Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.Br[CH2:16][CH2:17][CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:24]([O:23][P:19]([CH2:18][CH2:17][CH2:16][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1)(=[O:26])[O:20][CH2:21][CH3:22])[CH3:25]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CCOP(=O)(CCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and diethyl (3-bromopropyl)phosphonate according to Method AC (stirred in a sealed vial at r.t. for 16 h, then heating to 80° C. for 4 h before addition of further diethyl (3-bromopropyl)phosphonate, and heating to 90° C. for a further 3 days) and was isolated as a brown gum (64%). LCMS (ES+) 373 (M+H)+, RT 3.73 minutes (Method 1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[CH:27]O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[CH:27][NH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: O=C1Nc2ccc(Cl)cc2C1=CO
Product: O=C1Nc2ccc(Cl)cc2C1=CNc1ccc(OCCN2CCCC2)cc1
Yield: 78.9 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine (632 mg, 1.2 equiv.) and 5-chloro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.56 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (775 mg, 79%).
Reaction SMILES: C(N(CC)CC)C.Br[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10]1>C1COCC1>[C:11]1(=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: O=C1CC(Br)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (4.5 mL; 32 mmol; 1.2 equiv.) was added to 3-bromo-indan-1-one (5.6 g; 27 mmol) in 100 mL THF at 0° C. and stirred 1 h at r.t. The reaction mixture was filtered to remove triethylammonium bromide and concentrated in vacuo to give inden-1-one. 7-Fluoroindole (3.3 g, 22 mmol ) and Sc(OTf)3 (550mg, 5 mol %) were added to inden-1-one in 100 mL CH2Cl2 at 0° C. The reaction mixture was allowed to warm to room temperature over night. 100 mL ethyl acetate was added and the mixture was filtered through a silica gel plug and concentrated in vacuo. After flash chromatography (heptane/ethyl acetate, silica gel) 5.9 g 3-(7-fluoro-1H-indol-3-yl)-indan-1-one (82%) was isolated.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[C:24]([Cl:26])[C:23]([O:27][CH3:28])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[C:24]([Cl:26])[C:23]([O:27][CH3:28])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c(Cl)cc1Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,4-dichloro-5-methoxyaniline (44 mg, 0.232 mmol) similar to Example 117 and isolated as a brown solid (9 mg, 11%). 1H NMR (CDCl3): 9.64–9.63 (m, 1H), 8.76–8.70 (m, 2H), 8.12 (s, 1H), 7.49 (s, 1H), 7.46–7.41 (m, 2H), 6.95 (s, 1H), 4.00 (s, 3H).
Reaction SMILES: N(C1C=C(C=CC=1C)C(NOC)=[O:7])N.[NH2:15][C:16]1[N:20]([C:21]2[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:24](NOC)=[O:25])[N:19]=[CH:18][C:17]=1[C:33](=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36](I)[CH:35]=1.C(N(CC)CC)C>C(O)C>[NH2:15][C:16]1[N:20]([C:21]2[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:24]([OH:25])=[O:7])[N:19]=[CH:18][C:17]=1[C:33](=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CONC(=O)c1ccc(C)c(-n2ncc(C(=O)c3cccc(I)c3)c2N)c1
Reactant: CONC(=O)c1ccc(C)c(NN)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)O)cc1-n1ncc(C(=O)c2ccccc2)c1N
Temperature: 65 °C
Reaction time: 3 h
Yield: 24.8 %

Procedure:
To a stirred solution of 3-hydrazino-4-methyl-benzoic acid hydrochloride 2 (242 mg, 1.19 mmol, 1.0 eq) in 25 mL of ethanol was added 2-benzoyl-3-phenylamino-acrylonitrile 4 (296 mg, 1.19 mmol, 1.0 eq, preparation: Grothasu, Davis, J. Am. Chem. Soc., 58, 1334 (1936)) and triethylamine (161 μL, 1.19 mmol, 1.0 eq) and the mixture was heated to 65° C. All solids dissolved when temperature reached 65° C. After three hours, LC-MS indicates consumption of the hydrazine. The solids were filtered to provide 3-(5-amino-4-benzoyl-pyrazol-1-yl)-4-methyl-benzoic acid 5 (95 mg, 25%) as a beige solid: HPLC (4 minute gradient) tR 2.10 min; MS m/z 322 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 7.99 (d, J=7.6, 1 H), 7.81 (s, 2 H), 7.78 (s, 1 H), 7.57 (m, 4 H), 7.02 (s, 2 H, NH2, 2.18 (s, 3 H) ppm; 13C NMR (DMSO-d6, 75 MHz) 187.6, 166.3, 152.0, 141.3, 141.2, 139.6, 135.9, 131.6, 131.2, 130.1, 129.8, 128.6, 127.8, 102.6, 17.4 ppm.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([OH:23])[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C.CO>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([O:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCNC(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCNC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 1-{4-[2-(t-butyldimethylsilyloxy)ethylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (531.1 mg, 1.49 mmol) (obtained as described in Reference Example 33(4)) in methylene chloride (26.6 ml) were added methanesulfonyl chloride (0.3 ml, 3.9 mmol) and triethylamine (0.52 ml, 3.7 mmol) in an ice bath, and the mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, methanol was added to the reaction mixture and the resulting mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:ethyl acetate (1:1) as the eluant to afford 1-{4-[2-(t-butyldimethylsilyloxy)ethylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (647.1 mg, yield 100%) as a pale yellow solid.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.Cl.Cl[CH2:15][CH2:16][NH2:17].[C:18]([OH:25])(=[O:24])/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CC(O)C.C(#N)C>[C:18]([OH:25])(=[O:24])/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:15][CH2:16][NH2:17])=[CH:6][CH:5]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: NCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC#N
Solvent: CC(C)O
Product: NCCn1ccc2ccc(Br)cc21
Temperature: 25 °C
Yield: 81.1 %

Procedure:
To a stirred mixture of powdered sodium hydroxide (0.41 g, 10.2 mmol), tetrabutylammonium hydrogensulfate (0.034 g, 0.1 mmol), 6-bromoindole (0.5 g, 2.5 mmol) and acetonitrile (15 mL) was added 2-chloroethylamine hydrochloride (0.31 g, 2.75 mmol). The mixture heated under reflux for 16 h and partitioned between water (30 mL) and ether (2×30 mL). The combined organic extracts were washed with brine (2×), dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-methanol-0.880 ammonia solution (90:9:1)] to give a pale brown oil. The oil was dissolved in 2-propanol (10 mL) and the solution was heated to reflux, fumaric acid (0.29 g, 2.5 mmol) was added and the mixture was cooled to room temperature and filtered. The filter-cake was dried in vacuo to give the product (0.72 g, 81% yield) as a white solid: mp 214-216° C.; NMR δH (400 MHz, DMSO-d6) 3.08 (2H, t, J 8 Hz), 4.33(2H, t, J 8 Hz), 6.47-6.52 (1H, m), 7.14-7.19 (1H, m), 7.41-7.44 (1H, m), 7.52 (1H, d, J 6.5 Hz) and 7.82 (1H, brs).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[N:6][C:7]=1[NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH:17]1(NC2N=C(O)C=CC=2[N+]([O-])=O)CCCCC[CH2:18]1>CC(C)(C)C([O-])([O-])[O-]>[CH:9]1([N:8]2[C:7]3=[N:6][C:5]([OH:16])=[CH:4][CH:3]=[C:2]3[N:1]=[C:17]2[CH3:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(O)nc1NC1CCCCCC1
Reactant: O=[N+]([O-])c1ccc(O)nc1NC1CCCCCC1
Agent: CC(C)(C)C([O-])([O-])[O-]
Product: Cc1nc2ccc(O)nc2n1C1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-6-(cycloheptylamino)pyridin-2-ol, prepared in a similar manner as the one described in Example 1.3 from 6-(cycloheptylamino)-5-nitropyridin-2-ol, was taken up in trimethylorthoacetate and stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the title compound. LCMS m/z=246.1 [M+H]+; 1H NMR (400 MHz, acetonitrile-d3) δ ppm 1.55-1.80 (m, 6H), 1.85-2.05 (m, 4H), 2.50-2.60 (m, 2H), 2.80 (s, 3H), 4.50-4.60 (m, 1H), 6.84 (d, J=8.8 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=O.[NH2:18][OH:19]>CC(N(C)C)=O.CO>[CH3:17][O:16][C:14]([C:11]1[CH:12]=[CH:13][C:7]2[CH:6]=[C:5]([C:3](=[O:2])[NH:18][OH:19])[S:9][C:8]=2[CH:10]=1)=[O:15]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)sc2c1
Reactant: NO
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COC(=O)c1ccc2cc(C(=O)NO)sc2c1

Procedure:
To a solution of benzo[b]thiophene-2,6-dicarboxylic acid dimethyl ester (115 mg, 0.46 mmol) in DMA/MeOH (3/1 mL) NH2OH (50% aq., 1.5 mL). The solution was stilted until the disappearance of starting material as indicated by LC/MS. After removal of solvent, MeOH/H2O was added until a precipitate forms. The solid was filtered yielding the desired material. 1H NMR (DMSO-d6) δ 11.57 (br s, 1H), 9.36 (br s, 1H), 8.67 (s, 1H), 8.05-7.87 (m, 3H), 3.87 (s, 3H). MS (EI): cal'd (MH+) 252.07, exp (MH+), 252.20.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:5]=[C:6]([F:8])[CH:7]=1.BrBr>ClCCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]2[S:11][C:10]([NH2:12])=[N:9][C:4]=2[CH:3]=1
Reactant: NC(=S)Nc1cc(F)cc(F)c1
Agent: BrBr
Solvent: ClCCCl
Product: Nc1nc2cc(F)cc(F)c2s1
Temperature: 10 °C
Yield: 90.7 %

Procedure:
To a suspension of N-(3,5-difluorophenyl) thiourea (3.40 g, 18.07 mmol) in DCE (95 mL) was added a solution of bromine in DCE (5 mL) below 30° C. The mixture was heated at reflux for 2.5 h, then cooled to 10° C., and the precipitate formed was collected by filtration and washed with DCE. The solid was stirred with water (200 mL), basified by treatment with conc. ammonium hydroxide, filtered, and dried in a vacuum oven to afford 5,7-difluoro-1,3-benzothiazol-2-amine (3.05 g, 90%). ret. time 2.18; m/z 187.1 (NH+); 1H NMR (400 MHz, DMSO-d6) δ 6.92 (m, 1H), 7.00 (m, 2H), 7.92 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][C:23]1=[O:28]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]2=[O:28])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NC1CCCNC1=O
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NC1CCCNC1=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 3-aminopiperidin-2-one (11.4 mg, 0.1 mmol). The title compound was obtained as a solid (10.4 mg, 23% yield). MS m/z: 446 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[NH:13][CH:14]=1)[C:2]1C=CC=CC=1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].BrCCBr>O.[Pd].CN(C)C=O>[O:17]1[C:10]2[CH:11]=[C:12]([CH2:15][OH:16])[N:13]=[CH:14][C:9]=2[O:8][CH2:1][CH2:2]1
Reactant: O=c1cc(CO)[nH]cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: BrCCBr
Solvent: O
Product: OCc1cc2c(cn1)OCCO2
Temperature: 85 °C

Procedure:
A solution of (a) (2 g, 8.7 mmol) in water (220 ml) containing sodium hydroxide (17 mmol) was hydrogenated over 10% palladium on charcoal (1g) for 4 hours. The mixture was filtered and evaporated to give a white solid. This solid was dissolved in N,N-dimethylformamide (8 ml) then treated with potassium carbonate (2.9 g) and 1,2-dibromoethane (0.6 ml, 7 mmol). The mixture was heated at 85° C. overnight. The cooled mixture was evaporated onto silica and chromatographed eluting with 10–30% methanol in ethyl acetate affording a white solid (250 mg, 21%).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]2=[N:8][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][C:21]2=[O:26])=[CH:4]1.C(N(CC)CC)C.[C:34](Cl)(=[O:39])[O:35][CH2:36][CH2:37][F:38]>C(Cl)Cl>[CH3:2][N:3]1[C:7]2=[N:8][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:20]2[CH2:25][CH2:24][N:23]([C:34]([O:35][CH2:36][CH2:37][F:38])=[O:39])[CH2:22][C:21]2=[O:26])=[CH:4]1
Reactant: O=C(Cl)OCCF
Reactant: Cn1cc(N2CCNCC2=O)c2ccc(OCc3ccccn3)nc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(N2CCN(C(=O)OCCF)CC2=O)c2ccc(OCc3ccccn3)nc21
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of 1-[1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperazin-2-one, hydrochloride (0.15 g, 0.40 mmol) and triethylamine (0.121 g, 1.20 mmol) in DCM (15 mL) is added dropwise 2-fluoroethyl carbonochloridate (0.076 g, 0.602 mmol) at room temperature, and the reaction mixture is stirred for 3 h. The reaction is quenched with a saturated solution of sodium bicarbonate (20 mL) at 0° C. and extracted with DCM (3×50 mL). The combined organic layers are dried over sodium sulphate, filtered and concentrated in vacuo. The residue is purified on neutral alumina, eluting with 1% MeOH in DCM to give a product, which on triturating in Et2O, affords the title compound (0.07 g, 0.164 mmol) as an off-white solid. MS (m/z): 428 (M+1). 1H-NMR (400 MHz, DMSO-d6): δ 3.68 (s, 3H), 3.77 (m, 4H), 4.17 (bs, 2H), 4.28 (t, 1H), 4.35 (t, 1H), 4.58 (t, 1H), 4.71 (t, 1H), 5.49 (s, 2H), 6.66 (d, 1H), 7.30-7.34 (m, 2H), 7.50 (d, 1H), 7.77-7.83 (m, 2H), 8.56 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH3:11].C([Li])CCC.[B:17](OCCCC)([O:23]CCCC)[O:18]CCCC>C1COCC1>[CH2:10]([C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[B:17]([OH:23])[OH:18])[CH3:11]
Reactant: CCc1cc(OC)ccc1Br
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(OC)ccc1B(O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-3-ethyl anisole (94 g, 0.437 mol) in THF (900 ml) was cooled to −78° C. n-Butyl lithium (249 ml, 0.55 mol) was added dropwise at the same temperature. Stirring was continued for 1 hr at −78° C. Tri-n-butyl borate (177 ml, 0.655 mol) was added slowly at −78° C. The cooling bath was removed, the reaction mixture was allowed to warm to 0° C. and was quenched with 1.5 N hydrochloric acid at 0° C. The organic layer was separated. The aqueous layer was extracted with ethylacetate and the combined organic layers were washed with brine and concentrated. The residue obtained was stirred in petroleum ether for 30 min. The solid obtained was filtered and dried under vacuum. Yield: 65 g, 82%, as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10].[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(N(CC)CC)C.[Pd].[Cu]I>[C:16]1([C:22]#[C:23][C:2]2[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=2)[O:5][CH2:6][CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#Cc1ccccc1
Reactant: CCN(CC)CCOc1cccc(Br)c1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCN(CC)CCOc1cccc(C#Cc2ccccc2)c1
Yield: 74.4 %

Procedure:
To a solution of 15 g (0.06 mole) of 1-(3-bromophenoxy)-2-diethylaminoethane and 6.12 g (0.06 mole) of phenylacetylene in 150 ml of triethylamine are added, under nitrogen, 420 mg of the palladium complex PdCl2 [P(C6H5)3 ]2 and 228 mg of copper (I) iodide. This reaction mixture is refluxed for 24 hours, then concentrated, and the residue is taken up in water. After extraction with 200 ml of ether, the combined ethereal phases are washed 4 times with water, dried, and evaporated to dryness. The crude product is chromatographed on silica gel and then distilled, affording 13.1 g (75%) of 1-(3-phenylethynylphenoxy)-2-diethylaminoethane with a boiling point of 150°-160° C./0.02 mb and a refractive index of nD25 :1.5858.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>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.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[CH2:16]([O:15][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:14][CH:13]=3)[CH2:5][C:6]=2[CH:7]=1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCOc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCOc1ccc2c(c1)Cc1cc(C#C[Si](C)(C)C)ccc1-2
Yield: 51.5 %

Procedure:
A mixture of 2-bromo-7-pentyloxyfluorene (12 g), trimethylsilylacetylene (7.1 g), dichlorobis(triphenylphosphine)palladium (0.3 g), copper iodide (0.08 g), triphenylphosphine (0.2 g) and triethylamine (200 mL) was heated for 3 hours while refluxing. Insoluble matters were removed from the reaction mixture by filtration, and triethylamine was distilled off under reduced pressure. The residue was purified by means of column chromatography (silica gel, eluting solvent: toluene) to obtain 6.5 g of 2-pentyloxy-7-trimethylsilylethynylfluorene. This was dissolved in tetrahydrofuran (100 mL) and cooled down to −60° C. on a dry ice-acetone bath. A 1M solution (46 mL) of tetraethylammonium fluoride was added thereto, and then the dry ice-acetone bath was removed, followed by stirring the solution until the temperature came up to −10° C. At a point of time when −10° C. was reached, water (30 mL) was added and stirred until the temperature came up to a room temperature, and then water was further added to terminate the reaction. The product was extracted with toluene, and the toluene layer was dried on anhydrous magnesium sulfate. A residue obtained by distilling the solvent off was purified by means of column chromatography (silica gel, eluting solvent: toluene). Then, it was recrystallized from ethanol to obtain 2-pentyloxy-7-ethynylfluorene (5 g) of colorless needle crystal. The melting point of this compound was 108° C.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH3:24][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:12][C:9]2[CH:10]=[CH:11][C:6]([C:2]3[O:1][CH:5]=[N:4][N:3]=3)=[CH:7][CH:8]=2)[O:23][N:22]=1
Reactant: Oc1ccc(-c2nnco2)cc1
Reactant: Cc1cc(CCCCCBr)on1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(CCCCCOc2ccc(-c3nnco3)cc2)on1
Reaction time: 4 h
Yield: 40.6 %

Procedure:
A mixture of 23.6 g 4-(1,3,4-oxadiazolyl)phenol (U.S. Pat. No. 4,218,458, Example XIX), 35 g 5-(5-bromopentyl)-3-methylisoxazole and 40 g milled potassium carbonate in 1.5 liters acetonitrile under nitrogen was heated to reflux. A catalytic amount of sodium iodide was added and refluxing continued for 4 hrs. The reaction mixture was filtered and concentrated to a solid residue. The latter was dissolved in ethyl acetate and the solution washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from triethylamine to give 18.5 g 3-methyl-5-{5-[4-(1,3,4-oxadiazol-2-yl)phenoxy]pentyl}isoxazole, white needles, m.p. 84°-86° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH:10]=[CH2:11])[NH2:6].B.[OH-:15].[Na+].OO>O1CCCC1>[OH:15][CH2:11][CH2:10][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:2]([F:12])([F:13])[F:1]
Reactant: [OH-]
Reactant: C=Cc1ccc(N)cc1C(F)(F)F
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(CCO)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
3-Trifluoromethyl-4-vinylaniline (2.47 g, 13.2 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and borane.dimethyl sulfide complex (2.75 mL, 30.0 mmol) was dropwise added thereto under argon atmosphere. The mixture was stirred at room temperature for 4 hours, and then a sodium hydroxide aqueous solution (1 N, 5 mL) and a 30% hydrogen peroxide aqueous solution (3 mL) were added thereto. The resulting mixture was stirred at 0° C. for 1 hour. The reaction solution was concentrated, and the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The resulting product was purified by silica-gel column chromatography (n-hexane:ethyl acetate=2:1) to give 4-(2-hydroxyethyl)-3-(trifluoromethyl)aniline (1.3 g, 48%) as a light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:16].Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][NH2:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:16]
Reactant: N#CC1(c2ccc(Cl)c(F)c2)CCCCC1
Agent: Cl
Product: NCC1(c2ccc(Cl)c(F)c2)CCCCC1
Yield: 19 %

Procedure:
The title compound was synthesized from 1-(4-chloro-3-fluorophenyl)-cyclohexanecarbonitrile using General Procedure E and was obtained in 19% yield as a clear oil. HPLC Rt=8.28 min. LCMS Rt=8.13 min, m/z=242 (M+1). HCl salt −1H NMR (DMSO-d6, δ): 7.35 (t, J=8.1 Hz, 1H), 7.17 (d, J=11.3 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 2.82 (s, 2H), 2.1 (m, 2H), 1.7-1.1 (m, 8H). 13C NMR (DMSO-d6, δ, mult): 159.2(0), 156.7(0), 143.1(0), 143.0(0), 130.6(1), 124.1(1), 124.1(1), 118.5(0), 118.3(0), 116.2(1), 116.0(1), 50.2(2), 40.6(0), 33.3(2), 25.5(2), 21.4(2).