Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][CH:9]([O:16][CH3:17])[CH:10]([CH3:15])/[C:11](/[F:14])=[CH:12]\[OH:13]>[O-2].[O-2].[O-2].[Cr+6].C(Cl)Cl>[CH3:7][O:8][CH:9]([O:16][CH3:17])/[C:10](/[CH3:15])=[C:11](/[F:14])\[CH:12]=[O:13]
Reactant: COC(OC)C(C)/C(F)=C\O
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(OC)/C(C)=C(/F)C=O
Reaction time: 2 h

Procedure:
Chromium trioxide (145 g., 1.45 mol) was added to 5 l. of methylene chloride in a 12 l. round bottomed flask fitted with argon inlet and mechanical stirrer. Pyridine (230 ml., 2.9 mol) was added and the mixture was stirred for 2 hours. Celite (290 g.) was added and then E-4,4-dimethoxy-2-fluoro-3-methyl-buten-1-ol was added in one portion and stirred for 30 minutes. The mixture was filtered, evaporated at 30° C. to ≈5% of its volume and diluted with 500 ml. of ether. This mixture was filtered and evaporated to ≈100 ml. at 30° C. The resulting E-4,4-dimethoxy-2-fluoro-3-methyl-buten-1-al was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:34]CCl>C(O)C>[ClH:34].[F:30][C:26]1[CH:25]=[C:24](/[C:16](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:15]/[O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(/c2cccc(F)c2)c2ccccc2C)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1/C(=C\OCCN1CCC[C@@H](C(=O)O)C1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 24 %

Procedure:
E or Z-(R)-1-[2-[[2-(3-Fluorophenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (0.40 g, 0.00097 mol) (prepared as described in Method A) was dissolved in ethanol (5 ml) and 12N sodium hydroxide solution (0.3 ml) was introduced. After stirring the solution at room temperature for 5 h, 37% hydrochloric acid solution was added until the pH was measured as ca. 1. Dichloromethane (250 ml) was introduced, and the resultant precipitate was dissolved by addition of ice portionwise with vigorous stirring. The organic phase was separated, dried (Na2SO4) and evaporated to a residue, which was co-evaporated with acetone. Recrystallization from acetone provided the title compound (0.10 g, 24%) as a white solid, m.p. 193°-195°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=1.[OH-:13].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[NH:3][C:4](=[O:13])[C:5]2[S:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: Cc1cc2nc(Cl)nc(Cl)c2s1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2nc(Cl)[nH]c(=O)c2s1
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine (450 mg, 2.05 mmol), aqueous NaOH (1N, 4 mL) and THF (4 mL) was stirred at room temperature under N2. The reaction was monitored by HPLC until the reaction was completed. Then the mixture was neutralized to PH 5 by addition of 2N aqueous HCl. The solid was filtrated and dried to give 380 mg of 2-chloro-6-methylthieno[3,2-d]pyrimidin-4(3H)-one (yield was 92%) as a yellow solid. MS obsd. (ESI+) [(M+H)+]: 201.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH2:33])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCCCCCN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and hexane-1,6-diamine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (dd, J=1.2, 0.8 Hz, 1 H), 7.97 (s, 1 H), 7.92 (d, J=7.6 Hz, 1 H), 7.80 (d, J=8.8 Hz, 1 H), 7.70 (d, J=1.2 Hz, 1 H), 7.57 (dd, J=7.20, 1.6 Hz, 2 H), 5.91 (s, 1 H), 5.32 (s, 2 H), 4.52 (brs, 2 H), 3.75 (d, J=4.80 Hz, 2 H), 3.31 (d, J=1.60 Hz, 2 H), 2.94 (m, 2 H), 2.45 (s, 3 H), 1.72 (m, 4 H), 1.50 (m, 4 H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([OH:25])=O)[CH:13]=2)[CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:25])[CH:13]=2)[CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)O)cc2n1C
Product: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)N3CCN(C)CC3)cc2n1C
Yield: 34 %

Procedure:
The title compound was prepared as a white solid in 34% yield (30 mg) from 4-(3,4-dihydro-2H-chromen-4-yloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (70 mg, 0.21 mmol, STEP 2 of Example 11) and 1-methylpiperazine (41 mg, 0.42 mmol) by the same manner in STEP 3 of Example 11:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[C:5]([NH:11][C:12](=O)[CH3:13])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.O.Cl.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[CH2:12]([NH:11][C:5]1[CH:4]=[C:3]([N:2]([CH3:15])[CH3:1])[CH:8]=[CH:7][C:6]=1[O:9][CH3:10])[CH3:13]
Reactant: COc1ccc(N(C)C)cc1NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCNc1cc(N(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
N-(3-dimethylamino-6-methoxyphenyl)acetamide 26 (0.10 gm, 0.48 mmoles) was dissolved in 2 ml THF and stirred under argon at room temperature. Borane-methylsulfide complex (0.6 ml, 2.0M, 1.2 mmoles) was added by syringe. After 10 minutes at ambient temperature, the mixture was heated to reflux for 3 hours. After cooling to room temperature, 0.6 ml water was cautiously added with stirring 0.1 ml conc. HCl. After heating for 1 hour, 5 ml DCM and 0.3 ml 2N NaOH were added sequentially with vigorous stirring. The aqueous portion was extracted with three 30 ml portions of DCM which were combined, dried over MgSO4, filtered, and concentrated by rotary evaporation under reduced pressure to give 95 mg of crude [3-(ethylamino)-4-methoxyphenyl]dimethylamine 27.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([NH:11]CC2C=CC=CC=2)[C:8]2[NH:19][C:20](=[O:29])[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:7]=2[CH:6]=1)=[O:4].O>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([NH2:11])[C:8]2[NH:19][C:20](=[O:29])[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c([nH]c(=O)n2Cc2ccccc2)c(NCc2ccccc2)n1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc2c([nH]c(=O)n2Cc2ccccc2)c(N)n1
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
1-Benzyl-4-benzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid methyl ester (0.02 g) was taken up in sulfuric acid (2 mL), and stirred rapidly for 15 mins. The reaction mixture was cooled to 0C, and water was added, which resulted in a precipitate which was filtered and dried in vacuo to give the title compound (10 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][CH:26]=2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:28])[C:18](=[O:27])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:29].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[Br:29])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:28])[C:18](=[O:27])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [Br-]
Reactant: CC1C(=O)NN=C2COc3ccc(OC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(Br)c(OC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of 3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.234 g, 0.603 mmol) in DCM (4 mL) and MeOH (2 mL) was added tetrabutylammonium tribromide (0.291 g, 0.603 mmol) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 30% EtOAc in petroleum ether) to give 3-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.267 g, 95%). LC/MS (Table 1, Method 2) Rt=1.217 min.; MS m/z: 467/469 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:54]1[CH:59]=[C:58](B(O)O)[CH:57]=[N:56][CH:55]=1>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[C:15]([C:58]4[CH:59]=[N:54][CH:55]=[N:56][CH:57]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1cncnc1
Reactant: O=C1C(Br)=C(c2ccc(F)cc2)c2ccc(OCCN3CCOCC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2cncnc2)=C(c2ccc(F)cc2)c2ccc(OCCN3CCOCC3)cc21
Yield: 96 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(4-fluorophenyl)-1H-inden-1-one obtained in Step 6 of Example 24 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 5-pyrimidinylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (acetone/hexanes=1:1) to obtain the title compound (96%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]([OH:27])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@@H:13]2[CH2:25]O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[H-].[Na+].S(N1C=CN=C1)(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]2[O:27][CH2:25][C@H:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc(F)c(C#N)c2)[C@@H](CO)C1
Agent: Cc1ccc(S(=O)(=O)n2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2CC(c3ccc(F)c(C#N)c3)OC[C@H]2C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of tert-butyl (3R)-4-[2-(3-cyano-4-fluorophenyl)-2-hydroxyethyl]-3-(hydroxymethyl)piperazine-1-carboxylate (5.0 g, 13.2 mmol) in 100 mL of THF was stirred at 0° C. for 10 min, and then NaH (60%) (1.32 g, 33.0 mmol) was added at 0° C. The resulting white suspension was stirred vigorously at 0° C. for 5 min, then at r.t for 1 h. The reaction suspension was then recooled to 0° C., N-Tosylimidazole was added and the resulting solution was stirred for a further 10 min at 0° C. before being warmed again to r.t and stirred for 1 h. The reaction solution was then cooled once more to 0° C., and excess sodium hydride was carefully quenched by the slow addition of sat. NH4Cl solution. The resulting biphasic solution was partitioned between sat. NH4Cl and EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified with silica gel column chromatography to give the title compound: 1H-NMR (300 MHz, CDCl3) δ 7.76˜7.79 (m, 1H), 7.49˜7.58 (m, 1H), 7.11˜7.15 (m, 1H), 7.16˜7.12 (m, 1H), 3.86˜4.06 (m, 2H), 3.33˜3.48 (m, 1H), 3.08˜3.17 (m, 1H), 2.80˜2.94 (m, 2H), 2.64˜2.74 (m, 2H), 2.29˜2.46 (m, 2H), 2.09˜2.20 (m, 1H), 1.40 (d, J=3.0 Hz, 9H);
Reaction SMILES: Br.[Br:2][CH2:3][C:4]([C:6]1[N:13]2[C:9]([S:10][CH:11]=[CH:12]2)=[N:8][C:7]=1[CH3:14])=O.[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH2:27])=[S:26])=[CH:20][CH:19]=1)[CH3:16]>C(O)C>[BrH:2].[O:17]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]2[S:26][CH:3]=[C:4]([C:6]3[N:13]4[C:9]([S:10][CH:11]=[CH:12]4)=[N:8][C:7]=3[CH3:14])[N:27]=2)=[CH:20][CH:19]=1)[CH2:15][CH3:16]
Reactant: Cc1nc2sccn2c1C(=O)CBr
Reactant: CCOc1ccc(NC(N)=S)cc1
Agent: Br
Solvent: CCO
Product: CCOc1ccc(Nc2nc(-c3c(C)nc4sccn34)cs2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2-bromo-1-(6-methylimidazo[2,1-b]thiazol-5-yl)ethanone hydrobromide (18) (2.20 g, 6.5 mmol) and (p-ethoxyphenyl)thiourea (10) (1.30 g, 6.5 mmol) in 40 mL of anhydrous ethanol was refluxed under stirring for 20 h, and then cooled to room temperature. The solid was filtered. The crude white solid product was re-crystallized from methanol. The methanol solution was filtered while still hot to remove possible dust, and then heated into solution. It was re-crystallized two more times from methanol, and dried under vacuum to provide the desired product 20 as a white solid, yield 0.64 g (22.4%), HPLC purity 97.81%, mp >240° C. 1HNMR (CD3OD) δ 1.27 (t, 3H, J=6.8 Hz), 2.56 (s, 3H), 3.88-3.94 (m, 2H), 6.85 (d, 2H, J=8.8 Hz), 6.97 (s, 1H), 7.34 (d, 2H, J=8.8 Hz), 7.54 (d, 1H, J=4.4 Hz), 8.44 (d, 1H, J=4.4 Hz). ESI-MS m/z 357 (M+1)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:14]3[C:15](=[C:17]4[C:22](=[N:23][C:13]=3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]2[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18]4)[CH:16]=1.C1C=CC=CC=1.CO.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:14]3[C:15](=[C:17]4[C:22](=[N:23][C:13]=3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]2[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18]4)[CH:16]=1
Reactant: COc1cc2c3c(nc4ccccc4c3c1)-c1ccccc1N2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1c2ccccc2-c2nc3ccccc3c3cc(O)cc1c23
Yield: 99.7 %

Procedure:
The general procedure (Method K, described below) applied to 6-methoxy-8-methyl-8H-quino[4,3,2-kl]acridine, 31 (400 mg, 1.28 mmol), dry benzene (100 ml) aluminium chloride (900 mg), methanol (100 ml), sat. aq. sodium hydrogen carbonate (40 ml), and ethyl acetate (100 ml) gave the title compound (381 mg, 1.27 mmol, 99.7%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:15])([O-:11])=[O:10]
Reactant: Nc1ccccc1F
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: O=C(Nc1ccccc1F)c1ccccc1[N+](=O)[O-]
Yield: 70.2 %

Procedure:
Using the procedure described in Example 93, Part A, 2-fluoroaniline (20.7 mmol) and 2-nitrobenzoyl chloride (22.8 mmol) yielded 3.78 g (70%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[C@@H:17]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:16][NH:26][C@@H:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Reactant: N[C@H]1CCc2ccccc21
Solvent: CN1CCCC1=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CN[C@H]1CCc2ccccc21
Temperature: 85 °C

Procedure:
5-(4-Bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole (0.180 g, 0.64 mmol) and (S)-indan-1-ylamine (0.171 g, 1.29 mmol) were mixed in N-methylpyrrolidone (4.0 mL) and then heated to 85° C. over 2 nights while monitoring with analytical LCMS. The reaction was submitted to standard aqueous workup then purified via preparatory HPLC to afford the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:26]([O-])=O)[C:18]([NH:19][CH:20]4[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[NH2:26][C:17]1[C:18]([NH:19][CH:20]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCC(O)C1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCC(O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a solution of 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentanol (2.6 g, 6.47 mmol) in ethanol (100 mL) was added palladium on carbon (10%, 1 g), then the reaction mixture was stirred at room temperature under hydrogen (45 psi) for 3 hours. The resulting mixture was concentrated under reduce pressure to give 1.7 g (83%) of 3-(5-Amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentanol. 1H NMR (400 MHz, CDCl3): 8.12-8.05 (s, 1H), 7.74 (s, 1H), 7.52-7.32 (m, 5H), 6.64-6.53 (m, 1H), 4.43-4.40 (s, 1H), 4.30-4.29 (m, 1H), 2.94-2.84 (m, 3H), 2.02-1.90 (m, 1H), 1.90-1.73 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]2[CH:9]([OH:16])[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25].O>O1CCCC1>[Si:28]([O:1][CH2:2][C:3]1[C:8]2[CH:9]([OH:16])[CH2:10][CH2:11][C:12]([CH3:14])([CH3:15])[CH2:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30]
Reactant: CC1(C)CCC(O)c2c(CO)cccc2C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)CCC(O)c2c(CO[Si](C)(C)C(C)(C)C)cccc2C1
Reaction time: 8 h

Procedure:
To a solution of 4-(hydroxymethyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol (18.87 g, 85.65 mmol), 4-N,N-dimethylaminopyridine (0.5 g) and triethylamine (14.3 ml, 103 mmol) in tetrahydrofuran (100 ml) was added tert-butyldimethylchlorosilane (14.2 g, 94.2 mmol) at room temperature, and the mixture was stirred as it was overnight. The reaction solution was poured into water, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1-9/1) to give the objective substance.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][OH:16].O>N1C=CC=CC=1>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH:12]=[N:15][OH:16])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=Cc1coc(-c2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: ON=Cc1coc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a solution of 2-phenyloxazole-4-carboxaldehyde (2.18 g, 12.5 mmol) in pyridine (25 ml) was added hydroxylamine hydrochloride (0.96 g, 13.8 mmol) under stirring at room temperature. After 1 hour the mixture was poured into water (200 ml) and the resulting solids were collected, washed with water and dried under vacuum. 2.02 g (10.8 mmol) of the titled compound was obtained: mp 145°-147° C.; IR (KBr) 3195, 3075, 3035, 2850, 1646, 1555, 1486, 1445, 1431 cm-1 ; 1H NMR (270 MHz, CDCl3) d 8.87 (brs,1H), 8.51 (s,1H), 8.09-8.05 (m,2H), 7.68 (sy,1H), 7.52-7.47 (m,3H).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[Cl:9][C:10]1[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=1>C(O)C>[Cl:9][C:10]1[C:11]([C:18]([F:21])([F:19])[F:20])=[CH:12][C:13]([C:16]([NH2:17])=[O:2])=[N:14][CH:15]=1
Reactant: N#Cc1cc(C(F)(F)F)c(Cl)cn1
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(C(F)(F)F)c(Cl)cn1
Reaction time: 5 h
Yield: 74.6 %

Procedure:
To 7 ml of ethanol were added 0.61 g of sodium bicarbonate and 0.5 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.74 g of 5-chloro-4-trifluoromethylpyridine-2-carbonitrile was added at 0° C., and the mixture was stirred for 5 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.6 g of 5-chloro-4-trifluoromethylpyridine-2-carboxamide=oxime.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C[Si]([N-:45][Si](C)(C)C)(C)C.[Li+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[CH3:15][N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([NH2:45])=[N:7][CH:6]=2)[CH2:10][CH2:11]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN1CCN(Cc2ccc(Cl)nc2)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(N)nc2)CC1
Temperature: 100 °C
Yield: 37 %

Procedure:
To 1-((6-chloropyridin-3-yl)methyl)-4-methylpiperazine (6.79 g, 30.1 mmol, Eq: 1.00), 2-(dicyclohexylphosphino)biphenyl (2.11 g, 6.02 mmol, Eq: 0.20) and tris(dibenzylideneacetone)dipalladium (0) (2.75 g, 3.01 mmol, Eq: 0.10) in a sealed tube was added THF (75 ml). The solution was placed under nitrogen. Lithium bis(trimethylsilyl)amide (75.2 ml, 75.2 mmol, Eq: 2.50) was added. The solution was degassed with argon and the tube was sealed and heated at 100° C. for 18 h. The solution was filtered through Celite™. The solvent was evaporated under reduced pressure. The residue was taken up in DCM. HCl (1N, 10 ml) was added slowly to adjust to pH=1 by adding 6 N HCl and water (as needed). The layers were separated. The organic layer was extracted once with water. The aqueous layers were combined and were brought to pH 10 by a slow addition of solid NaOH. Dichloromethane was added. The layers were separated. The aqueous layer was extracted three times with DCM. The organic layers were combined and dried over Na2SO4. The solvent was evaporated. The residue was triturated with Et2O. The solid was collected by filtration and dried to give 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (2.3 g, 37%). LC/MS-ESI observed [M+H]+ 207.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](ON2C(=O)CCC2=O)=[O:31])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([O:12][C:10](=[O:11])[C:9]1[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:31])[NH:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])[CH:19]=[C:7]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:40])[CH:8]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1
Reactant: NCCCC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)NCCCC(=O)O)cc(C(=O)OC(C)(C)C)c1
Reaction time: 48 h

Procedure:
5-[9-(2,5-Dioxo-pyrrolidin-1-yloxycarbonyl)-nonyloxy]-isophthalic acid di-tert-butyl ester (100 mg, 0.18 mmol) was dissolved in dry DMF (2 ml). 4-Aminobutyric acid (GABA, 23 mg, 0.2 mmol) and DIPEA (0.05 ml) was added. The mixture was stirred under nitrogen for 2 days. The mixture was concentrated. The residue was dissolved in EtOAc and washed with 0.1 N HCl (2×) and brine (1×), dried (Na2SO4) and concentrated to give a clear syrup.