Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:36].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C@@H:17]([OH:36])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: COc1cc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc(OC)c1OC
Reactant: [OH-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc(OC)c1OC

Procedure:
In analogy with Example 44d), 1.097 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(3,4,5-trimethoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 36.48 ml of dimethoxyethane and 18.39 ml of water are hydrolysed with 9.03 ml of 1M lithium hydroxide solution to give the title compound, which is subjected, without purification, to further processing.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2-].[Li+].[SH:21][CH2:22][CH2:23][C:24](OC)=[O:25]>C1(C)C=CC=CC=1>[SH:21][CH2:22][CH2:23][C:24]([O:16][CH:11]1[CH2:10][C:9]([CH3:18])([CH3:17])[N:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:13]([CH3:14])([CH3:15])[CH2:12]1)=[O:25]
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Reactant: COC(=O)CCS
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: CC1(C)CC(OC(=O)CCS)CC(C)(C)N1OC1CCCCC1

Procedure:
The general procedure of Example 1 is followed using 2.00 grams (7.8 mmol) of 1-cyclohexyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, 0.18 gram of lithium amide and 0.94 gram (7.8 mmol) of methyl 3-mercaptopropionate in 50 ml of toluene to afford the title compound after purification by silical gel chromatography.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:12]([C:13](Cl)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH2:23][C:24]1[O:25][CH:26]=[CH:27][N:28]=1.C(N(CC)CC)C>C(OCC)(=O)C>[F:1][C:2]([F:22])([F:21])[C:3]1[C:12]([C:13]([NH:23][C:24]2[O:25][CH:26]=[CH:27][N:28]=2)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Reactant: Nc1ncco1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ncco1)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A solution of 15.9 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid chloride in 210 ml of ethyl acetate was added with stirring at 5°-8° C. under nitrogen to a solution of 3.57 g of 2-amino-oxazole and 4.3 g of triethylamine in 50 ml of ethyl acetate and after the temperature returned to room temperature, it stood overnight at that temperature. The mixture was vacuum filtered and the filtrate was washed and evaporated to dryness under reduced pressure. The 14.23 g of residue was triturated with 100 ml of N sodium hydroxide solution for 3 hours and was then diluted with 200 ml of water. The mixture was vacuum filtered and the filtrate was treated with activated carbon. The pH was adjusted to 1 by addition of N hydrochloric acid and the mixture was vacuum filtered. The recovered product was washed with water and dissolved in ethyl acetate. The solution was evaporated to dryness and the 8.77 g of product were crystallized twice from acetic acid to obtain 5.73 g (30.8% yield) of 2,8-bis-(trifluoromethyl)-4-hydroxy-N-(oxazol-2-yl)-3-quinoline-carboxamide melting at 258° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=2[C:11]([NH:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=[O:20])=[O:12])=[CH:3][CH:2]=1.[NH:29]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]1>>[OH:34][CH:31]1[CH2:32][CH2:33][N:29]([C:19]([C:18]2[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=2)[CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=2[NH:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[O:20])[CH2:30]1
Reactant: OC1CCNC1
Reactant: O=C(O)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1
Product: O=C(NOCc1cccc(C(=O)N2CCC(O)C2)c1)c1ccccc1NCc1ccncc1

Procedure:
Prepared by a similar procedure as described for preparation of example 405. Starting materials: 3-{2-[(Pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid (see example 403) and 3-pyrrolidinol (Aldrich).
Reaction SMILES: C1COCC1.Cl[CH2:7][C:8]([Si:12]([O:17][CH3:18])([O:15][CH3:16])[O:13][CH3:14])=[CH:9][CH2:10]Cl>[Zn].CCCCC>[CH3:14][O:13][Si:12]([O:15][CH3:16])([O:17][CH3:18])[C:8]([CH:9]=[CH2:10])=[CH2:7]
Reactant: CO[Si](OC)(OC)C(=CCCl)CCl
Agent: [Zn]
Solvent: CCCCC
Solvent: C1CCOC1
Product: C=CC(=C)[Si](OC)(OC)OC
Temperature: 25 °C
Yield: 70 %

Procedure:
Four grams (41×1.5 mmols) of Zn powder and 15 ml of THF were added, under agitation, to 10 g (41 mmols) of the 1,4-dichloro-2-(trimethoxy)silyl-2-butene obtained by the above procedure. The mixed solution was heated and refluxed for 1 hour and then cooled down to room temperature, followed by adding 30 ml of dried pentane. The resulting ZnCl2 was removed by filtration and the solvent was distilled off under reduced pressure, followed by vacuum distillation to obtain 5.0 g of 2-(trimethoxy) silyl-1,3-butadiene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:43][C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=32)=[CH:4][CH:3]=1
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Cl)cc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 564.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12](SC)=[NH:13])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:16]([NH:18][NH2:19])=O>C(O)C>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:19][N:18]=[CH:16][N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NNC=O
Reactant: CCCCCNc1nc[nH]c1C(=N)SC
Solvent: CCO
Product: CCCCCNc1nc[nH]c1-c1ncn[nH]1

Procedure:
A mixture of methyl 4-(pentylamino)-1H-imidazole-5-carbimidothioate (0.53 g, 2.4 mmol) and formic hydrazide (0.21 g, 3.5 mmol) in ethanol (10 mL) was refluxed overnight. The reaction mixture was concentrated under reduced pressure to yield the desired product as a slightly green viscose oil. LCMS calculated for C10H17N6 (M+H): 221.2; found: 221.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH:13]([Mg]Br)=[CH2:14].[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH:13]=[CH2:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a solution of 3,4-dimethoxybenzaldehyde (5.30 g, 31.9 mmol) in THF (50 mL) was added dropwise under a nitrogen atmosphere at 0° C. over a period of 30 min vinylmagnesium bromide (1 M in THF, 32 mL, 32 mmol) and stirred for 2 h at 0° C. followed by 1 h at ambient temperature. Further vinylmagnesium bromide (1 M in THF, 32 mL, 32 mmol) was added at 0° C. and the solution was stirred for 1 h at this temperature. The reaction mixture was added onto a mixture of ice (50 g) and aqueous ammonium chloride (saturated, 50 mL). The mixture was extracted with tert-butylmethylether and the organic layers were washed with water (50 mL) and brine (50 mL). Drying over sodium sulfate und purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (5.18 g, 84%) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3]1.[ClH:10].[NH2:11]O>[Ni].CO>[ClH:10].[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([NH2:11])[CH2:3]1
Reactant: NO
Reactant: CC1(C)CCCC(=O)C1
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: CC1(C)CCCC(N)C1
Temperature: 60 °C

Procedure:
A 100 mL RBF was charged with 3,3-dimethylcyclohexanone (3.48 g, 27.6 mmol), hydroxylamine hydrochloride (2.01 g, 29.0 mmol), and 20 mL of MeOH. This mixture was heated to 60° C. for 1 h. To this solution was added Raney Nickel (approx 300 mg). This mixture was placed under a hydrogen atmosphere (1 atm) and heating was continued (60° C.) for 12 h. After that time, the solution was filtered, acidified with 1M HCl, and concentrated to give 3,3-dimethylcyclohexanamine HCl as an off-white solid. Step 2: A 20 mL vial was charged with (R)-3-(2-(tert-butylamino)-6-o-tolylquinolin-3-yl)-2-methylpropanoic acid (0.13 g, 0.33 mmol, prepared as in Example 8, Step 3-6), 3,3-dimethylcyclohexanaminium chloride (0.068 g, 0.42 mmol), TBTU (0.13 g, 0.42 mmol), and 2 mL of NMP. To this was added Hünig's base (0.11 g, 0.83 mmol). After stirring at RT for 2 h, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried and concentrated to give an oil, which was purified via silica gel column chromatography to give the t-Bu protected amide intermediate. To this material, was added 3 mL of TFA and 3 mL of DCM. This mixture was heated at 40° C. for 12 h, then concentrated and purified by silica gel column chromatography (0-8% NH3/MeOH in CH2Cl2) to give (2R)-3-(2-amino-6-o-tolylquinolin-3-yl)-N-(3,3-dimethylcyclohexyl)-2-methylpropanamide as a white solid. MS (ESI, pos. ion) m/z: 430 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:24]3[C:19](=[C:20]([F:26])[CH:21]=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C1(C)C=CC=CC=1>[N:8]1([C:5]2[C:4]([NH:14][C:15]3[C:24]4[C:19](=[C:20]([F:26])[CH:21]=[CH:22][C:23]=4[F:25])[N:18]=[C:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[C:16]=3[CH3:33])=[CH:3][C:2]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:7][N:6]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Cc1c(-c2ccccn2)nc2c(F)ccc(F)c2c1Nc1cc(Br)cnc1N1CCOCC1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(F)ccc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure H using N-(5-bromo-2-morpholinopyridin-3-yl)-5,8-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (40.0 mg, 0.131 mmol) and morpholine in toluene to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-5,8-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 8.68 (1H, d, J=3.9 Hz), 8.00 (1H, d, J=7.8 Hz), 7.78-7.96 (2H, m), 7.63 (1H, d, J=2.3 Hz), 7.34-7.44 (1H, m), 7.28-7.34 (1H, m), 7.11 (1H, ddd, J=12.8, 8.7, 3.9 Hz), 6.47 (1H, d, J=2.3 Hz), 3.87-4.01 (4H, m), 3.76-3.87 (4H, m), 3.15-3.49 (4H, m), 2.98-3.13 (4H, m), 2.26 (3H, s). Mass Spectrum (ESI) m/e=519.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.ON1C2C=CC=CC=2N=N1.[NH:61]1[CH2:65][CH2:64][CH2:63][CH2:62]1>C1COCC1>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([N:61]1[CH2:65][CH2:64][CH2:63][CH2:62]1)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Reactant: C1CCNC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)N6CCCC6)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 2.8 %

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (56 mg, 0.082 mmol) in THF (2 mL) was added polystyrene carbodiimide (0.15 mg, 0.17 mmol) and 1-hydroxybenzotriazole hydrate (22 mg, 0.16 mmol), and then the reaction mixture was stirred at room temperature under nitrogen. After 15 min, pyrrolidine (11 mg, 0.16 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen. After 5 h, the reaction mixture was filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic). The resulting product was lyophilized from acetonitrile (3 mL) and water (1 mL) to give (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-2-(pyrrolidine-1-carbonyl)-6,6a-dihydrobenzo[a]tetracene-7,9,12,14(5H,14aH)-tetraone (1.7 mg, 2.8%) as a mixture of diastereomers and as a dark red solid: 1H NMR (500 MHz, CD3OD) δ 8.10 (s, 1H), 6.64 (s, 1H), 6.17 (s, 0.3H), 6.01 (s, 0.7H), 4.96-4.87 (m, 2H), 3.74 (s, 3H), 3.64 (s, 1H), 3.57 (s, 3H), 3.52 (d, J=18.0 Hz, 3H), 3.46-3.39 (m, 6H), 3.26-3.20 (m, 1H), 3.08-3.02 (m, 2H), 2.08 (s, 3H), 1.93-1.87 (m, 4H), 1.28 (d, J=6.0 Hz, 2.1H), 1.22 (d, J=6.0 Hz, 0.9H); MS (ESI+) m/z 737 (M+H); HPLC 94.4% (AUC), tR 10.71 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH2:8]2)=[O:4].O[Li].O>C1COCC1.O>[C:14]([N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13][CH:12]=2)[CH2:8][CH2:9]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc2c(c1)CCN2C(=O)c1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)CCN2C(=O)c1ccccc1
Yield: 99 %

Procedure:
A solution of compound 55g (87 mg, 0.31 mmol), and LiOH.H2O (52 mg, 1.24 mmol) in THF/H2O (2/2 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜6 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 55h (82 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 268.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:33][CH3:34])=[C:30]([OH:32])[CH:31]=1>C(OCCO)C>[OH:32][C:30]1[CH:31]=[C:26]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:27]=[CH:28][C:29]=1[O:33][CH3:34]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: COc1ccc(N)cc1O
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)cc1O
Yield: 89.2 %

Procedure:
Using an analogous procedure to that described in Example 367, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 167.0 mg (1.2 mmol) of 5-amino-2-methoxyphenol to give 313.3 mg (89.3%) of the product as a gray solid, m.p. 254-256° C., mass (electrospray, m/e): M+H351.2.
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]([OH:17])[C:15]#[CH:16])=[CH:4][CH:3]=1.[N:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:19]=[N-:20]>>[CH2:21]([N:18]1[CH:16]=[C:15]([CH:14]([C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[OH:17])[N:20]=[N:19]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C#CC(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: [N-]=[N+]=NCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccccc2)nn1

Procedure:
Prepared according to the procedure described in Example 25, Step 2, using 1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1-ol (Enantiomer B) and azidomethyl-benzene.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[N+:18]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[NH2:18][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[NH:7][CH2:6][C:5]1[CH:21]=[CH:22][C:2]([Br:1])=[CH:3][CH:4]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(NCc2ccc(Br)cc2)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(NCc2ccc(Br)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-(4-bromobenzylamino)-3-nitrobenzoate (1 g, 2.73 mmol) in methanol (10 mL) and THF (15 mL) was added sat. NH4Cl aqueous solution (15 mL), then zinc powder (2.11 g, 27.3 mmol) was added in one portion. The mixture was stirred at RT for 1 hr. Then the solid was filtered and the filtrate was concentrated. The residue was washed with water (20 mL) and EtOAc (30 mL×3), the combined organic layers were concentrated to the titled compound which was used to the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH:4][N:3]=1.ClC1C(C(OO)=[O:21])=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH:4][N+:3]=1[O-:21]
Reactant: O=C(OO)c1ccccc1Cl
Reactant: CC(=O)OCc1ccc(C)nc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1ccc(C)[n+]([O-])c1

Procedure:
2-Methyl-5-acetoxymethylpyridine (0.05 mole) is stirred in 50 ml. of chloroform at 15° C. while chloroperbenzoic acid (0.06 mole) is added over 10 min. The solution is extracted with saturated sodium bicarbonate solution (3×20 ml.) and 2×20 ml. of water. The chloroform is dried over magnesium sulfate, and concentrated to dryness to give 2-methyl-5-acetoxymethylpyridine-N-oxide.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9](/[CH:11]=[CH:12]/[C:13]([O:15]CC)=[O:14])[CH:8]=[CH:7][C:6]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.Cl>CO.C1COCC1>[CH3:3][O:4][C:5]1[N:10]=[C:9](/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:8]=[CH:7][C:6]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1
Reactant: CCOC(=O)/C=C/c1ccc(-n2cnc(C)c2)c(OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A 5 N sodium hydroxide solution (4 mL) was added to a solution of ethyl (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylate (1.5 g) in methanol (10 mL) and THF (6 mL). The reaction solution was stirred at room temperature for two hours, and then 5 N hydrochloric acid (5 mL) was added to the reaction solution. The generated precipitate was filtered and washed with THF to obtain 755 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [N:1]1[S:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[Cl:10][S:11](O)(=[O:13])=[O:12]>>[N:1]1[S:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([Cl:10])(=[O:13])=[O:12])[C:5]=12
Reactant: c1ccc2nscc2c1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cccc2csnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.6 %

Procedure:
Benzo[c]isothiazole 24B (1 g, 7.45 mmol) was added dropwise to chlorosulfonic acid (5.5 mmol) at 0° C. After the addition was complete, the mixture was stirred at room temperature for 0.5 h and then heated at 105° C. and stirred overnight. The resulting mixture was cooled to −10° C. and quenched by pouring on crushed ice slowly. The resulting mixture was extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (15% PE/EtOAc) afforded 200 mg of title compound. 1H NMR (CHLOROFORM-d) δ: 9.68 (s, 1H), 8.66 (d, J=1.9 Hz, 1H), 8.10 (d, J=9.4 Hz, 1H), 7.99 (dd, J=9.4, 2.1 Hz, 1H).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:16][CH:17]([CH3:19])[CH3:18]>CC#N>[CH2:16]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CI
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)COc1ccccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A 50 mL round-bottom flask was charged with catechol (499 mg, 4.53 mmol), CH3CN (4.5 mL), and Cs2CO3 (1.50 g, 4.60 mmol) and purged with nitrogen. This white suspension was allowed to stir for 10 minutes prior to the addition of 1-iodo-2-methylpropane (1.67 g, 9.06 mmol). The reaction was brought to reflux and allowed to stir for 18 h. After cooling to room temperature the solvent was concentrated in vacuo, and the residue partitioned between ethyl acetate (50 mL) and 1 N HCl (50 mL). The organic layer was separated, dried, filtered, and concentrated in vacuo. Flash chromatography (3:1 hexane:ethyl acetate) afforded a yellow oil weighing 316 mg (30% yield). 1H NMR (CDCl3): δ 1.05 (dd, J=1.95 Hz, J=6.85 Hz, 6H), 2.13 (s-7, J=6.60 Hz), 3.81 (d, J=6.60 Hz), 6.81-6.88 (m, 3H), 6.93-6.95 (m, 1H); 13C NMR (CDCl3): δ 19.39, 28.38, 75.31, 111.77, 114.57, 120.22, 121.12, 121.44, 146.16.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH:8]([C:12]1[NH:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:6][NH:7][CH:8]([C:12]1[NH:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)c1nc(-c2ccccc2)c[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC(c1nc(-c2ccccc2)c[nH]1)C(C)C
Temperature: 25 °C
Yield: 843.1 %

Procedure:
A solution of [2-methyl-1-(4-phenyl-1-H-imidazol-2-yl)-propyl]-carbamic acid tert-butyl ester (0.095 g, 0.30 mmol) in THF (2.0 mL) was added dropwise over 10 min to a refluxing 1.0 M solution of LiAlH4 in THF (3.0 mL). The reaction was maintained at reflux for 2 h, cooled to room temperature, and quenched by sequential treatment with 0.11 mL of cold water (5° C.), 0.11 mL of 15% NaOH in aqueous solution, and 0.33 mL of cold water (5° C.). The resultant solid was removed by suction filtration and the filtrate (pH 8-9) was extracted three times with EtOAc. The combined organic fractions were dried over MgSO4, filtered, and concentrated to afford 0.58 g (84%) of methyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine as a light yellow oil (HPLC: 97% @ 254 nm and 214 nm). 1H NMR (300 MHz, CDCl3): δ 7.69 (2H, d, J=7.4 Hz), 7.36 (2H, t, J=7.6 Hz), 7.26 (1H, s), 7.25-7.20 (1H, m), 3.62 (1H, d, J=6.3 Hz), 2.35 (3H, s), 2.06 (1H, m), 0.99 (3H, d, J=6.7 Hz), 0.89 (3H, d, J=6.7 Hz); MS (ES+) (relative intensity): 230.2 (100) (M+1).