Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH2:10][N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:26][CH2:25][C:24]5[N:23]=[C:22]([CH2:27][CH2:28][CH3:29])[C:21]([C:30]([O:32]CC)=[O:31])=[CH:20][C:19]=5[C:18]4=[O:35])[CH2:13][CH2:12]3)[C:7]([O:36][CH2:37][CH3:38])=[CH:6][C:5]=2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[F:46])[CH2:3][CH2:2]1.C(O)C.[OH-].[Na+].Cl>C1COCC1.O>[CH:1]1([C:4]2[CH:9]=[C:8]([CH2:10][N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:26][CH2:25][C:24]5[N:23]=[C:22]([CH2:27][CH2:28][CH3:29])[C:21]([C:30]([OH:32])=[O:31])=[CH:20][C:19]=5[C:18]4=[O:35])[CH2:13][CH2:12]3)[C:7]([O:36][CH2:37][CH3:38])=[CH:6][C:5]=2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[F:46])[CH2:2][CH2:3]1
Reactant: CCCc1nc2c(cc1C(=O)OCC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4F)cc3OCC)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4F)cc3OCC)CC1)CC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of ethyl 6-(1-((2-cyclopropyl-5-ethoxy-2′,4′-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (13.2 g) in THF (33 mL)-ethanol (33 mL) was added 2M aqueous sodium hydroxide solution (31.2 mL). The mixture was stirred for 1 hour at 50° C. The mixture was cooled to room temperature. 2M hydrochloric acid (31.2 mL) was added to the reaction mixture. Then water (62.5 mL) was added to the reaction mixture. After cooled to 0° C., the precipitate was collected by filtration, washed with water, dried by airstream to give the title compound (12.4 g).
Reaction SMILES: C[C:2]1(C)[CH2:11][CH2:10][C:9](C)(C)[C:8]2C=[C:6]([OH:14])[CH:5]=[CH:4][C:3]1=2.C(OCC)(=O)CC(C)=[O:19]>OS(O)(=O)=O.C([O-])(O)=O.[Na+]>[O:19]1[C:8]2[C:3](=[CH:2][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][C:6]1=[O:14]
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1ccc2ccccc2o1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
1,2,3,4-Tetrahydro-1,1,4,4,6-pentamethylbenzo[5,6-g]coumarin (Structure 4 of Schemes 1 and 2, where R1, R4, R6=H, R2 and R3 together form a tetramethyl saturated six-membered carbocyclic ring, R5=methyl). To a flame-dried 50-mL r.b. flask containing 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-ol (2.03 g, 9.94 mmol) in 4 mL 75% H2SO4 was added ethyl acetoacetate (Structure 3 of Scheme 1, where R5=methyl, R6=H, R′=ethyl) (3.19 mL, 25.0 mmol, 2.52 equiv), and the mixture was heated to 100° C. for 3 h. Upon cooling to room temperature, the mixture was poured over ice (50 g), diluted with saturated NaHCO3 (50 mL), and stirred for 30 min. The mixture was then extracted with EtOAc (3×50 mL) and the organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude product mixture was purified by flash column chromatography (silica gel, hexanes/EtOAc, 4:1) to remove residual ethyl acetoacetate, providing the desired coumarin as a white solid (Rf0.62, hexanes/EtOAc, 2:1). Recrystallization from hexanes/EtOAc afforded 2.12 g (79%) of 1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylbenzo[5,6-g]coumarin as white prisms (mp 126-128° C.). 1H NMR (400 MHz, CDCl3) 7.51 (s, 1H), 7.25 (s, 1H), 6.20 (d, 1H, J=0.8 Hz), 2.43 (d, 3H, J=0.9 Hz), 1.72 (s, 4H), 1.33 and 1.31 (2s, 2×3H). 13C NMR (100 MHz, CDCl3) 161.2, 152.2, 151.4, 150.4, 141.5, 122.2, 117.9, 114.3, 107.1, 34.92, 34.84, 34.58, 34.20, 32.22, 31.83, 18.49. IR (thin film) 2923 (m), 1716 (s), 1612 (m). Anal. Calcd for C18H22O: C, 79.96; H, 8.20. Found: C, 80.06; H, 8.06.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:18][N:19]([CH3:32])[C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O)(=O)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15]([CH:23]2[CH2:22][CH2:21][C:20]([N:19]([CH3:32])[CH3:18])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24]2)[CH2:14][CH2:13]1
Reactant: COc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCCCC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc2[nH]cc(C3CCN(C4CCC(c5ccccc5)(N(C)C)CC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-methoxy-3-piperidine-4-yl-1H-indole (461 mg, 2 mmole) and 4-dimethylamino-4-phenylcyclohexane (435 mg, 2 mmole) were dissolved in dry 1,2-dichloroethane (40 ml). Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg, 2.8 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluting with water (20 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The product was a mixture of two diastereoisomeric compounds, which were separated by chromatography with methanol. The non-polar diastereoisomer was obtained as a colourless oil in a yield of 590 mg (68%) and the polar diastereoisomer was obtained as a colourless oil in a yield of 170 mg (20%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4](F)[N:3]=1.[CH3:13][O-:14].[Na+].Cl>O1CCCC1.CO>[F:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([O:14][CH3:13])[N:3]=1
Reactant: C[O-]
Reactant: COC(=O)c1ccc(F)nc1F
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)nc1F
Temperature: 0 °C

Procedure:
To a stirred solution of 15.0 g (0.0867 mol) of the product from Example 12 in 240 mL dry tetrahydrofuran cooled to -78° was added dropwise 22.7 mL (0.0993 mol) of 25% sodium methoxide in methanol solution over 45 minutes. After warming to -20°, the mixture was poured into ice water, acidified with 1 normal hydrochloric acid and extracted with ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to a semisolid which was purified by flash chromatography to afford 3.2 g (17%) light yellow solid: m.p. 81°-82°; NMR (CDCl3, 200 MHz) 3.9 (3H, s), 3.98 (3H, s), 6.67 (1H, d, J=9 Hz), 8.25 (1H, m); IR (nujol) 1715, 1615, 1290 cm-1.
Reaction SMILES: Cl.O1CCOCC1.[CH3:8][C:9]1([CH3:40])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N:18]3[CH2:22][CH2:21][N:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][C:28]=4[CH3:29])[C:19]3=[O:30])[CH:16]=2)[N:11]([CH2:31][O:32]CC[Si](C)(C)C)[C:10]1=[O:39].CO.C(=O)(O)[O-]>C(Cl)(Cl)Cl>[OH:32][CH2:31][N:11]1[C:12]2[C:17](=[CH:16][C:15]([N:18]3[CH2:22][CH2:21][N:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][C:28]=4[CH3:29])[C:19]3=[O:30])=[CH:14][CH:13]=2)[C:9]([CH3:8])([CH3:40])[C:10]1=[O:39]
Reactant: Cc1ccncc1N1CCN(c2ccc3c(c2)C(C)(C)C(=O)N3COCC[Si](C)(C)C)C1=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1N1CCN(c2ccc3c(c2)C(C)(C)C(=O)N3CO)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Dioxane HCl (4 mL) was added to 3,3-dimethyl-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indol-2-one (I-147a: 50 mg) and the resulting mixture was stirred room temperature for 1 hour. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was basified with bicarbonate solution and extracted with DCM. The organic layer was concentrated; the concentrate was recrystallized with DCM and hexane and dried to afford 37 mg of the product (94.87% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=2)=[CH:4][C:3]=1[C@:17]1([CH3:29])[C:23]([F:25])([F:24])[C:22]([CH3:27])([CH3:26])[O:21][CH2:20][C:19](=O)[NH:18]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=2)=[CH:4][C:3]=1[C@:17]1([CH3:29])[C:23]([F:25])([F:24])[C:22]([CH3:27])([CH3:26])[O:21][CH2:20][C:19](=[S:39])[NH:18]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ncc(-c2cc([C@@]3(C)NC(=O)COC(C)(C)C3(F)F)c(F)cc2F)cn1
Solvent: C1COCCO1
Product: COc1ncc(-c2cc([C@@]3(C)NC(=S)COC(C)(C)C3(F)F)c(F)cc2F)cn1
Yield: 62.3 %

Procedure:
The reaction of (R)-5-[2,4-difluoro-5-(2-methoxy-pyrimidin-5-yl)-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (82 mg, 198 μmol) with Lawesson's reagent (80.2 mg, 198 μmol) in 1,4-dioxane (3 ml) yielded the (R)-5-[2,4-difluoro-5-(2-methoxy-pyrimidin-5-yl)-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (53 mg, 62% yield) as a white solid. MS (ISP): m/z=430.3 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[C:19]2[CH:20]=[CH:21][C:22]3[N:23]([C:24]([CH3:27])=[N:25][N:26]=3)[C:18]=2[CH:17]=[C:16]1[C:28](O)=[O:29])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:31]([N:34](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN.C1COCC1>CN(C=O)C.CO>[CH2:8]([N:15]1[C:19]2[CH:20]=[CH:21][C:22]3[N:23]([C:24]([CH3:27])=[N:25][N:26]=3)[C:18]=2[CH:17]=[C:16]1[C:28]([NH:34][CH3:31])=[O:29])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3ccccc3)n12
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc2c(ccc3nnc(C)n32)n1Cc1ccccc1
Reaction time: 0.03 h

Procedure:
To a solution of 6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid trifluoroacetate (0.044 g, 0.10 mmol, from Step 4) in DMF (1 mL) was added N,N-diisopropylethylamine (0.17 mL, 0.98 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.14 g, 0.37 mmol). After stirring this combination for 2 minutes, 2.0 M methylamine in THF (0.42 mL, 0.84 mmol) was added. After a reaction time of 15 minutes, the reaction was diluted with MeOH, and the product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) (0.03 g, 90%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])O)[OH:11])[OH:9])[OH:7].OCCNC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O>>[CH2:5]1[N:4]([CH2:3][CH2:2][OH:1])[CH:12]([CH2:14][OH:15])[CH:10]([OH:11])[CH:8]([OH:9])[CH:6]1[OH:7]
Reactant: OCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: OCCNC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O
Product: OCCN1CC(O)C(O)C(O)C1CO
Reaction time: 24 h
Yield: 95 %

Procedure:
N-(2-hydroxyethyl)glucamine is microbially oxidized in substantial accordance with the teaching of Example 26, except N-(2-hydroxyethyl)glucamine is used in place of N-ethylglucamine and N-(2-hydroxyethyl)-1-deoxynojirimycin is obtained instead of N-ethyl-1-deoxynojirimycin. HPLC analysis after 24 hours indicates that 79% of the initial charge of N-(2-hydroxyethyl)glucamine has been converted to 6-(2-hydroxyethyl)amino-6-deoxy-α-L-sorbofuranose. After 48 hours, at least 90% of the initial charge has been converted. After 72 hours, the supernatant is separated from the cells and sterile filtered. The pH of an aliquot (10 mL) is adjusted to pH 9.0 with concentrated NH4OH, chilled in an ice bath, and 100 mg NaBH4 is added. After standing in the ice bath overnight, the samples are acetylated and assayed by gas chromatography mass spectroscopy (GC-MS). GC-MS indicates a 95% yield of N-(2-hydroxyethyl)-1-deoxynojirimycin from 6-(2-hydroxyethyl)amino-6-deoxy-α-L-sorbofuranose (chemical ionization mass spectroscopy of the acetylated product indicated the GC peak corresponding to the reduced, cyclized product has a parent peak mass of 418 (M+H) corresponding to the penta-acetylated N-2-hydroxyethyl-1-deoxynojirimycin.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[N:12]=[C:13]([Cl:15])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.O.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:15][C:13]1[CH:14]=[C:9]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:10](=[O:17])[N:11]([CH3:16])[N:12]=1
Reactant: Nc1ccccn1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(Cl)cc(Nc2ccccn2)c1=O
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A 250-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 2-aminopyridine (500 mg, 5.31 mmol), 103a (1.19 g, 5.31 mmol), cesium carbonate (5.19 g, 15.9 mmol), and 1,4-dioxane (75 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (261 mg, 0.451 mmol) and tris(dibenzylideneacetone)dipalladium(0) (243 mg, 0.266 mmol) were added, and the reaction mixture was heated at reflux for 3 h. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (350 mL) and water (40 mL). The organic layer was separated, and the aqueous layer was extracted with a 20% (v/v) solution of methanol in methylene chloride (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with methanol (30 mL) to afford a 92% yield (1.16 g) of 104a as an off-white solid: mp 201-202° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.38 (m, 2H), 7.75 (m, 1H), 7.54 (d, 1H, J=8.1 Hz), 7.03 (m, 1H), 3.67 (s, 3H); MS (ESI+) m/z 237.0 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][O:26]COC)=[CH:21][CH:20]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CO>O>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOCc1ccc(Cn2nc(C(C)(C)C)cc2COc2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(COc2ccccc2)n(Cc2ccc(CO)cc2)n1
Yield: 91.5 %

Procedure:
A mixture of 3-tert-butyl-1-{4-[(methoxymethoxy)methyl]benzyl)-5-(phenoxymethyl)-1H-pyrazole (1.66 g, 4.21 mmol), concentrated hydrochloric acid (0.2 mL) and methanol (20 mL) was refluxed overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (1.35 g, yield 91%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([NH:30][NH2:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:22]([NH:30][NH:31][C:19](=[O:20])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: NNC(=O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)NNC(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200 mg, 0.7 mmol), benzohydrazide (142.2 mg, 1.04 mmol) and HATU (397.02 mg, 1.04 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA)(0.1819 ml, 1.04 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=3:1) and dried so that ivory (E)-tert-butyl 3-(3-(2-benzoyl hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (223.5 mg, 79.2%).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3C=O)=[N:7][O:8][C:4]=2[CH:3]=1.[CH:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])OCC>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:19]([O:23][CH2:24][CH3:25])[O:26][CH2:27][CH3:28])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1ccccc1-c1noc2cc(Br)ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(OCC)c1ccccc1-c1noc2cc(Br)ccc12
Temperature: 45 °C
Yield: 101.2 %

Procedure:
To a stirred suspension of 2-(6-bromobenzo[d]isoxazol-3-yl)benzaldehyde (Compound 4a) (10 g) in dry ethanol (100 mL) was added p-toluenesulfonic acid (0.315 g) followed by triethyl orthoformate (11.01 mL, 9.81 g). The suspension was stirred at 45° C. until a clear solution resulted and then maintained at 45° C. for 45 min. The solvent was removed under vacuum and then the mixture was diluted with ethyl acetate and then washed with saturated sodium carbonate solution, brine and then dried over anhydrous sodium sulfate, filtered and evaporated to give the title product (12.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([C:22]([O:26][N:27]1N=NC2C=CC=C[C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([N:27]([O:26][CH3:22])[CH3:28])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (4-benzyloxy-phenyl)-acetic acid (61.9 mmol, 15.0 g), HBTU (74.3 mmol, 28.1 g), and N,O-dimethylhydroxylamine hydrochloride (92.9 mmol, 9.0 g) in DMF (100 mL) at 0° C. was added DIEA (136.3 mmol, 17.5 g) drop-wise. The reaction mixture was warmed to room temperature and stirred for 30 min. The mixture was diluted with ethyl acetate, washed with water, and 1.0 N HCl, followed by brine. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to provide 2-(4-benzyloxy-phenyl)-N-methoxy-N-methyl-acetamide.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:17][CH2:18][CH2:19]Br.C(N(CC)CC)C.C1OC1C>O.CN(C)P(=O)(N(C)C)N(C)C>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:17][CH2:18][CH3:19])=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: CCCBr
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1O
Agent: CC1CO1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCOc1c(OC)cc([N+](=O)[O-])c2ncccc12
Yield: 62.2 %

Procedure:
To a stirred mixture of 15 g (0.068 mole) of 5-hydroxy-6-methoxy-8-nitroquinoline, 16.8 g (0.14 mole) of n-propyl bromide, 1.5 g of triethylamine and 20 g of hexamethylphosphoric triamide, heated at a bath temperature of 110°, was added dropwise, during 2 hr, 20 g of propylene oxide. After an additional 48 hr at 110° the green-brown mixture was poured into 150 ml of water. The aqueous mixture was extracted with diethyl ether and the extract was dried (magnesium sulfate) and concentrated to give a dark yellow residue. Crystallization from hexane provided 11.1 grams (62%) of 6-methoxy-8-nitro-5-(n-propoxy)quinoline as yellow crystals, mp 100°-104°. Recrystallization from methanol gave an analytical sample as pale yellow crystals, mp 101°-103°.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.CC1(C)C(C)(C)OB([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[O:22][CH2:21][CH2:20][CH2:19]3)O1.Br[C:28]1[S:32][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:30][C:29]=1[CH:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([O:42][CH3:43])=[O:41]>CN(C)C=O.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.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.[Pd]>[C:45]([O:44][CH:39]([C:29]1[N:30]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[S:32][C:28]=1[C:16]1[CH:25]=[CH:24][C:23]2[O:22][CH2:21][CH2:20][CH2:19][C:18]=2[CH:17]=1)[C:40]([O:42][CH3:43])=[O:41])([CH3:48])([CH3:46])[CH3:47]
Reactant: COC(=O)C(OC(C)(C)C)c1nc(-c2ccccc2)sc1Br
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1nc(-c2ccccc2)sc1-c1ccc2c(c1)CCCO2
Temperature: 120 °C
Yield: 70.5 %

Procedure:
Under a nitrogen atmosphere, sodium carbonate (8.5 mg, 0.08 mmol), water (500 μL), palladium tetrakis(triphenylphosphine) (13 mg, 0.012 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (21 mg, 0.078 mmol) were added to a solution of methyl 2-(5-bromo-2-phenyl-1,3-thiazol-4-yl)-2-(tert-butoxy)acetate (30 mg, 0.078 mmol) in N,N-dimethylformamide (2 mL). The mixture was heated at 120° C. for 2 hours. The mixture was then cooled at room temperature and water (10 mL) was added. The aqueous layer was extracted with ethyl acetate (2×10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired product (6d) as a white solid (24 mg, 0.055 mmol, 70%).
Reaction SMILES: ClC1C=CC(C(N)C(N)CCCC)=CC=1.Cl.C(OC1C=C(OC)C=CC=1C(=N)OCC)C.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[NH:44][C:43]([C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=3[O:53][CH2:54][CH3:55])=[N:42][CH:41]2[CH2:56][CH:57]2CC[CH2:59][CH2:58]2)=[CH:36][CH:35]=1>>[CH2:56]([CH:41]1[CH:40]([C:37]2[CH:36]=[CH:35][C:34]([Cl:33])=[CH:39][CH:38]=2)[NH:44][C:43]([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH2:54][CH3:55])=[N:42]1)[CH2:57][CH2:58][CH3:59]
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: CCCCC(N)C(N)c1ccc(Cl)cc1
Agent: CCOC(=N)c1ccc(OC)cc1OCC
Agent: Cl
Product: CCCCC1N=C(c2ccc(OC)cc2OCC)NC1c1ccc(Cl)cc1

Procedure:
4-Butyl-5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-hexane-1,2-diamine and ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 387.1839, calculated for C22H28N2O2Cl [(M+H)+]387.1834.