Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])S(C(F)(F)F)(=O)=O.[Br:19][CH2:20][C@H:21]([CH3:25])[CH2:22][CH2:23]O.N1C(C)=CC=CC=1C.Cl>C(Cl)Cl>[CH:10]([Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:1][CH2:23][CH2:22][C@@H:21]([CH3:25])[CH2:20][Br:19])([CH3:12])[CH3:11]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: C[C@@H](CBr)CCO
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](OCC[C@@H](C)CBr)(C(C)C)C(C)C
Temperature: 0 °C

Procedure:
15.4 ml of triisopropylsilyl triflate are added to a solution of 8.7 g of (R)-4-bromo-3-methylbutan-1-ol in 320 ml of methylene chloride at 0° C., and 6.6 ml of 2,6-lutidine are then added in the course of 30 min. The reaction mixture is subsequently poured onto 100 ml of ice-water and the aqueous phase is acidified by addition of 2N hydrochloric acid (pH 3). It is extracted with methylene chloride and the organic phase is washed with a 5% sodium bicarbonate solution and saturated sodium chloride solution and dried over sodium sulfate. After purification of the crude product by FC over 200 g of silica gel (mobile phase J), the title compound is obtained: Rf (J)=0.48.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=O)[N:6]=[N:5]1)[CH:2]=[CH2:3].[CH3:27][O:28][CH:29]([O:38][CH3:39])[CH2:30][NH:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CCCC(C)C>[CH2:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([N:31]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:30][CH:29]([O:38][CH3:39])[O:28][CH3:27])=[O:19])[N:6]=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)nn1
Reactant: COC(CNC1CCCCC1)OC
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Product: C=CCn1cc(-c2cccc(CCOCCC(=O)N(CC(OC)OC)C3CCCCC3)c2)nn1

Procedure:
The subtitled compound (584 mg) was prepared from tert-butyl 3-(3-(1-allyl-1H-1,2,3-triazol-4-yl)phenethoxy)propanoate [Ex 4, Step iii)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii) the elution gradient 20 to 100% ethyl acetate in isohexane. 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.69 and 7.67 (2 s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.322 and 7.318 (2×t, J=7.7 Hz, 1H), 7.20 (d, J=6.9 Hz, 1H), 6.17-6.06 (m, 1H), 5.36-5.27 (m, 2H), 5.06 (d, J=5.9 Hz, 2H), 4.52 and 4.36 (2×t, J=5.5 Hz, 1H), 3.99 and 3.65 (tt, J=5.3 and 11.7 Hz, 1H), 3.76-3.66 (m, 4H), 3.34 (s, 3H), 3.32 (s, 3H), 3.34 and 3.25 (2×d, J=4.9 Hz, 2H), 2.92-2.85 (m, 2H), 2.68-2.61 (m, 2H), 1.79-1.02 (m, 10H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11]C(=O)C)=[CH:10][C:5]=2[O:4][C:3]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](C)=[CH:18][CH:17]=1.[ClH:24].C(OC(=O)C)C>CO>[NH2:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([CH3:1])=[C:3]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:24])=[CH:18][CH:17]=3)=[O:23])[O:4][C:5]=2[CH:10]=1
Reactant: Cl
Reactant: CC(=O)Nc1ccc2c(C)c(C(=O)c3ccc(C)cc3)oc2c1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)c2ccc(Cl)cc2)oc2cc(N)ccc12
Temperature: 25 °C

Procedure:
3.1 g (10 mmol) of N-[3-methyl-2-(4-methyl-benzoyl)benzofuran-6-yl]-acetamide were suspended in 40 ml methanol. 20 ml 2.6N HCl were added with stirring. The reaction mixture was heated to reflux. After 1 hour a clear solution was obtained. After 3 hours reflux the solution was cooled to room temperature and ethylacetate was added. The organic layer was washed once with NaOH-solution, two times with water, dried over Na4SO4 and concentrated in vacuo. The residue was further purified by crystallisation.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)[CH2:8][N:7]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][CH2:5]2.Cl[C:29]1[CH:34]=[C:33]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:32]=[C:31]([NH2:42])[N:30]=1>>[NH2:42][C:31]1[N:30]=[C:29]([C:11]2[CH:10]=[C:9]3[C:4]([CH2:5][CH2:6][N:7]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:8]3)=[CH:3][C:2]=2[CH3:1])[CH:34]=[C:33]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:32]=1
Reactant: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Reactant: Cc1cc2c(cc1B1OC(C)(C)C(C)(C)O1)CN(C(=O)OC(C)(C)C)CC2
Product: Cc1cc2c(cc1-c1cc(N3CCN(C)CC3)nc(N)n1)CN(C(=O)OC(C)(C)C)CC2

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 75, Step 4 starting from tert-butyl 6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate and 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine Analytic LCMS (M+H)+: m/z=439.2.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:25])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#N)=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[OH-:32].[K+].C(O)C.Cl.[OH2:38]>>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:25])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]([OH:38])=[O:32])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: O
Reactant: [OH-]
Reactant: CCCc1c(OCc2ccc(C(O)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CCCc1c(OCc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Yield: 75 %

Procedure:
A mixture of 3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile (320 mg, 0.772 mmol), potassium hydroxide (1.0 g, 17.85 mmol), water (2 mL), and ethanol (10 mL) is stirred at reflux overnight. The reaction is cooled, the pH is adjusted to 2 with aqueous 5N hydrochloric acid and diluted with water (50 mL). The product is extracted with ethyl acetate (2×50 mL). The combined extracts are washed with water (50 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound (250 mg, 75%) as a white powder. 1H NMR (DMSO-d6) δ 12.85 (bs, 2H), 7.98 (s, 1H), 7.80 (d, 2H), 7.64 (d, 1H), 7.38-7.47 (m, 5H), 6.72 (d, 1H), 6.05 (d, 1H), 5.81 (d, 1H), 5.23 (s, 2H), 2.56-2.61 (m, 5H), 1.45-1.53 (m, 2H), 0.87 (t, 3H). LCMS 433 M−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>C1COCC1>[F:32][C:33]([F:37])([F:36])[CH2:34][NH:35][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[C:13]2[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCC(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NCC(F)(F)F)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The product of Example 48 (300 mg, 0.67 mmol) and trifluoroethylamine (300 mg, 3 mmol) were dissolved in THF (10 ml) and sealed in a vial under Ar. The mixture was heated in an oil bath to 60° for 4 days. The solvents were removed ill vacuo, and the residue was flash chromatographed with 60-90% CH2Cl2/hexane. Recrystallization from CH2Cl2/hexane gave the title compound as a white crystalline solid. mp 195-196°, LC MS m/z=465(MH+) Retention time=2.38 min.
Reaction SMILES: BrCCBr.[Mg].[CH3:6][N:7]1[CH2:12][CH2:11][CH:10](Cl)[CH2:9][CH2:8]1.[Br:14][C:15]1[CH:31]=[CH:30][C:18]2[N:19]3[CH2:29][CH2:28][C:27]4[C:20]3=[C:21]([CH:24]=[CH:25][CH:26]=4)[CH:22]=[N:23][C:17]=2[CH:16]=1.[Cl-].[NH4+]>O1CCCC1>[Br:14][C:15]1[CH:31]=[CH:30][C:18]2[N:19]3[CH2:29][CH2:28][C:27]4[C:20]3=[C:21]([CH:24]=[CH:25][CH:26]=4)[CH:22]([CH:10]3[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]3)[NH:23][C:17]=2[CH:16]=1
Reactant: CN1CCC(Cl)CC1
Reactant: Brc1ccc2c(c1)N=Cc1cccc3c1N2CC3
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CN1CCC(C2Nc3cc(Br)ccc3N3CCc4cccc2c43)CC1
Reaction time: 1 h

Procedure:
1,2-Dibromoethane (0.5 ml) was added to a refluxing slurry of magnesium chips (12 gm) in tetrahydrofuran (60 ml) to initiate a Grignard reaction. N-Methyl-4-chloropiperidine (55 ml) in tetrahydrofuran (100 ml) was added rapidly. The mixture was refluxed for 1 hour, during which a white precipitate formed. A solution of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (30 gm) in tetrahydrofuran (150 ml) was added at 0° C. After one hour of stirring, the mixture was poured into cold saturated ammonium chloride solution (750 ml) and extracted with ethyl acetate (2×400 ml). The ammonium chloride solution was basified with ammonium hydroxide and extracted once with ethyl acetate (400 ml). The combined ethyl acetate solutions were washed with brine (2×500 ml), dried over anhydrous magnesium sulfate and concentrated to a solid (38 gm). The crude solid was purified by flash chromatography (700 gm silica, eluted with 4% methanol/dichloromethane, 6 L; 4 % methanol/0.5% ammonium hydroxide/dichloromethane, 4 L). The fractions containing the desired product were pooled and concentrated to give 23 gm of a solid. Recrystallization from dichloromethane/ethanol (200 ml:1 L) yielded 17.0 gm of crystals, m.p. 206°-208° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:16][OH:17])[CH2:11][O:12][CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[Cl:19][CH2:20][CH2:21][NH2:22].[OH-].[K+]>CN(C)C=O>[ClH:19].[NH2:22][CH2:21][CH2:20][O:17][N:16]=[C:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH2:11][O:12][CH2:13][CH2:14][CH3:15]
Reactant: NCCCl
Reactant: CCCOCC(=NO)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCOCC(=NOCCN)c1ccc([N+](=O)[O-])cc1
Temperature: 10 °C

Procedure:
10 Mmol of 4'-nitro-2-propoxyacetophenone oxime, 10.4 mmol of 2-chloroethyl amine hydrochloride and 1.4 g of powdered potassium hydroxide were added to 25 ml of dimethyl formamide while stirring at 10° C. After stirring for two days at room temperature the dimethyl formamide was evaporated in vacuo, the residue was brought in water and then 2 N hydrochloric acid was added until pH 3. The remaining oxime was removed by means of ether, after which 30 ml of 2 N sodium hydroxide solution were added. Then three extractions with ether were carried out. The collected ether layers were washed twice with a 5% sodium bicarbonate solution and then dried on sodium sulphate. After removing the ether in vacuo the residue was dissolved in absolute ethanol and converted into the little compound by means of alcoholic hydrochloric acid. After recrystallization from alcohol/ether the melting point was 128°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH:16]1[CH:20]=[C:19]([CH:21]=[O:22])[N:18]=[CH:17]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O1CCOCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:11][C:12](=[O:15])[CH2:13][CH2:14][N:16]2[CH:20]=[C:19]([CH:21]=[O:22])[N:18]=[CH:17]2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=CC(=O)NC(C)(C)c1ccc(Cl)cc1
Reactant: O=Cc1c[nH]cn1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(NC(=O)CCn1cnc(C=O)c1)c1ccc(Cl)cc1
Temperature: 95 °C

Procedure:
A mixture of N-[1-(4-chlorophenyl)-1-methylethyl]acrylamide (22.35 g), imidazole-4-carboxaldehyde (9.6 g), benzyltrimethylammonium hydroxide (2.24 ml of a 40% solution in methanol, Triton®B) and 1,4-dioxane (112 ml) was stirred and heated at 95° C. for 6 hours and then worked up as described in Example 19a to give N-[1-(4-chlorophenyl)-1-methylethyl]-3-(4-formylimidazol-1-yl)propionamide, m.p. 151-153° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:20])[F:19])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C(O)(C)C>[F:22][C:23]([F:31])([F:32])[C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:18]([F:21])([F:20])[F:19])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:29][CH:30]=1.[ClH:1]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)c1ccccc1-c1ccc2c(Cl)ncnc2c1
Solvent: CC(C)O
Product: Cl
Product: FC(F)(F)c1ccc(Nc2ncnc3cc(-c4ccccc4C(F)(F)F)ccc23)cc1

Procedure:
Reflux a solution of 4-chloro-7-(2-trifluoromethyl-phenyl)-quinazoline (258 mg, 0.836 mmol) and 4-(trifluoromethyl)-aniline (269 mg, 1.67 mmol) in isopropyl alcohol for 8 hours. Cool the solution, collect the precipitate via filtration and wash with dry ether (3×) to give pure (4-Trifluoromethyl-phenyl)-[7-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]amine (Cmpd 2) HCl salt. Mass spec. 433.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:24]4[O:23][CH:27]=[CH:26][CH:25]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1ccco1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccco4)c3)cnc2c1F
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and furan-2-boronic acid were coupled in the same way as in Example 30 to give 2-{8-fluoro-3-[4-fluoro-3-(fur-2-yl)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (6 mg, 4%): m/z (ES+) 355 [MH+].
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ON1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2C1=O>C(#N)C>[CH:3](=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:15]([O:2][CH3:1])(=[O:16])[C:14]1[CH:13]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COCc1ccccc1
Solvent: CC#N
Product: COC(=O)c1ccccc1
Product: O=Cc1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 20 %
Yield: 52 %

Procedure:
A mixture of 1 mmol of benzyl methyl ether, 0.1 mmol of N-hydroxyphthalimide, and 5 ml of acetonitrile was stirred at 60° C. under a nitrogen monoxide atmosphere (1 atm) for 5 hours. Gas chromatographic analysis of products in the reaction mixture revealed that benzyl methyl ether was converted, at a rate of 78%, into benzaldehyde (yield: 52%), and methyl benzoate (yield: 20%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=3[CH3:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].C([O:43][P:44]([CH2:49]OS(C(F)(F)F)(=O)=O)([O:46]CC)=[O:45])C>CN(C)C(=O)C>[C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][CH2:49][P:44](=[O:43])([OH:46])[OH:45])=[CH:26][C:25]=3[CH3:31])[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:14]=1)(=[NH:9])[NH2:7]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccc(N)cc2C)c1
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2ccc(NCP(=O)(O)O)cc2C)c1
Temperature: 50 °C
Yield: 128.1 %

Procedure:
To a mixture of {[4-(4′-amino-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (30 mg, 58.0 μmol), as prepared according to the procedure of step b of Example 120, cesium carbonate (19 mg, 58 μmol), and N,N-dimethylacetamide (0.4 mL) was added a solution of trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester (18 mg, 58 μmol) (Xu, Y. et al, J. Org. Chem. 61, 7697 (1996); Phimon, D. et al, Tetrahedron Lett. 27, 1477 (1986)), and heated at 50° C. for 48 h. Additional trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester (18 mg, 58 μmol) was added. The mixture was heated at 50° C. for additional 24 h. Solvent was evaporated. The resulting mixture was partitioned between DCM and H2O. Aqueous layer was separated and extracted with DCM. All the DCM layers were combined, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel column, eluting with EtOAc/DCM (20 and 30%) to give the title compound (38 mg, 98% yield) as an orange oil. 1H NMR (CDCl3): δ 8.23 (s, 1H), 7.92–7.88 (m, 2H), 7.53–7.46 (m, 2H), 6.98 (d, 1H, J=8.0 Hz), 6.56–6.53 (m, 2H), 4.23–4.15 (m, 4H), 3.56 (d, 2H, J=12.5 Hz), 2.43 (s, 3H), 2.16 (s, 3H), 1.52 (s, 9H), 1.35 (t, 6H, J=7.0 Hz). ESI-MS (m/z): Cald. For C29H39N3O7PS3: 668.2 (M+H); found: 667.8.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:9])([CH3:8])[O:4][CH:5]([CH3:7])[CH3:6].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:19]([CH:28]=[O:29])=[CH:20][C:21]3[NH:25][CH:24]=[N:23][C:22]=3[C:26]=2[F:27])=[C:13]([Cl:30])[CH:12]=1>C1COCC1>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:19]([CH:28]([OH:29])[CH2:2][Si:3]([O:4][CH:5]([CH3:7])[CH3:6])([CH3:9])[CH3:8])=[CH:20][C:21]3[NH:25][CH:24]=[N:23][C:22]=3[C:26]=2[F:27])=[C:13]([Cl:30])[CH:12]=1
Reactant: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: CC(C)O[Si](C)(C)CCl
Solvent: C1CCOC1
Product: CC(C)O[Si](C)(C)CC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of the Grignard reagent prepared from Mg and chloromethyl dimethylisopropoxy silane (Org. Synth. 1992, 69, 96) [4.4 mL, 3.26 mmol, 0.74 M solution (based on 90% purity)] in THF, is added a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde 10f (200 mg, 0.54 mmol) in THF (1 mL) at −78° C. After stirring for 1 hour at −78° C., the reaction is quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, concentrated in vacuo to afford the crude desired product which is directly used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:17]=[CH:18][CH:19]=1.[N:13]1[NH:12][N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=12
Reactant: Brc1ccccn1
Reactant: C#CCCn1nc2cccc(Cl)c2n1
Product: Clc1cccc2nn(CCC#Cc3ccccn3)nc12
Product: c1ccc2n[nH]nc2c1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (25 mg, 0.16 mmol) and 2-(but-3-ynyl)-4-chloro-2H-benzo[d][1,2,3]triazole (30 mg, 0.15 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 12 mg (42 μmol, 29%) of 4-chloro-2-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as an orange solid.
Reaction SMILES: [CH3:1][N:2]1[CH:9]([CH3:10])[CH2:8][CH:7]2[CH:3]1[CH2:4][N:5](C(OCC)=O)[CH2:6]2.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH3:1][N:2]1[CH:9]([CH3:10])[CH2:8][CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2CC(C)N(C)C2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1CC2CNCC2N1C

Procedure:
7.25 g (34.2 mmol) of ethyl 2,3-dimethyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate together with 50 ml of concentrated hydrochloric acid are refluxed overnight. The mixture is rendered alkaline using potassium carbonate and extracted ten times using 50 ml portions of chloroform, the extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#N.[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.C([O:22]CC)C>>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[O:22])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCOCC
Reactant: N#Cc1ccccc1N
Agent: Cl
Product: Nc1ccccc1C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-aminobenzonitrile (4.25 g, 36 mmol) in anhydrous diethyl ether (40 ml) at 0° C. is treated under argon with benzylmagnesium chloride (2M in tetrahydrofuran; 50 ml; 100 mmol). The reaction medium is maintained under agitation for 1 hour at ambient temperature, then hydrolyzed at 0° C. by adding hydrochloric acid at 10%, agitated for 1 hour, and neutralized with soda. The resulting mixture is extracted with ethyl acetate. The combined extracts are washed with water and with a saturated solution of sodium chloride, then dried over magnesium sulphate and concentrated to produce 3.5 g of the desired product, in the form of a white solid (m.p.: 100–101° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]([O:18][CH3:19])([CH3:17])[CH3:16])[C:6]([O:8]C)=[O:7].[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]([O:18][CH3:19])([CH3:16])[CH3:17])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(OCC(C)(C)OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)ccc1OCC(C)(C)OC
Temperature: 80 °C
Yield: 77.5 %

Procedure:
Methyl 3-methoxy-4-(2-methoxy-2-methyl-propoxy)benzoate (177 mg, 0.66 mmol), dioxane (1.9 mL) and NaOH (1.8 mL of 1 M, 1.80 mmol) were combined and the reaction mixture was heated at 80° C. for 15 minutes. The reaction mixture was concentrated in vacuo and the crude mixture was dissolved in water. The mixture was washed with EtOAc (3×). The aqueous layer was acidified with 1N HCl then washed with EtOAc (3×). The combined organic layers was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to yield 3-methoxy-4-(2-methoxy-2-methyl-propoxy)benzoic acid (130 mg, 77%). ESI-MS m/z calc. 254.1. Found 255.5 (M+1)+; Retention time: 1.14 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 12.61 (s, 1H), 7.54 (dd, J=8.4, 1.9 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 3.89 (s, 2H), 3.81 (s, 3H), 3.17 (s, 3H), 1.22 (s, 6H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][C:30]1[C:31]([CH:39]=O)=[CH:32][C:33]2[O:37][CH2:36][O:35][C:34]=2[CH:38]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:39][C:31]3[C:30]([Br:29])=[CH:38][C:34]4[O:35][CH2:36][O:37][C:33]=4[CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc2c(cc1Br)OCO2
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cc5c(cc4Br)OCO5)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 6-bromo benzo[1,3]dioxole-5-carbaldehyde. MS (ESI) m/z 591.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc(F)c(F)c1F
Product: O=C(O)Cc1ccccc1Nc1ccc(F)c(F)c1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,3,4-trifluoroaniline to yield 2-[(2,3,4-trifluorophenyl)amino]phenylacetic acid.