].O=[Al-]=O.[Na+]>>[Br:15][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2
Reactant: c1ccc2cnccc2c1
Reactant: BrBr
Agent: O=[Al-]=O
Agent: [Al+3]
Agent: [Al]
Product: Brc1cccc2cnccc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
The apparatus consisted of a 500 mL three-necked flask equipped with a condenser, dropping funnel and a stirrer terminating in a stiff, crescent-shaped Teflon polytetrafluroethylene paddle. To isoquinoline (57.6 g, 447 mmol) in the flask was added AlCl3 (123 g, 920 mmol). The mixture was heated to 75-85° C. Bromine (48.0 g, 300 mmol) was added using a dropping funnel over a period of 4 hours. The resulting mixture was stirred for one hour at 75° C. The almost black mixture was poured into a vigorously hand-stirred cracked ice. The cold mixture was treated with sodium hydroxide solution (10N) to dissolve all the aluminum salts as sodium aluminate and the oily layer was extracted with ether. After being dried with Na2SO4 and concentrated, the ether extract was distilled at about 0.3 mm. A white solid (16.3 g, 78 mmol) from a fraction of about 1.25° C. was obtained (26% yield). The product was further purified by recrystallization (pentane or hexanes): mp 80-81° C.;
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=2[F:35])[CH2:24][CH2:23]1)C1C=CC=CC=1.C(O)C>C(OCC)(=O)C>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]1[CH2:23][CH2:24][C@H:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=2[F:35])[CH2:26][CH2:27]1
Reactant: Fc1cccc([C@H]2CC[C@H](C=CCCCCCCCCCCCOCc3ccccc3)CC2)c1F
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCCCCCCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
First, 10.9 g of 1-[trans-4-{13-benzyloxy-1-tridecenyl}cyclohexyl]-2,3-difluorobenzene, 1 g of 10% Pd--C, 50 ml of ethanol, and 50 ml of ethyl acetate were placed in a 500 ml autoclave. The mixture was stirred at room temperature for 5 days under a hydrogen pressure of 8 kg/cm2. A catalyst was filtered away and a filtrate was concentrated. Thereafter, the residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=4/1) and recrystallized from acetone to obtain 5.7 g of 1-[trans-4-(13-hydroxytridecyl)cyclohexyl]-2,3-difluorobenzene (Y: 64%). The compound thus obtained had a purity of 97.2% by GC and 99.8% by HPLC.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:13]O>C(O)(=O)C>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=2[O-:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccccn2)cc1
Reactant: OO
Solvent: CC(=O)O
Product: [O-][n+]1ccccc1-c1ccccc1
Yield: 72 %

Procedure:
The N-oxide was prepared by modifying the method outlined by Zhang et al.25 using 2-phenylpyridine (5.00 g, 32.2 mmol) and 30% H2O2 in glacial acetic acid to yield the title compound as a light yellow solid (4.00 g, 72%), m.p. 154-157° C. (lit.26 m.p. 155-155.5° C.). The spectral data were consistent with literature data.27
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12]I)[C:7]=2[CH:14]=1.[CH3:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12][N:29]3[CH2:30][CH2:31][N:26]([C:24]4[CH:25]=[C:16]([CH3:15])[CH:17]=[C:18]5[C:23]=4[N:22]=[CH:21][CH:20]=[CH:19]5)[CH2:27][CH2:28]3)[C:7]=2[CH:14]=1
Reactant: Cc1cc(N2CCNCC2)c2ncccc2c1
Reactant: COc1ccc2occ(CCI)c2c1
Product: COc1ccc2occ(CCN3CCN(c4cc(C)cc5cccnc45)CC3)c2c1

Procedure:
8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methyl-quinoline was prepared by generally following the procedure outlined in example 21, step 6, starting from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown oil. Yield: 150 mg (37%); (M+H): 402; 1HNMR (400 MHz, CDCl3): δ 8.82˜8.73 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H); 8.03-802 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H), 8.00˜6.88 (m, 7H); 3.87 (s, 3H) 3.49˜2.57 (m, 12H), 2.5 (s, 3H).
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C([O-])(=O)C.[NH4+].[Br:27]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>C(OCC)C.C(OCC)(=O)C>[Br:27][CH:2]([C:1]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(OCc1ccccc1)C(Br)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
To a solution of dibenzyl malonate (10.0 g, 35.0 mmol) in diethyl ether (20 mL) were added ammonium acetate (270 mg, 3.5 mmol) and N-bromosuccinimide (6.9 g, 39 mmol), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the mixture was stirred for 30 min. The organic layer was washed with saturated aqueous potassium carbonate solution (100 mL) and saturated brine (10 mL) and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50) to give the title compound (3.8 g, 29%) as a brown oil.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.Cl.[CH3:10][O:11][C:12](=[O:15])[CH2:13][NH2:14].C>O1CCOCC1>[N-:14]=[C:4]=[O:3].[CH3:10][O:11][C:12](=[O:15])[CH2:13][NH2:14]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: COC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Product: [N-]=C=O
Temperature: 80 °C

Procedure:
38.8 mL diphosgene is added dropwise over 1 hour to a mixture of 35 g glycine methyl ester hydrochloride and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is warmed to 80° C. during this time. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the filtrate is fractionally distilled to give pure glycine methyl ester isocyanate in about 70% yield (b.p. 60° C., 13 mm Hg.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[C:9](=[O:23])[N:8]([CH2:24][C:25]([OH:27])=[O:26])[C:7]2=[O:28].[CH2:29](Br)[CH2:30][OH:31].Cl>O.CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[C:9](=[O:23])[N:8]([CH2:24][C:25]([O:27][CH2:29][CH2:30][OH:31])=[O:26])[C:7]2=[O:28]
Reactant: O=C(O)Cn1c(=O)c2cc(Cl)ccc2n(Cc2ccc(Cl)cc2Cl)c1=O
Reactant: OCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1c(=O)c2cc(Cl)ccc2n(Cc2ccc(Cl)cc2Cl)c1=O)OCCO
Yield: 54.2 %

Procedure:
Into 10 ml of dried dimethylformamide were suspended 60 mg of sodium hydride (60%), and, to this was added dropwise a solution dissolved 500 mg of 6-chloro-1-(2,4-dichlorophenyl)methyl-1,4-dihydro-2,4-dioxo-3-(2H)-quinazolineacetic acid into 3 ml of dried dimethylformamide under stirring. After stirring the mixture for 30 minutes at room temperature, 160 mg of ethylene bromohydrin were added and the mixture was stirred for 4 hours at 110° C. After cooling by allowing to stand, the reaction mixture was poured into 200 ml of water and acidified with hydrochloric acid, which was extracted with ethyl acetate. After dried over anhydrous magnesium sulfate, solvent was distilled off and the residue was recrystallized from ethanol to obtain 300 mg of title compound. m.p. 167°-168° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][OH:42])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH2:36][N:37]([CH2:40][CH2:41][OH:42])[CH2:38][CH2:39]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCN(CCO)CC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCN(CCO)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)ethanol. MS (ESI): mass calcd. for C22H24FN5O3S, 457.16; m/z found, 458.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.38 (m, 1H), 8.21 (d, J=1.5, 1H), 8.16-8.13 (m, 1H), 7.98 (m, 1H), 7.79-7.73 (m, 1H), 7.68-7.63 (m, 1H), 7.49-7.45 (m, 1H), 7.36-7.30 (m, 2H), 3.86-3.78 (m, 2H), 3.66-3.32 (m, 4H), 3.24-3.20 (m, 2H), 3.15-2.72 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH2:15](Cl)[C:16]#[C:17][CH2:18][CH3:19]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:15][C:16]#[C:17][CH2:18][CH3:19])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1ccc(O)cc1
Reactant: CCC#CCCl
Product: CCC#CCOc1ccc(SCC(=O)OCC)cc1

Procedure:
(4-Pent-2-ynyloxy-phenylsulfanyl)-acetic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 2). Starting from (4-hydroxy-phenylsulfanyl)-acetic acid ethyl ester (5 g, 30 mmol) and 2-pentynyl chloride (3.7 g, 36.6 mmol) 7.15 g of the product isolated. Yield 7.15 g (86%); brown oil; MS: 278 EI (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=3[F:29])[CH:11]=2)=[O:9])[CH2:4]1>CC(O)=O.Cl.[Fe]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:11]=[C:10]([C:8]([N:5]4[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:30])[CH3:1])[CH2:4]4)=[O:9])[S:18][C:17]=23)=[C:21]([F:29])[CH:22]=1
Reactant: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)C1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc(N)cc4F)c3s2)C1
Reaction time: 0.33 h
Yield: 77 %

Procedure:
To a solution of the nitro compound 25 (708 mg, 1.64 mmol) in AcOH (16 mL) at 90° C., was added iron powder (928 mg, 16.6 mmol) and the reaction mixture was stirred vigorously for 20 min. The grey suspension was dissolved in 1N HCl (50 mL) and washed with CHCl3 (50 mL). The aqueous phase was basified with NH4OH to pH˜10, extracted with CHCl3. The organic phase was collected, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound 26 (506 mg, 77%) as a white solid. MS (m/z): 401.1 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15](C)[C:16](=O)OCC3C=CC=CC=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1>CO>[CH3:1][N:2]([CH3:27])[C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][CH2:11][CH:12]([NH:15][CH3:16])[CH2:13][CH2:14]2)[CH:6]=[CH:5][N:4]=1
Reactant: CN(C)c1cc(N2CCC(N(C)C(=O)OCc3ccccc3)CC2)ccn1
Solvent: CO
Product: CNC1CCN(c2ccnc(N(C)C)c2)CC1
Reaction time: 3 h
Yield: 96 %

Procedure:
Benzyl 1-(2-(dimethylamino)pyridin-4-yl)piperidin-4-yl(methyl)carbamate (280 mg, 0.76 mmol, 1.0 eq.) was dissolved in MeOH (10 ml) and degassed with N2. Pd(OH)2 (140 mg, 50%) was then added and hydrogenation was carried out for 3 hours. After monitoring by TLC, the reaction mixture was filtered over Celite, the filtrate was concentrated under reduced pressure and the crude product was used in the next stage without being purified further. Yield: 96% (170 mg, 0.726 mmol)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[C:17]([NH2:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[C@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[C:17]([NH2:19])=[O:18])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: NC(=O)[C@@H]1CCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: N#Cc1ccc(CN([C@H]2CCC[C@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 20 %

Procedure:
The titled compound (68 mg) was prepared in 20% yield from cis-2-(4-Chlorobenzenesulfonylamino)-cyclopentanecarboxylic acid amide (250 mg, 0.83 mmol) and 4-bromomethyl-benzonitrile according to the N-alkylation procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.70 (d, 2 H, J=8.0 Hz), 7.71 (d, 2 H, J=12.0 Hz), 7.60 (d, 2 H, J=8.0 Hz), 7.42 (d, 2 H, J=8.0 Hz), 7.07 (s br, 1 H), 6.73 (s br, 1 H), 4.65 (AB2,2 H,ΔV=20,Jab=24 Hz), 4.33 (m, 1 H), 2.84 (m, 1 H), 1.72 (m, 4 H), 1.47 (m, 2 H); MS m/e 418.00 (M+H)+.
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2].Cl>O1CCOCC1>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][N:26]=3)[CH2:23][CH2:24]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1

Procedure:
tert-Butyl [(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl }carbonyl)cyclopentyl]carbamate (150 mg, 0.31 mmol) was treated with a 4.0 M solution of HCl in 1,4-dioxane (10 mL) at room temperature for 1 hr and concentrated at reduced pressure to give the product which was used for next step without purification. MS calculated for C19H27F3N4O:(M+H)385; found 385.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)(=[O:7])=[O:6].[I-].[Na+].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C.C(Cl)Cl>[N:25]1([CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]3)(=[O:7])=[O:6])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)c1cc2cc(NS(=O)(=O)CCCCl)ccc2[nH]1
Reactant: C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1cc2cc(NS(=O)(=O)CCCN3CCCCC3)ccc2[nH]1
Reaction time: 8 h

Procedure:
Ethyl 5-[(3-chloropropyl)sulfonamido]indole-2-carboxylate (PREPARATION 82, 2.3 g) is dissolved in acetonitrile (10 ml) and piperadine (27 ml). Solid sodium iodide (1.0 g) is added and the reaction is stirred overnight at 20°-25°. The reaction is diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography, eluting with a gradient of 5% methanol/methylene chloride to 10% methanol/methylene chloride, pooling and concentration of the appropriate fractions gives the title compound, NMR (300 MHz, d4-CD3OD) 7.45, 7.32, 7.12, 7.03, 4.28, 2.96, 2.28, 1.18, 1.42, 1.33 and 1.30.
Reaction SMILES: ClC1C=CC=C2C=1NC([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=C2.[CH3:20][O:21][C:22]1[C:30]2[O:29][CH:28]=[CH:27][C:26]=2[CH:25]=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[C:30]2[O:29][C:28]([B:11]3[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]3)=[CH:27][C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc2ccoc12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: COc1cccc2cc(B3OC(C)(C)C(C)(C)O3)oc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-methoxy-benzofuran.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[N:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:2].C(O)(=O)C.[Br:19]Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:19][C:5]1[C:4]([O:3][CH2:1][CH3:2])=[N:13][C:12]([NH2:14])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: BrBr
Reactant: CCOc1cc2cccnc2c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1nc(N)c2ncccc2c1Br
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a 250 mL round bottom flask was added 6-ethoxy-1,7-naphthyridin-8-amine (0.65 g, 3.43 mmol), glacial acetic acid (20 mL), followed by the dropwise addition of bromine (0.60 g, 3.78 mmol) dissolved in carbontetrachloride (40 mL). After addition was complete, the mixture was stirred for 2 h then neutralized with saturated NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The resultant residue was purified by silica gel to yield 5-bromo-6-ethoxy-1,7-naphthyridin-8-amine as a pale yellow solid (0.6 g, 2.24 mmol, 65%). 1H NMR (400 MHz, CDCl3): δ ppm 8.53 (d, J=3.95 Hz, 1H), 8.22 (d, J=8.79 Hz, 1H), 7.50 (dd, J=8.57, 4.17 Hz, 1H), 5.87 (br. s., 2H), 4.48 (q, J=7.03 Hz, 2H), 1.44 (t, J=7.03 Hz, 3H). LC/MS m/z 270 [M+H].
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C@H:6]2[CH2:11][CH2:10][C@H:9]([C:12]([O:21][Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Cl([O-])(=O)(=O)=O.[Li+].[C:35]1([CH:41]2[O:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[NH4+].[Cl-]>C(#N)C.CCOCC>[CH:1]1([CH2:4][N:5]([C@H:6]2[CH2:7][CH2:8][C@H:9]([C:12]([O:21][Si:22]([CH2:25][CH3:26])([CH2:27][CH3:28])[CH2:23][CH3:24])([C:13]([F:16])([F:15])[F:14])[C:17]([F:18])([F:19])[F:20])[CH2:10][CH2:11]2)[CH2:42][CH:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[OH:43])[CH2:2][CH2:3]1
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NCC2CC2)CC1)(C(F)(F)F)C(F)(F)F
Reactant: c1ccc(C2CO2)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOCC
Product: CC[Si](CC)(CC)OC([C@H]1CC[C@H](N(CC2CC2)CC(O)c2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 100 mg (0.23 mmol) of trans cyclopropylmethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amine (example 24.2) in 0.5 mL of acetonitrile was treated with 41 mg (0.38 mmol) of lithiumperchlorate and 46 mg (0.38 mmol) of (rac) phenylethylenoxide. The mixture was stirred in a sealed tube at 80° C. for 6 hrs and distributed between a saturated aqueous solution of NH4Cl and Et2O. Drying of the combined organic phases over Na2SO4, evaporation of the solvent and column chromatography on silica gel with heptane/EtOAc 1:1 gave 52 mg (49%) of (rac) trans 2-{cyclopropylmethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amino}-1-phenyl-ethanol as a colorless oil, MS: 554 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:11]2[CH2:13][CH2:12]2)=[C:7]([F:10])[CH:8]=O)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]S(F)(=O)=O)=[CH:19][C:18]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:11]2[CH2:13][CH2:12]2)=[C:7]([F:10])[CH:8]=[CH:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[C:18]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(F)Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: O=CC(F)=C(c1ccc(Cl)cc1)C1CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(C=Cc1ccc(F)c(Oc2ccccc2)c1)=C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A mixture of p-chloro-β-cyclopropyl-α-fluorocinnamaldehyde (224.6 mg, 1 mmol), (4-fluoro-3-phenoxyphenyl)methanesulfonyl fluoride (312.7 mg, 1.1 mmol), potassium carbonate (552.8 mg, 4 mmol), and 18-crown-6 (13.2 mg, 0.05 mmol) in acetonitrile is stirred at room temperature overnight, quenched with water, and extracted with ethyl acetate. The organic extract is washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product (380 mg, 94% pure by GC analysis, 93% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:14][CH:13]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Brc1ccc(I)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 140 °C

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (1.63 mL) and 1-bromo-4-iodobenzene (3 g) are dissolved in toluene (75 mL), treated with sodium tert-butoxide (1.53 g) and purged for 10 minutes with argon. Acetato-(2′-di-tert.-butylphosphino-1,1′-biphenyl-2-yl)-palladium-(II) (245 mg) is added and the mixture is heated for 15 minutes at 140° C. Then the mixture is partitioned between saturated aqueous NH4Cl solution and ethylacetate. The organic phase is washed with brine and dried (MgSO4). The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. LC (method 2): tR=1.06 min; Mass spectrum (ESI+): m/z=298 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.CO.C[C:12](C)([O-:14])C.[K+]>CN(C)C=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:14][CH3:12])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,5-dibromopyridine (6.95 g, 29 mmol) in N,N-dimethylformamide (5 ml) was added methanol (3.56 ml) and 1M potassium tert-butoxide (32.3 ml) and the resulting mixture was stirred at room temperature for 18 hours. The resulting slurry was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 1:9 mixture of ether and hexane to afford the 5-Bromo-2-methoxypyridine compound as an oil.