Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([S:16][CH:17]([CH3:19])[CH3:18])=[C:12]([CH:14]=O)[S:13][C:7]=2[N:6]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:5]1=[O:24].[CH2:25](O)[CH3:26]>O>[N:4]1([CH2:14][C:12]2[S:13][C:7]3[N:6]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:5](=[O:24])[N:4]([CH3:3])[C:9](=[O:10])[C:8]=3[C:11]=2[S:16][CH:17]([CH3:19])[CH3:18])[C:9]2[CH:8]=[CH:11][CH:12]=[CH:25][C:26]=2[N:6]=[CH:5]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(C=O)sc21
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(Cn3cnc4ccccc43)sc21
Reaction time: 24 h

Procedure:
Sodium borohydride (0.11 g) was added to 1,2,3,4-tetrahydro-3-methyl-5-[(1-methylethyl)thio]-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-6-carboxaldehyde (0.50 g) in ethanol (20 ml) and the mixture was stirred for 24 hours. The reaction was diluted with water (50 ml) and was then extracted with ethyl acetate (3×50 ml). The organic phases were washed with brine and then dried, filtered and evaporated to give the subtitle compound as a yellow solid (0.45 g).
Reaction SMILES: [I-].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:7][C:8]1[C:9]2[CH:26]=[C:25]([O:27]C)[C:24]([O:29]C)=[CH:23][C:10]=2[S:11][C:12]=1[C:13]([N:15]1[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]1)=[O:14].Cl.[O-]S([O-])=O.[Na+].[Na+]>C(#N)C.O>[Cl:7][C:8]1[C:9]2[CH:26]=[C:25]([OH:27])[C:24]([OH:29])=[CH:23][C:10]=2[S:11][C:12]=1[C:13]([N:15]1[CH2:16][CH:17]([CH3:22])[O:18][CH:19]([CH3:21])[CH2:20]1)=[O:14]
Reactant: COc1cc2sc(C(=O)N3CC(C)OC(C)C3)c(Cl)c2cc1OC
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Al+3]
Solvent: CC#N
Solvent: O
Product: CC1CN(C(=O)c2sc3cc(O)c(O)cc3c2Cl)CC(C)O1
Temperature: 50 °C

Procedure:
Sodium iodide (1.62 g) was added to a solution of aluminum chloride (2.16 g) in acetonitrile (5 ml). After 30 minutes stirring (3-chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-(2,6-dimethyl-morpholin-4-yl)-methanone was added and the mixture was heated at 50° C. for 12 hours. To the mixture 2 N HCl (4 ml), Na2SO3 (0.68 g) and water were added and the mixture was heated at 60° C. for 30 minutes and then cooled to room temperature. The precipitate was filtered.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][OH:15])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[H-].[Na+].O.[CH2:21]1COCC1>>[CH3:17][O:16][CH:3]([O:2][CH3:1])[C:4]1[N:5]=[C:6]2[C:11]([CH2:10][CH2:9][CH2:8][NH:7]2)=[CH:12][C:13]=1[CH2:14][O:15][CH3:21]
Reactant: C1CCOC1
Reactant: COC(OC)c1nc2c(cc1CO)CCCN2
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCc1cc2c(nc1C(OC)OC)NCCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methanol (intermediate 40, 94 mg, 0.394 mmol) in THF (2 ml) was added NaH (60% dispersion in mineral oil, 16.6 mg, 0.414 mmol). The resulting suspension was stirred at room temperature for 15 min, then Mel (0.026 ml, 0.414 mmol) was added and the reaction mixture was stirred for 28 h. The reaction mixture was poured into water and extracted with DCM (2×). The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, DCM/(DCM/MeOH 9/1) 100:0 to 50:50) to give the title compound as a yellow oil. (UPLC-MS 3) tR 0.51 min; ESI-MS 253.2 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:2][CH2:3][Cl:4])[N:10]=[CH:9]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: ClCCn1ncc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.3 %

Procedure:
1-Bromo-2-chloroethane (2.9 mL, 35 mmol) was added to a suspension of 5-bromo-1H-indazole (4.302 g, 21.95 mmol) and Cs2CO3 (28.56 g, 87.81 mmol) in DMSO (50 mL) under N2. The resulting suspension was stirred at 25° C. for 6 h. H2O (50 mL) was added, and the resulting suspension was cooled in an ice bath. The suspension was filtered, and the solid was dried under reduced pressure to afford a pink powder. Flash chromatography on silica gel (19:1 to 5:2 hexanes/EtOAc) gave the title compound (3.094 g, 54%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.00 (br s, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.50 (dd, J=9.0, 1.5 Hz, 1H), 7.38 (d, J=9.0 Hz, 1H), 4.68 (t, J=6.3 Hz, 2H), 3.98 (t, J=6.3 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)C(O)CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Methyl 3-oxo-2,3-dihydro-1H-indene-5-carboxylate (3.5 g, 18.421 mmol, 1.0 eq.) was dissolved in MeOH (40 ml) and cooled to 0° C.; NaBH4 (749 mg, 20.263 mmol, 1.1 eq.) was added in portions and the mixture was stirred for 3 hours at RT. After monitoring by TLC, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was taken up in water (100 ml) and extracted with dichloromethane (2×100 ml). The combined org. phases were dried over sodium sulfate, concentrated under reduced pressure and used in the next stage without being purified further. Yield: 92% (3.2 g, 16.66 mmol)
Reaction SMILES: Cl.[O:2]1[C@:14]2([CH3:20])[C@@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@:10]3([O:22][CH2:23][CH3:24])[CH2:11][CH2:12][C:13]2=[O:21])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:25][CH3:26])[CH:5]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[C:33]1([CH2:39][CH2:40]Br)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O>[O:2]1[C@:14]2([CH3:20])[C@@:15]34[CH2:17][CH2:18][N:19]([CH2:40][CH2:39][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C@@H:9]([C@:10]3([O:22][CH2:23][CH3:24])[CH2:11][CH2:12][C:13]2=[O:21])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:25][CH3:26])[CH:5]=[CH:6]2
Reactant: BrCCc1ccccc1
Reactant: CCO[C@@]12CCC(=O)[C@]3(C)Oc4c(OC)ccc5c4[C@@]31CCN[C@@H]2C5
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCO[C@@]12CCC(=O)[C@]3(C)Oc4c(OC)ccc5c4[C@@]31CCN(CCc1ccccc1)[C@@H]2C5
Yield: 59.5 %

Procedure:
A mixture of 4,5α-epoxy-14-ethoxy-3-methoxy-5-methylmorphinan-6-one hydrochloride (H. Schmidhammer et al., Helv. Chim. Acta Vol. 76, 476-480,1993) (3.0 g, 7.88 mmol), potassium carbonate (3.9 g, 28.2 mmol), 2-phenylethyl bromide (1.41 ml, 10.4 mmol), and of 20 ml anhydrous NN-dimethyl formamide was stirred at 80° C. (bath temperature) for 2h. After cooling and addition of 130 ml of H2O, the mixture was extracted with diethyl ether (3×60 ml). The combined organic layers were washed with H2O(3×70 ml), dried over Na2SO4 and evaporated. The residue (3.6 yellow oil) was crystallized from MeOH to afford 2.1 g (70%) of 4,5α-epoxy-14-ethoxy-3-methoxy-5-methyl-17-(2-phenyl)ethylmorphinan-6-one (compound 3). M.p. 86-89° C. IR (KBr): 1725 (CO) cm-1. CI-MS: m/z 448 (M+ +1). 1H-NMR (CDCl3): δ 7.21 (m, 5 arom. H), 6.64 (d,J=8.2 Hz, 1 arom. H, 6.54 (d, J=8.2 Hz, 1 arom. H.), 3.85 (s, OCH3), 1.60 (s, CH3 --C(5)), 1.12 (t, J=6.8 Hz, CH3). Analysis calculated for C28H33NO4 (447.55): C 75.14, H 7.43, N 3.13; found: C 75.04, H 7.69, N 3.26.
Reaction SMILES: [BH4-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=O)[C:13](Cl)=[O:14])=[CH:4]1.Cl>COCCOCCOC.O>[CH:8]1[CH:9]=[CH:10][C:11]2[NH:3][CH:4]=[C:5]([CH2:12][CH2:13][OH:14])[C:6]=2[CH:7]=1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: OCCc1c[nH]c2ccccc12

Procedure:
A suspension of sodium borohydride (22.6 g.) in diglyme (800 ml.) was stirred in a jacketted flask with water cooling. 3-Indolylglyoxylyl chloride (41.5 g.) was cautiously added in small portions then the mixture was heated to 95°-100° for 5 hours. The cooled reaction mixture was diluted with water (2 l.), acidified with hydrochloric acid and extracted with dichloroethane. The extract was washed with sodium carbonate solution then with water and evaporated to give crude tryptophol as a brown oil. This was distilled at 0.1 mm and the distillate collected at 155°-160° was crystallised from toluene (50 ml.), giving pure tryptophol as white crystals m.p. 57°-59°.
Reaction SMILES: [N+]([O-])(O)=O.N([O-])=O.[Na+].[OH:9][CH2:10][C:11]1[N:15]([CH2:16][CH2:17][CH3:18])[C:14](S)=[N:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O>[OH:9][CH2:10][C:11]1[N:15]([CH2:16][CH2:17][CH3:18])[CH:14]=[N:13][CH:12]=1
Reactant: CCCn1c(CO)cnc1S
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCCn1cncc1CO
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To 5.0M nitric acid (370 ml) was added sodium nitrite (1.14 g), and 5-hydroxymethyl-2-mercapto-1-propylimidazole (71.0 g) was added to the mixture by portions at 0° C. The mixture was allowed to be at room temperature and the mixture was stirred for 2 hours, and water (200 ml) was added to the mixture. The mixture was neutralized with potassium carbonate at 0° C., and the solvent was distilled off under reduced pressure. Ethanol was added to the mixture, and the insolubles were filtered off, and the solvent was distilled off under reduced pressure. To the obtained residue was added methanol-ethyl acetate, and basic silica gel was added to the mixture. This mixture was purified by basic silica gel column chromatography (methanol-ethyl acetate=0.1:8), to obtain solid, which was recrystallized from diisopropyl ether-ethyl acetate, to give 5-hydroxymethyl-1-propylimidazole (33.6 g) as brown crystals.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH:17]([CH3:24])[O:16][C:15]2=[O:25])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:26]>C(OCC)(=O)C>[ClH:26].[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH:17]([CH3:24])[O:16][C:15]2=[O:25])[CH2:12][CH2:13]1
Reactant: CC1OC(=O)N(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1OC(=O)N(C2CCNCC2)c2ccccc21

Procedure:
1-(1-Boc-4-piperidyl)-4-methyl-3,1-benzoxazin-2-one from Step 3 above (1.98 g, 5.72 mmol) was stirred in ethyl acetate in an ice bath, then saturated with HCl gas and stirred another 15 min in the cold. The mixture was evaporated in vacuo. Three portions of ethyl acetate were successively added and evaporated in vacuo to give 1-(4-piperidyl)-4-methyl-3,1-benzoxazin-2-one hydrochloride.
Reaction SMILES: Br[C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:42][N:43](C=O)C>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].[C-]#N.[Zn+2].[C-]#N.O>[F:11][C:10]1[CH:9]=[CH:8][C:7]2[C:6](=[O:12])[CH2:5][CH2:4][C:3]=2[C:2]=1[C:42]#[N:43]
Reactant: O=C1CCc2c1ccc(F)c2Br
Reactant: CN(C)C=O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1c(F)ccc2c1CCC2=O
Temperature: 175 °C

Procedure:
To a microwave tube charged with 4-bromo-5-fluoro-2,3-dihydro-1H-inden-1-one (500 mg, 2.2 mmol) and a stir bar was added Pd2(dba)3 (40.0 mg, 0.044 mmol), S-phos (45 mg, 0.11 mmol), zinc cyanide (333 mg, 2.84 mmol), DMF (15 mL), and Water (0.15 mL). The tube was sealed, and purged three times with nitrogen. The reaction was then heated to 175° C. for 3 minutes in a microwave reactor. TLC showed formation of the desired product, along with a small amount of the dimethylaniline adduct. The crude product mixture was diluted with EtOAc, washed with brine, dried over sodium sulfate, adsorbed onto silica, and purified by MPLC. After removal of solvent, 5-fluoro-1-oxo-2,3-dihydro-1H-indene-4-carbonitrile was collected.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.[OH-].[Na+].Cl>O.C1COCC1>[CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)ccc1C(=O)O
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To two batches of methyl 2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate (0.452 g, 1.198 mmol) in a 250 mL round-bottomed flask equipped with a stir bar was added MeOH (12 ml), THF (12 ml) and 2N sodium hydroxide (5.99 ml, 11.98 mmol). The reaction was stirred overnight. The reaction mixture was diluted with water and acidified with 1N HCl. The solid was extracted with EtOAc (3×). The organic layer was dried over MgSO4, filtered and concentrated providing the title compound as a yellow solid (0.412 g, 1.134 mmol, 95%): 1H NMR (300 MHz, DMSO-d6) δ 12.94 (s, 1H), 9.43 (s, 1H), 8.14-8.03 (m, 2H), 8.03-7.89 (m, 3H), 7.61 (d, J=8.7 Hz, 2H), 2.60 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.95; ESIMS m/z 364 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:13][CH:14]=3)=[O:19])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc2cccnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-aminoquinoline (D55) (100 mg, 0.69 mmol) in DCM (3 ml) was added 4-biphenylcarboxylic acid (206 mg, 1.04 mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (197 mg, 1.04 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol) and the reaction stirred at room temperature overnight. The mixture was diluted with DCM, washed with sat. aqueous sodium bicarbonate solution, dried over MgSO4 and concentrated in vacuo to give the crude product which was purified by SPE column chromatography. Elution with 50% EtOAc in 40-60° C. petroleum ether gave the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.91 (dd, 1H), 8.19 (d, 1H), 8.12 (m, 2H), 8.02, (d, 2H), 7.86 (d, 1H), 7.75 (d, 2H), 7.65 (d, 2H), 7.49 (t, 2H), 7.42 (t, 1H), 7.36 (dd, 1H).
Reaction SMILES: [CH:1]1([N:7]([CH3:30])[S:8]([CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=[CH:17][C:16]=2[NH2:29])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:31]#[C:32]Br>C(O)C>[CH:1]1([N:7]([CH3:30])[S:8]([CH2:11][CH2:12][N:13]2[CH2:14][C:15]3[C:16](=[CH:17][CH:18]=[C:19]([C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[N:29]=[C:32]2[NH2:31])(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C1CCCCC1)S(=O)(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1N
Reactant: N#CBr
Solvent: CCO
Product: CN(C1CCCCC1)S(=O)(=O)CCN1Cc2cc(C(=O)c3ccccc3)ccc2N=C1N
Temperature: 25 °C

Procedure:
A mixture of 2-(2-amino-5-benzoyl-benzylamino)-ethanesulfonic acid cyclohexyl-methyl-amide (0.0054 mol) and cyanogen bromide (0.0080 mol) in ethanol (100 mL) was stirred and refluxed for 2 hours, and then the reaction mixture was cooled to room temperature. After filtration, the filter residue was washed with diisopropyl ether and dried under vacuum to yield the title compound as a solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[CH:28]=[CH:29][C:30](OCC)=[O:31].Cl>C1(C)C=CC=CC=1.ClCCl>[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:14][C:13]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27](/[CH:28]=[CH:29]/[CH2:30][OH:31])[CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)C=Cc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(/C=C/CO)c1
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A solution of diisobutyl aluminum hydride in toluene (1.5M, 51 ml) was added dropwise to a solution of ethyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamate (14.0 g) in dichloromethane (200 ml) at 0° C. After stirring for 30 minutes, 2N hydrochloric acid (150 ml) was added at 0° C., and the mixture was stirred for 1 hour. The dichloromethane layer was separated, washed with saturated brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave crystals of (E)-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-propenol (11.5 g, 92%). The crystals were recrystallized from ethyl acetate. Colorless prisms, mp: 118-119° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]#[N:16])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].COC(N1CCC(C(C(C2C=CC=CC=2)C#N)=O)CC1)=O.Cl.[NH2:45][OH:46].C([O-])(=O)C.[Na+]>O.C(O)C>[NH2:16][C:15]1[O:46][N:45]=[C:12]([CH:9]2[CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)[C:14]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)N1CCC(C(=O)C(C#N)c2ccccc2)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: COC(=O)N1CCC(C(=O)C(C#N)c2ccccc2)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1CCC(c2noc(N)c2-c2ccccc2)CC1
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A mixture (1:1, 17.5 g) of α-(1-ethoxycarbonylpiperidin-4-yl)carbonylphenylacetonitrile and α-(1-methoxycarbonylpiperidin-4-yl)carbonylphenylacetonitrile, hydroxylamine hydrochloride (5.63 g) and sodium acetate (13.1 g) were suspended in water (20 mL) and ethanol (160 mL), and the suspension was heated under reflux for 6 hrs. After the completion of the reaction, the mixture was cooled to room temperature. The insoluble material was filtered off using ethanol, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, and washed with water and saturated brine. The chloroform layer was concentrated under reduced pressure, and the obtained crystals were purified by column chromatography (n-hexane:ethyl acetate=3:1→1:1) to give a mixture (1:1, 7.02 g) of 5-amino-3-(1-ethoxycarbonylpiperidin-4-yl)-4-phenylisoxazole and 5-amino-3-(1-methoxycarbonylpiperidin-4-yl)-4-phenylisoxazole as pale-yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ccnc2)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of the title compound from Step B (4.0 g, 14.32 mmoles) in DMF (120 mL) was added to a stirred solution of NaH (0.52 g, 21.66 mmoles) and imidazole (1.46 g, 21.47 mmoles) in DMF (20 mL) under nitrogen atmosphere. The mixture was stirred at 60° C. for 16 h. DMF was evaporated in vacuo. The resulting crude product was extracted with CH2Cl2 and the extract was successively washed with water and brine, and the CH2Cl2 was evaporated to leave the title residue which was chromatographed on silica gel using 3% (10% cone NH4OH in methanol)-CH2Cl2 as eluant to give the title compound (0.94 g, 26%). FABMS (M+1)=252; δH (CDCl3) 1.4 (s, 9H), 1.6-1.8 (m, 2H), 2.0 (dd, 2H), 2.8 (dt, 2H), 4.05 (m, 1H), 4.2 m, 2H), 6.9 (s, 1H), 7.0 (s, 1H), 7.65 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:20][CH3:21]>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([CH2:20][CH3:21])[C:7]#[N:8])=[CH:2]1
Reactant: CCI
Reactant: N#CCc1ccsc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(C#N)c1ccsc1
Reaction time: 0.5 h
Yield: 18.3 %

Procedure:
A cooled solution of 2-(3-thienyl)acetonitrile (3.144 g, 25.52 mmol) in THF (30 mL) under nitrogen was treated with LHMDS in THF (22.70 g, 25.51 mL of 1 M, 25.50 mmol) dropwise over a period of 20 minutes. The mixture was allowed to stir for 30 minutes and then treated with iodoethane (4.180 g, 2.144 mL, 26.80 mmol) dropwise. The reaction was stirred at RT for a further hour and then quenched by the addition of MeOH and concentrated in vacuo. The residue was diluted with water and extracted with EtOAc (2×). The combined organics were dried (MgSO4), filtered, concentrated and purified by column chromatography (6:1 Petroleum ether/EtOAc) to give the product as an oil (708 mg, 18% Yield). 1H NMR (CDCl3, 400 MHz) δ 1.08 (3H, t), 1.93-2.00 (2H, q), 3.86 (1H, m), 7.03 (1H, m), 7.25 (1H, m), 7.37 (1H, m)
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[CH3:25][N:26]([CH3:42])[C:27]1[N:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH:20]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:30]5[CH:29]=[N:28][C:27]([N:26]([CH3:42])[CH3:25])=[N:32][CH:31]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: CN(C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnc(N(C)C)nc4)cc2OCC3)n(C(C)C)n1

Procedure:
8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was reacted with Dimethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-amine to give 245. MS(ESI+) 431.2
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C@H:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[C:3]([OH:5])=[O:4])=[CH:8][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid (2.7 g, 0.010 mol), 4-fluoro-benzenesulfonyl chloride (2.0 g, 0.010 mol), and sodium carbonate (2.2 g, 0.020 mol) in a mixture of tetrahydrofuran (20 mL) and water (20 mL) was stirred at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and 1 M hydrochloric acid. The organic layer was washed with saturated sodium chloride solution, dried (MgSO4), and rotary-evaporated under reduced pressure to give an oil. The oil was chromatographed on silica gel (445 g, 230-400 mesh) eluting with dichloromethane-methanol (20:1), and the fractions containing product were rotary-evaporated to give a solid. The solid was recrystallized from toluene to give the title compound as a light yellow solid; yield 0.22 g (5%), mp=138-139° C.