Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[N:56]=[C:55]([O:57][CH3:58])[C:54]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=[CH:53][N:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[N:56]=[C:55]([O:57][CH3:58])[C:54]([C:59]2[CH:60]=[C:61]([NH:65][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:62]=[CH:63][CH:64]=2)=[CH:53][N:52]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1ncc(-c2cccc(N)c2)c(OC)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)c(OC)n1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,4-dimethoxy-pyrimidin-5-yl)-phenylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.010 g of product in 39% yield: LCMS (ESI) m/z 420 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([C@@H:10]2[C@@H:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][NH:12][CH2:11]2)[CH3:9])=[O:7])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41]([N:12]2[CH2:11][CH:10]([N:8]([C:6](=[O:7])[C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[C:3]([C:24]([F:27])([F:26])[F:25])[CH:4]=3)[CH3:9])[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13]2)=[O:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)[C@H]1CNC[C@@H]1c1ccc(Cl)cc1
Product: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)C1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 4-{(3SR,4RS)-3-(4-chloro-phenyl)-4-[(4-chloro-3-trifluoromethyl-benzoyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 4-chloro-N-[(3R,4S)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide instead of {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using piperidine-1,4-dicarboxylic acid mono-tert-butyl ester instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a white foam. MS m/e: 528.2 [M-BOC]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:25][C:26]([C:28]2[C:29](=[O:41])[N:30]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:31]([CH3:34])[C:32]=2[CH3:33])=[O:27])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:20][C:21]3([OH:24])[CH2:23][CH2:22]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:42]([NH:49][CH2:50][C:51](O)=[O:52])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:45]([O:44][C:42]([NH:49][CH2:50][C:51]([O:24][C:21]1([CH2:20][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:25][C:26]([C:28]5[C:29](=[O:41])[N:30]([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[N:31]([CH3:34])[C:32]=5[CH3:33])=[O:27])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:22][CH2:23]1)=[O:52])=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCC5(O)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCC5(OC(=O)CNC(=O)OC(C)(C)C)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a mixture of N-(3-fluoro-4-(7-((1-hydroxycyclopropyl)methoxy)-quinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (100 mg, 0.18 mmol), N-Boc-glycine (63 mg, 0.36 mmol, Alfa), and DMAP (3 mg, 0.018 mmol, Aladdin) in 10 mL of dichloromethane was added DCC (189 mg, 0.9 mmol, Aldrich) slowly at 0° C. After stirring at rt overnight, the mixture was filtered and washed with dichloromethane (10 mL×2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on a silica gel column (PE: EtOAc=1:6) to give the title compound as a yellow solid (100 mg, 78%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>>[CH2:33]([S:35]([N:16]1[CH2:15][CH2:14][N:13]([C:6]2[C:5]([CH3:19])=[C:4]([NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:26]=3)[C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[N:7]=2)[CH2:18][CH2:17]1)(=[O:37])=[O:36])[CH3:34]
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: CCS(=O)(=O)N1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)CC1

Procedure:
Prepared according to Procedure M using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and ethylsulfonyl chloride to give 2-(4-(ethylsulfonyl)piperazin-1-yl)-5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (DMSO-d6) δ ppm 1.15 (t, J=7.2 Hz, 3H), 2.08 (s, 3H), 3.05-3.11 (br s, 4H), 3.13 (q, J=7.2 Hz, 2H), 3.33 (br s, 8H), 3.69 (m, 4H), 6.51 (br s, 1H), 7.10-7.15 (m, 1H), 7.28-7.31 (m, 1H), 7.46 (s, 1H), 7.74 (s, 1H), 8.39 (s, 1H). Mass Spectrum (ESI) m/e=533.4 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[N:12]2)[CH:6]=[CH:7][C:8]=1[O:9]C)#[N:2].[Cl-].[Al+3].[Cl-].[Cl-].O>ClC(Cl)C>[C:1]([C:3]1[CH:4]=[C:5]([N:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[N:12]2)[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(OC)c(C#N)c2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cnn(-c2ccc(O)c(C#N)c2)c1
Temperature: 70 °C
Yield: 84.7 %

Procedure:
To a solution (280 ml) of ethyl 1-(3-cyano-4-methoxyphenyl)pyrazole-4-carboxylate (28 g) in dichloroethane was added aluminum chloride (47.6 g with stirring, and the mixture was heated at 70° C. for 4 hours. After the completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from ethyl acetate to give 22.5 g of ethyl 1-(3-cyano-4-hydroxyphenyl)pyrazole-4-carboxylate, melting point 233-234° C. ##STR19##
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:9]1[Br:26])=O)(C)(C)C.C[O-].[Na+]>CO>[Br:26][C:9]1[NH:8][C:16]2[C:11]([C:10]=1[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: CC(C)(C)OC(=O)n1c(Br)c(CCOC2CCCCO2)c2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Brc1[nH]c2ccccc2c1CCOC1CCCCO1
Temperature: 60 °C
Yield: 88 %

Procedure:
1-tert-Butoxycarbonyl-2-bromo-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole (7.12 g) was added to a 1 mol solution of sodium methoxide in methanol (200 ml) and the resulting mixture warmed to 60° C. for 2 h. After cooling the solvent was removed under reduced pressure and the residue purified immediately by flash chromatography (SiO2; n-hexane/ethyl acetate 10:1) to give the product as a pale yellow oil (4.79 g); 1H (250 MHz, CDCl3) δ1.60-2.00 (6H, br m), 3.03 (2H, t, J=7.5 Hz), 3.42 (1H, m), 3.67 (1H, m), 3.78 (1H, m), 3.83 (1H, m), 4.63 (1H, t, J=2.5 Hz), 7.09 (2H, m), 7.25 (1H, d, J=5.0 Hz), 7.58 (1H, d, J=5.0 Hz) and 8.09 (1H, br s).
Reaction SMILES: C([O:5][C:6]([CH:8]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:9](OCC)=O)=O)(C)(C)C.CC(C)([O-])C.[Na+].ClC(F)[F:31].O.[Cl-].[Na+].O>O1CCCC1>[F:31]/[CH:9]=[C:8](\[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)/[CH2:6][OH:5]
Reactant: CCOC(=O)C(CCc1ccc(F)cc1)C(=O)OC(C)(C)C
Reactant: FC(F)Cl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OC/C(=C/F)CCc1ccc(F)cc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Combine ethyl 2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate (32.14 g) and sodium t-butoxide (19.81 g) in tetrahydrofuran (400 mL). Stir the mixture for 1 hour, then heat to 45° C. Add an excess of chlorodifluoromethane over about 15 minutes. After 1 hour under an atmosphere of chlorodifluoromethane, allow the temperature to fall to ambient. Pour the reaction mixture into water/brine. Extract with diethyl ether. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[C:22]1([C:28]([NH2:31])([CH3:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:31][C:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([CH3:30])[CH3:29])=[O:16])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(O)c1ccc2c(ccn2Cc2ccc(F)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(NC(=O)c1ccc2c(ccn2Cc2ccc(F)cc2F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2,4-difluorobenzyl)-1H-indole-5-carboxylic acid (50 mg, 0.17 mmol, 1 equiv) in DCM (2 mL) was added 2-phenylpropane-2-amine (27 μL, 0.18 mmol, 1.05 equiv), DIEA (30 μL, 0.17 mmol, 1 equiv) and HATU (68 mg, 0.18 mmol, 1.05 equiv). The reaction mixture was stirred 2 h at room temperature.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[Cl:14])[NH2:10].[CH:15]([S:17]([F:20])(=[O:19])=[O:18])=[CH2:16]>O>[Cl:6][C:7]1[CH:8]=[C:9]([NH:10][CH2:16][CH2:15][S:17]([F:20])(=[O:19])=[O:18])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: C=CS(=O)(=O)F
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(F)CCNc1ccc(Cl)c(Cl)c1

Procedure:
A N,N-dimethylformamide solution (DMF, 100 ml) of 3,4-dichloroaniline (6.48 g, 40 mmol) and ethenesulfonyl fluoride (6.7 g, 57.9 mmol) was warmed to 110° C. for three hours. The cooled dark solution was diluted to 400 ml with water and the resulting dark oily precipate was decanted from the supernatant layer. This layer was extracted with ether (4×50 ml). The combined ether extracts were added to the oily precipitate and this dark solution was washed with brine and dried over MgSO4. The organic solution was evaporated to give the crude 2-[(3,4-dichlorophenyl)amino]ethanesulfonyl fluoride as a dark liquid in quantitative yield.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH2:16]>CN(C)C=O.O>[C:17]1([C:15](=[CH2:14])[CH2:16][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=C(CBr)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(CN1C(=O)c2ccccc2C1=O)c1ccccc1
Yield: 98.3 %

Procedure:
A mixture of 60 g of potassium phthalimide and 66.4 g of α-bromomethyl styrene (prepared by the method of S. F. Reed, Jr., J. Org. Chem., 30, 3258 (1965)) in 150 ml of dimethylformamide is refluxed for 2 hours, cooled, and diluted with 400 ml of water. The resulting solid is filtered and dried in vacuo to give 83.4 g of N-(2-phenyl-2-propenyl)phthalimide. A small sample that is recrystallized from acetone-hexane has a melting point of 118°-121°C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1)([CH3:23])[CH3:22]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:21]([CH3:23])[CH3:22])[CH2:31][C:32]3[N:33]=[N:34][N:35]([CH3:37])[N:36]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: CC(C)c1ccccc1NCc1nnn(C)n1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccccc2C(C)C)[C@H]1O
Yield: 35 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (300 mg, 1.07 mmol) obtained in step 1 of example 2 and N-(2-isopropylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (192 mg, yield: 35%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]2[C:25]3[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[S:19][CH2:18][CH:17]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.Cl.O>O1CCCC1>[CH3:27][O:26][C:22]1[CH:21]=[C:20]2[C:25]([CH:16]([C:12]3[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=3)[CH2:9][OH:8])[CH:17]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[CH2:18][S:19]2)=[CH:24][CH:23]=1
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2c2cccc(CO[Si](C)(C)C(C)(C)C)c2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2CSc3cc(OC)ccc3C2c2cccc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
4-[3-(t-butyldimethylsilyloxymethyl)phenyl]-7-methoxy-3-(4-methoxyphenyl)thiochroman (480 mg, 0.947 mmol) was dissolved in tetrahydrofuran (40 ml), and added 3N hydrochloric acid solution (2.7 ml) thereto. The reaction mixture was stirred at room temperature for 4 h. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was washed with sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was flash chromatographied on silica gel (n-hexane:ethyl acetate=1:1) to obtain 358 mg (yield: 96%) of the title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH2:12]([NH2:14])[CH3:13]>>[CH2:12]([NH:14][C:2]1[C:3]([NH2:4])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH3:13]
Reactant: CCN
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Product: CCNc1ccc([N+](=O)[O-])cc1N
Yield: 72 %

Procedure:
2-fluoro-5-nitroaniline (5 g, 32 mmol) and a solution of ethyl amine (32 ml, 2M in THF) were coupled according to the procedure of intermediate example one part A to give the title compound as a dark red solid 4.16 g, 72%). 1H NMR (300 MHz, d6-DMSO) δ7.51 (dd, J=8.7 and 2.7 Hz, 1H), 7.38 (d, J=2.7 Hz, 1H), 6.44 (d, J=8.7 Hz, 1H), 5.86 (t, J=4.6 Hz, 1H), 5.15 (s, 2H), 3.20 (m, 2H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 2,2,2-trifluoroethanol (5.0 g, 50.0 mmol) and triethylamine (10.5 ml, 7.6 g, 75.0 mmol) in 25 ml of methylene chloride at -10° is added methanesulfonyl chloride (4.25 ml, 6.3 g, 55.0 mmol) over 20 min., maintaining the temperature at 0° to -10°. After addition is complete, the mixture is stirred at 0°-5° for 30 min. It is then poured into ice water and additional methylene chloride is added. The layers are separated, and the methylene chloride layer is washed with cold 10% HCl, with cold saturated sodium bicarbonate, with cold water until neutral, and with cold brine. The organic layer is dried over calcium sulfate with swirling and is filtered and the solvent is removed to give 2,2,2-trifluoroethyl methanesulfonate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: O=[N+]([O-])c1ccc(-c2ccccc2)cc1
Yield: 97 %

Procedure:
From 4-nitro-bromobenzene and phenyl boronic acid, yield 97%; mp 110-113° C. (lit.,8 114-115° C.); IR: 1596, 1513, 1481, 1350 and 1236; 1H NMR (400 MHz; CDCl3): 8.32-8.28 (2H, m), 7.76-7.72 (2H, m), 7.65-7.61 (2H, m) and 7.52-7.42 (3H, m); 13C NMR (CDCl3): 147.6, 147.1, 138.7, 129.1, 128.8, 127.7, 127.3 and 124; m/z (EI) 199 (20%, M+), 169(70), 131 (85) and 119 (100)(Found: M+, 199.063. C12H9NO2 requires M, 199.063).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]=1[CH2:34][C:35]#[N:36].CN(C)C=O.[H-].[Na+]>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH2:34][C:35]#[N:36])=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: N#CCc1c(O)ccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc3ccccc3c2CC#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (4.52 g), 2-(2-hydroxy-1-naphthyl)acetonitrile (0.58 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.14 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.11 g, 76%) of 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 178-179° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:3]=[C:4]([C:8]#[C:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=3)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=2)=[O:26])=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: COC(=O)c1cncc(C#Cc2cccc(N)c2)c1
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Product: COC(=O)c1cncc(C#Cc2cccc(NC(=O)c3ccc(Cl)c(C(F)(F)F)c3)c2)c1

Procedure:
In a manner similar to that described in Example 1, methyl 5-((3-aminophenyl)ethynyl)nicotinate and 4-chloro-3-(trifluoromethyl)benzoic acid are converted to the title compound.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][CH:3]=1.[Mg].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:41])[CH:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][CH3:34])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:2]2[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][CH:3]=2)([OH:41])[CH:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][CH3:34])=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCC(C(=O)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(c1ccccc1)C(O)(c1ccc(OCc2ccccc2)cc1)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C
Yield: 93 %

Procedure:
A solution of 19.32 g of (4-bromophenoxy)-tert-butyldimethylsilane in 50 ml of tetrahydrofuran is added in drops to a suspension of 1.58 g of magnesium chips in 100 ml of tetrahydrofuran at 80° C. bath temperature, and it is refluxed for 1 hour. Then, it is cooled to 0° C., and 6.0 g of 1-(4-benzyloxyphenyl)-2-phenyl-butan-1-one [D. W. Robertson; J. A. Katzenellenbogen; D. -J. Ellen; A. Rorke; B. S. Katzenellenbogen, J. Steroid Biochem., 1982, 16, 1-13] is added, and it is stirred for 24 more hours at room temperature. For working-up, 60 ml of saturated ammonium chloride solution is added, diluted with ethyl acetate, washed neutral with water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 9.1 g of 1-(4-benzyloxyphenyl)-1-(4-tert-butyldimethylsiloxy-phenyl)-2-phenyl-butan-1-ol is obtained as oil.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH:6]=[CH:7][C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[CH:22]=[CH:21][C:20]([O:23]COC)=[C:19]([O:27][CH3:28])[CH:18]=4)=[CH:14][CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([NH:38][CH2:39][C:40](O)=[O:41])(OC(C)(C)C)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C1C=CN=CC=1)C>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]2[CH:12]=[C:11]3[C:16]([C:8](/[CH:7]=[CH:6]/[C:5]4[CH:29]=[CH:30][C:2]([NH:1][C:40](=[O:41])[CH2:39][NH2:38])=[CH:3][CH:4]=4)=[N:9][NH:10]3)=[CH:15][CH:14]=2)=[CH:18][C:19]=1[O:27][CH3:28]
Reactant: COCOc1ccc(-c2ccc3c(C=Cc4ccc(N)cc4)n[nH]c3c2)cc1OC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2ccc3c(/C=C/c4ccc(NC(=O)CN)cc4)n[nH]c3c2)ccc1O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
3-(4-aminostyryl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (90 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL) and was treated with Boc-glycine (196 mg, 1.12 mmol, 5 equiv), DMAP (82 mg, 3 equiv) and HATU (426 mg, 5 equiv). The mixture was allowed to stir for 30 min. The mixture was partitioned between ethyl acetate and water. The organic material was concentrated, taken up in methanol (5 mL) and was treated with potassium carbonate (100 mg). The mixture was heated to 50° C. for 3 d. The resulting mix was-again partitioned between ethyl acetate and water. The organic material was concentrated, and purified by silica (109 mg, 66%): Rf sm 0.32, p 0.46 (ethyl acetate-hexane 6:4); 1H NMR (300 MHz, CDCl3) δ 8.18 (bs, 1H), 8.03 (d, 1H, J=8.1 Hz), 7.56 (m, 5H), 7.40 (m, 3H), 7.20 (m, 3H), 5.29 (s, 2H), 5.20 (bs, 1H), 3.98 (s, 3H), 3.96 (d, 2H), 3.54 (s, 3H), 1.48 (s, 9H).