Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][C:8]([NH:15][C:16]([C:18]1[N:22]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH2:28][C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[C:21]2=[N:20][C:19]=1[CH3:37])=[O:17])([C:10]1[N:11]=[N:12][NH:13][N:14]=1)[CH3:9])(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH3:56][C:57]1([CH3:60])[CH2:59][O:58]1.C(OC(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C.O>[F:35][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([F:36])[C:29]=1[CH2:28][O:27][C:26]1[C:21]2[N:22]([C:18]([C:16]([NH:15][C:8]([C:10]3[N:14]=[N:13][N:12]([CH2:56][C:57]([OH:58])([CH3:60])[CH3:59])[N:11]=3)([CH3:9])[CH2:7][OH:6])=[O:17])=[C:19]([CH3:37])[N:20]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)CO1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1nn[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(CO)c1nnn(CC(C)(C)O)n1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 180 mg of N-[1-{[tert-butyl (diphenyl)silyl]oxy}-2-(2H-tetrazol-5-yl)propan-2-yl]-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 3 ml of DMF were added 100 mg of potassium carbonate and 50 μl of 2,2-dimethyloxirane, followed by stirring at 60° C. for 4 hours and then at 100° C. overnight. To the reaction mixture were added 100 mg of potassium carbonate and 50 μl of 2,2-dimethyloxirane, followed by stirring at 140° C. for 1 hour under the microwave irradiation condition. To the reaction mixture was added 50 μl of 2,2-dimethyloxirane, followed by stirring at 150° C. for 1 hour under the microwave irradiation condition. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The obtained residue was purified by silica gel column chromatography. To the obtained crude product were added ethyl acetate and diisopropyl ether, and the insoluble materials were collected by filtration and dried under reduced pressure to obtain 42 mg of 8-[(2,6-difluorobenzyl)oxy]-N-{1-hydroxy-2-[2-(2-hydroxy-2-methylpropyl)-2H-tetrazol-5-yl]propan-2-yl}-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:7][NH:8][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)OCc2ccccc2)[C@H](O)C1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CNC[C@H]1O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a stirred solution of (±)-1,1-dimethylethyl trans-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (4.44 g, 12.7 mmole) in DCM (75 mL) was added TFA (25 mL). After stirring for 2 h, the reaction contents were concentrated under vacuum and the residue dissolved in DCM (150 mL). MP-carbonate resin (18.8 g, 50.8 mmole) was added and the reaction contents were stirred vigorously overnight. The reaction contents were filtered through a scinter-glass funnel and the resin washed with MeOH. The filtrate was concentrated and dried under vacuum to give an off-white foam: LC-MS (ES) m/e 251 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].C(C1NC=CN=1)(C1[NH:25]C=CN=1)=O.N>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH2:25])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)O)cn1
Agent: N
Solvent: C1CCOC1
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.1 %

Procedure:
2-[N-(5-Bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-5-carboxylic acid (example 7) (1.8 g, 5.1 mmol) in tetrahydrofuran (40 ml) treated with carbonyl diimidazole (1.8 g, 11 mmol) and heated at gentle reflux for 4 hours. The mixture was cooled and added to 0.88 aqueous ammonia solution (60 ml), stirred for 1 hour at ambient temperature and then evaporated to low bulk. The resultant white solid was diluted with ice/water, filtered, washed with cold water and air dried to give the title compound as a white solid (1.93 g, 100%).
Reaction SMILES: O=C1[NH:7]C=C(C2C=CC(C(O)=O)=CN=2)C=C1.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].Cl[C:25]1[C:30]2[CH:31]=[C:32]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([C:42]4[CH:43]=[CH:44][C:45]([C:48]5[CH:53]=[CH:52][C:51](=[O:54])[NH:50][CH:49]=5)=[N:46][CH:47]=4)=[O:41])[CH2:36][CH2:35]3)[NH:33][C:29]=2[CH:28]=[CH:27][N:26]=1>>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[NH2:7][C:25]1[C:30]2[CH:31]=[C:32]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([C:42]4[CH:43]=[CH:44][C:45]([C:48]5[CH:53]=[CH:52][C:51](=[O:54])[NH:50][CH:49]=5)=[N:46][CH:47]=4)=[O:41])[CH2:36][CH2:35]3)[NH:33][C:29]=2[CH:28]=[CH:27][N:26]=1
Reactant: O=C(O)c1ccc(-c2ccc(=O)[nH]c2)nc1
Reactant: O=C(c1ccc(-c2ccc(=O)[nH]c2)nc1)N1CCC(c2cc3c(Cl)nccc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc2[nH]c(C3CCN(C(=O)c4ccc(-c5ccc(=O)[nH]c5)nc4)CC3)cc12

Procedure:
The title compound is prepared as described in EXAMPLE 44, parts A and B, but with 6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-5-carboxylic acid, and 5-[4-(4-chloro-1H-pyrrolo[3,2-c]pyridin-2-yl)piperidine-1-carbonyl]-1′H-[2,3′]bipyridinyl-6′-one trifluoroacetate as starting materials, respectively. 1H NMR (d4-MeOH) δ 8.67-8.65 (m, 1H), 8.32 (dd, 1H), 8.25 (d, 1H), 7.92 (dd, 1H), 7.85 (dd, 1H), 7.40 (d, 1H), 6.94 (d, 1H), 6.68-6.63 (m, 2H), 4.85-4.70 (m, 1H), 3.99-3.82 (m, 1H), 3.42-3.03 (m, 3H), 2.24-2.06 (m, 2H), 1.88-1.68 (m, 2H). ESI MS (M+1)+: 415.
Reaction SMILES: C([Mg]Br)C.[CH:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].[CH2:13]=[O:14].CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)C>[CH3:12][C:6]1[CH:5]=[C:10]([OH:11])[C:9](=[CH:8][CH:7]=1)[CH:13]=[O:14]
Reactant: Cc1cccc(O)c1
Reactant: C=O
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
A 1M solution of ethylmagnesium bromide in tetrahydrofuran (100 ml) was cooled to 15° C., and a solution of 10.81 g (0.100 mole) of m-cresol was added during a 45 minute period while the temperature was held at 15° C. Upon completion of the addition, the mixture was stirred at room temperature for 30 minutes, and then a mixture of 7.5 g (0.25 mole) of paraformaldehyde and 17.92 g (0.100 mole) of hexamethylphosphoramide in 200 mL of toluene was added in one portion. The resulting solution was heated at 80° C. for approximately seventeen hours, after which the solvent was evaporated under reduced pressure, leaving a yellow residue. This residue was dissolved in diethyl ether, and this solution was extracted with 50 mL of hydrochloric acid and 100 mL of water. The organic phase was separated, washed with water, and dried over anhydrous magnesium sulfate. After filtration the solution was evaporated under reduced pressure, leaving an orange solid as a residue. This solid was placed on a silica gel column and eluted with methylene chloride/petroleum ether (50/50). Evaporation of the solvents yielded 6.30 g of 4-methylsalicylaldehyde as a yellow solid, m.p. 51°-53° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:14][CH2:13][C@H:12]1[C:21](O)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[C:15]2([CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[O:14][CH2:13][C@H:12]1[C:21](=[O:22])[NH:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1COC2(CCOCC2)N1C(=O)OCc1ccccc1
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CNC(=O)[C@@H]1COC2(CCOCC2)N1C(=O)OCc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-1,8-Dioxa-4-aza-spiro[4.5]decane-3,4-dicarboxylic acid 4-benzyl ester (1.05 gm, 3.27 mmol) was dissolved in DMF (10 mL) and the HCl salt of 2-amino-1-(4-bromo-phenyl)-ethanone (0.8 gm, 3.21 mmol) and HATU (1.34 gm, 3.5 mmol) were added, followed by diisopropylethyl amine (1.33 gm, 10.27 mmol). The mixture was stirred at room temperature for 3 hours, and then added dropwise into saturated aqueous NaHCO3 solution with stirring. The solid that crashed out was filtered and dried followed by redissolving (DCM) and filtration through a silica plug (eluting with ethyl acetate). This afforded 1.3 gm (78%) of the desired product as beige solid. LCMS: 519.2 (M+2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:16])[CH2:11][C:10]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.C(OC(N1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])=O)C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:16]3[C:26](=[O:27])[C:25]4[C:24](=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]3=[O:32])[CH2:11][C:10]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: NC1(c2ccc(Br)cc2)CC2(C1)OCCO2
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1C1(c2ccc(Br)cc2)CC2(C1)OCCO2
Temperature: 70 °C

Procedure:
To a solution of Compound [XXXV] (6.03 g, 21.2 mmol, 1.0 eq.) in CHCl3 (100 mL, anhydrous) was added N-ethoxycarbonylphthalimide (5.12 g, 23.3 mmol, 1.1 eq.) and triethylamine (11.8 mL, 84.9 mmol, 4.0 eq.). The mixture was then heated to 70° C. for 24 hours. The reaction was then cooled and concentrated. Methanol was added to the residue, and the mixture concentrated, then methanol was added again, and the resulting solid collected by filtration to provide Compound [XXXVI] as a light tan solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.30-3.39 (m, 2H) 3.44-3.53 (m, 2H) 3.89 (s, 4H) 7.42-7.49 (m, 2H) 7.50-7.58 (m, 2H) 7.69 (dd, J=5.34, 3.10 Hz, 2H) 7.78 (dd, J=5.54, 3.00 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].ClC(OCC)=O.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]1[O:35][CH3:36]>ClC(Cl)Cl>[NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:11])([CH3:12])[O:10][C:6]=2[C:5]([C:13]([NH:23][C@H:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][C@H:25]2[O:35][CH3:36])=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CC1(C)Cc2c(N)c(Cl)cc(C(=O)O)c2O1
Reactant: CCOC(=O)N1CCC(N)C(OC)C1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC[C@H](NC(=O)c2cc(Cl)c(N)c3c2OC(C)(C)C3)[C@H](OC)C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 8.1 parts of 4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylic acid in 218 parts of trichloromethane and 3.43 parts of N,N-diethylethamine were added dropwise 3.63 parts of ethyl chloroformate, keeping the temperature below 10° C. After stirring for 1/2 hour at 10° C., the whole was added to a solution of 6.26 parts of ethyl 4-amino-3-methoxy-1-piperidinecarboxylate in 145 parts of trichloromethane at 10° C. Stirring was continued for 1/2 hour at room temperature. The reaction mixture was washed with water, NaOH 5% and water and was then dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 12.3 parts (93.2%) of ethyl cis-4-[(4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl)carbonylamino ]-3-methoxy-1-piperidinecarboxylate (interm. 1).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[NH:30][CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1>>[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[NH:30][CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:34][CH:33]=1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(CNc2ncccn2)cc1
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CNc2ncccn2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 89 by reacting 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone with 4-(pyrimidin-2-ylaminomethyl)-aniline.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[NH:18][C:19]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21]([OH:23])=O.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[NH:18][C:19]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21]([NH:42][O:41][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:23]
Reactant: NOCc1ccccc1
Reactant: COc1cccc(Nc2cc(F)c(F)cc2C(=O)O)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: COc1cccc(Nc2cc(F)c(F)cc2C(=O)NOCc2ccccc2)c1
Yield: 105.7 %

Procedure:
Using General Method 2, the reaction of carbonyldiimidazole (2.90 g, 17.6 mmol), 2-(3-methoxy-anilino)-4,5-difluorobenzoic acid (Example Q, 4.48 g, 16 mmol), O-benzylhydroxylamine hydrochloride (2.6 g, 16 mmol), and triethylamine (2.5 mL, 17.6 mmol) provided 6.5 g of the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]=1[N+:25]([O-:27])=[O:26].[CH:28]1([CH:31]([NH2:34])[CH2:32][CH3:33])[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:34][CH:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][CH3:33])[C:12]=1[N+:25]([O-:27])=[O:26]
Reactant: CCC(N)C1CC1
Reactant: COc1cc(Cl)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1C
Product: CCC(Nc1nccc(-c2cc(C)c(OC)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 47 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-5-methyl-phenyl)-3-nitro-pyridin-2-yl ester (0.22 g, 0.51 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclopropyl-propylamine (0.17 g, 1.29 mmol) were treated substantially as described in Part C of Example 19a to produce 90 mg (47%) of crude [4-(2-chloro-4-methoxy-5-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine: MS (EI) m/z 376.18 [(M+H)+, 100].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][C:12]=2[C:13]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:28][Mg]Br.S(=O)(=O)(O)O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[CH:25]=[CH:24][C:23]([CH:26]([OH:27])[CH3:28])=[CH:22][C:12]=2[C:13]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2cccnc2)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(O)c1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-{[(3,4-difluorophenyl)methyl]oxy}-5-formyl-N-3-pyridinylbenzamide (may be prepared as described in Example 80; 100 mg, 0.27 mmol) in tetrahydrofuran (5 ml) was cooled to 0° C. and methylmagnesium bromide (0.18 ml, 0.54 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. An additional 3 eq of methylmagnesium bromide was added and the mixture was stirred at room temperature. 5 ml of 1M aqueous sulphuric acid was then added. After stirring for 30 min the mixture was extracted with ethyl acetate (3×10 ml). The organics were combined, evaporated under reduced pressure and the residue was purified by MDAP to yield the title compound. 48 mg.
Reaction SMILES: O[CH2:2][CH:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[C:17]4[CH:30]=[CH:29][S:28][C:18]=4[C:19](=[O:27])[NH:20][C:21]=3[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Cl:57])C(=O)C1>CN(C=O)C.C(Cl)(Cl)(Cl)Cl.O>[Cl:57][CH2:2][CH:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[C:17]4[CH:30]=[CH:29][S:28][C:18]=4[C:19](=[O:27])[NH:20][C:21]=3[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NC(C)CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NC(C)CCl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
To a mixture of N-(1-hydroxypropan-2-yl)-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzenesulfonamide (140 mg, 0.30 mmol) and triphenylphosphine (160 mg, 0.62 mmol) in DMF/CCl4 (1 mL/3 mL) was added NCS (41 mg, 0.31 mmol) and the reaction mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with water (ca. 20 mL), and extracted with DCM (1×50 mL). The extract was washed with water (2×20 mL), brine (1×10 mL), dried over sodium sulfate, and evaporated under vacuum. The residue was purified by flash chromatography to afford the desired product (100 mg, 74%) as light yellow solid; ESI MS m/z 464 [C21H19ClN2O4S+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>CS(C)=O.[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(Cl)ccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: C[Si](C)(C)C#Cc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 56.5 %

Procedure:
To a solution of 4-chloro-2-fluoro-1-iodobenzene (2.0 g, 7.8 mmol) in DMSO (10 mL) was added ethynyl(trimethyl)silane (1.14 g, 11.0 mmol), copper iodide (0.029 g, 0.15 mmol), bis(triphenylphosphine) palladium(II) chloride (0.218 g, 0.3 mmol) and TEA (1 mL). The reaction mass was stirred at RT for 4-5 h. The reaction mass quenched in water, passed through celite bed and extracted with ethyl acetate and concentrated to afford 1.0 g of desired product.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:15]([OH:17])=O)[C:11]([C:12](O)=[O:13])=[C:6]2[CH:5]=[N:4]1)[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)[N:37]=[N:36]C=2C=1.C(N(CC)CC)C.NN>C1COCC1.O>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:17])[NH:36][NH:37][C:12](=[O:13])[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCn1ncc2c(C(=O)O)c(C(=O)O)cnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1ncc2c3c(=O)[nH][nH]c(=O)c3cnc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
An alternative method could be used by starting with 1-ethyl-1H-pyrazolo[3,4-b]pyridine-4,5-dicarboxylic acid. The diacid was dissolved in anhydrous THF with EDAC.HCl (1.2 eq), HOBT (1.2 eq), and triethylamine (5.0 eq). To this solution was added anhydrous hydrazine (2.0 eq). The resulting solution was stirred at rt for 5 h and then diluted with water. The precipitated solid was collected by filtration to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12]C)=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25]Cl.O>CN(C=O)C.CCOC(C)=O>[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][O:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Fc1ccc(CCl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)C[C@@H]1COc2cc(OCc3ccc(F)cc3F)ccc21
Temperature: 55 °C
Reaction time: 15 h
Yield: 34.4 %

Procedure:
To a stirred mixture of methyl(3S)-(2,3-dihydro-6-hydroxy-1-benzofuran-3-yl)acetate (20.8 mg) and K2CO3 (20.7 mg) in DMF (0.5 mL) was added 2,4-difluorobenzyl chloride (24.4 mg) at room temperature. After stirring at 55° C. for 15 h, water (2.0 mL) and EtOAc (3.0 mL) were added to the mixture with stirring. The organic layer was separated by phase separation filter kit, and the filtrate was evaporated by blowing away with the air at 60° C. The resulting residue was dissolved in MeOH (0.5 mL) and 1N LiOH (0.3 mL), and the mixture was stirred at room temperature for 1 h. To the mixture was added 1N HCl (0.2 mL) and the solution was evaporated by blowing away with the air at 60° C. The resulting residue was dissolved in DMSO (1.0 mL) and the solution was purified by preparative HPLC (C18, eluent: water/CH3CN (including 5 mM AcONH4)). The eluted fraction was evaporated by air blowing at 60° C. to give the title compound (11.0 mg, 34.4%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH:14]=[O:15])[CH3:2].[Li+].[BH4-]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH2:14][OH:15])[CH3:2]
Reactant: CCOc1ccc(C(=O)OC)cc1C=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1ccc(C(=O)OC)cc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A suspension of methyl 3-formyl-4-hydroxy-benzoate (3.0 g, 16.7 mmol), bromoethane (2.7 g, 1.85 mL, 24.9 mmol) and powdered K2CO3 (6.9 g, 49.9 mmol) in DMF (15 mL) was heated at 40° C. for 16 hours. After 16 hours, a further aliquot of bromoethane (1 mL) was added and the reaction mixture was heated for a further 2 hours. The reaction mixture was diluted with DCM (50 mL), filtered and concentrated in vacuo to give a yellow solid, which was diluted with ether (200 mL), washed sequentially with water (50 mL), sat. aq. NaHCO3 (50 mL) and brine solution (50 mL). The organics were separated, dried over MgSO4 and concentrated in vacuo to give methyl 4-ethoxy-3-formylbenzoate (3.52 g, 100%) as a white solid. ESI-MS m/z calc. 208.0. found 209.3 (M+1)+; Retention time: 1.34 minutes (3 min run). Methyl 4-ethoxy-3-formylbenzoate (1.73 g, 8.91 mmol) was dissolved in THF (20 mL) and cooled to 0° C. LiBH4 (100 mg, 4.59 mmol) was added and the reaction mixture was stirred for 1 hour, then slowly quenched with dropwise addition of acetic acid. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL), washed sequentially with sat. aq. NaHCO3 (20 mL) and brine (20 mL). The organics were separated, dried over MgSO4 and purified by silica gel column chromatography using 0-100% EtOAc/DCM as eluent to give methyl 4-ethoxy-3-(hydroxymethyl)benzoate (1.6 g, 46%) as a white solid. ESI-MS m/z calc. 210.0. found 211.3 (M+1)+; Retention time: 1.11 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 8.05-7.86 (m, 2H), 6.99-6.79 (m, 1H), 4.72 (s, 2H), 4.16 (q, J=7.0 Hz, 2H), 3.89 (s, 3H), 1.64 (d, J=7.0 Hz, 2H), 1.47 (t, J=7.0 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.[NH2:14]O.[Al]>[OH-].[Na+].[Ni]>[NH2:14][CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:8][CH2:9]1
Reactant: NO
Reactant: O=C1CCN(Cc2cccs2)CC1
Agent: [Ni]
Agent: [Al]
Agent: [Na+]
Product: NC1CCN(Cc2cccs2)CC1

Procedure:
N-(2-Thienylmethyl)-4-piperidone is reacted with hydroxylamine, followed by nickel, aluminium alloy in 30% sodium hydroxide solution, in a similar manner to that described in Example 19 to give 4-amino-N-(2-thienylmethyl)piperidine.