Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:5][CH:4]([C:6]2[C:10]([CH2:11][OH:12])=[C:9]([C:13]([F:16])([F:15])[F:14])[S:8][N:7]=2)[CH2:3]1.[F:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH:22]=[C:23]([F:26])[C:24]=1O>>[F:17][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[C:10]([CH2:11][O:12][C:24]3[C:23]([F:26])=[CH:22][C:21]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:20][C:19]=3[F:18])=[C:9]([C:13]([F:15])([F:16])[F:14])[S:8][N:7]=2)[CH2:3]1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: OCc1c(C2CC(F)(F)C2)nsc1C(F)(F)F
Product: O=C(O)CCc1cc(F)c(OCc2c(C3CC(F)(F)C3)nsc2C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(3,3-difluorocyclobutyl)-5-(trifluoromethyl)isothiazol-4-yl)methanol and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 6.96 (d, J=7.2 Hz, 2H), 5.19 (s, 2H), 3.80-3.93 (m, 1H), 2.99-3.16 (m, 4H), 2.89 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.2 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C18H14F7NO3S, 456.1 (M−H). found 456.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:5][NH:4][C:3]1=[S:17].[C:18]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:1][N:2]1[C:3]([S:17][CH3:18])=[N:4][N:5]=[C:6]1[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(-c2ccc3ccccc3c2)n[nH]c1=S
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSc1nnc(-c2ccc3ccccc3c2)n1C

Procedure:
A mixture of 2,4-dihydro-4-methyl-5-(2-naphthyl)-3-H-1,2,4-triazole-3-thione (5.26 g, 2.18×10-2 mole), K2CO3 (3.01 g, 2.18×10-2 mole), methyl iodide (1.5 ml, 2.4×10-2 mole), and acetone (65 ml) was stirred and warmed to reflux. After refluxing overnight, the solvent was evaporated at reduced pressure and the concentrate was treated with water. The aqueous mixture was extracted with EtOAc three times. The EtOAc extracts were combined, washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure to yield the desired product Mp 177°-179° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13]2[CH:25]3[C:26](=[O:30])[NH:27][C:28](=[O:29])[CH:24]3[C:23]3[C:22]4[CH:21]=[C:20]([O:31][CH3:32])[CH:19]=[CH:18][C:17]=4[NH:16][C:15]=3[CH2:14]2)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>>[N+:10]([C:8]1[CH:7]=[C:6]([C:13]2[C:25]3[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:24]=3[C:23]3[C:22]4[CH:21]=[C:20]([O:31][CH3:32])[CH:19]=[CH:18][C:17]=4[NH:16][C:15]=3[CH:14]=2)[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)([O-:12])=[O:11]
Reactant: COc1ccc2[nH]c3c(c2c1)C1C(=O)NC(=O)C1C(c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: COc1ccc2[nH]c3cc(-c4cc([N+](=O)[O-])cc([N+](=O)[O-])c4)c4c(c3c2c1)C(=O)NC4=O
Yield: 42 %

Procedure:
The reaction of 4-(3,5-Dinitrophenyl)-9-methoxy-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-1,3(2H,3aH)-dione (IV; Ar=3,5-dinitrophenyl, R═H) (41) prepared as described in example 47 with DDQ according to the procedure described in example 70 gave 4-(3,5-dinitrophenyl)-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=3,5-dinitrophenyl, R10═H) (42) in a 42% yield as a reddish solid which was used without further purification.
Reaction SMILES: [CH2:1]([O:13][C@H:14]([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:15][O:16]CC1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>CCO.[OH-].[Pd+2].[OH-]>[CH2:1]([O:13][C@H:14]([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOC[C@H](COCc1ccccc1)OCCCCCCCCCCCC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCOC[C@H](CO)OCCCCCCCCCCCC
Reaction time: 8 h

Procedure:
To a solution of (R)-((2,3-bis(dodecyloxy)propoxy)methyl)benzene (1 eq) in EtOH (0.1 M) was added palladium hydroxide (1.1 eq). The reaction mixture was stirred under hydrogen (1 atm) overnight. The palladium was filtered off and the filtrate was concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% EtOAc/Hex to give the product.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH:3]=O.N1CCCCC1.[C:18]([CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])#[N:19].C(O)(=O)C.Cl>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[C:20]([C:18]#[N:19])=[CH:3][C:2]([CH3:11])([CH3:1])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)CCCC(C)(C)C=O
Reactant: N#CCC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)CCCC(C)(C)C=C(C#N)C(=O)OCc1ccccc1
Yield: 61.6 %

Procedure:
To a mixture of 2,2,6-Trimethyl-heptanal (1.05 g, 6.73 mmol), piperidine (0.19 mL, 2.01 mmol) and benzyl cyanoacetate (1.29 g, 7.4 mmol) in toluene (50 mL) was added glacial acetic acid (0.72 g, 12.1 mmol). The flask was fitted with a Dean-Stark trap, and the mixture was heated at reflux for 18. The mixture was cooled, treated with dilute HCl, and the layers were separated. The organics were washed with a saturated sodium bicarbonate solution followed by brine, and dried (MgSO4), filtered and concentrated. The residual oil was purified by silica gel chromatography (98/2 hexane/EtOAc) to give 1.3 g of 2-Cyano-4,4,8-trimethyl-non-2-enoic acid benzyl ester m/z 314 (M+).
Reaction SMILES: [C:1]1([C:6]2([CH2:12][C:13]([CH3:15])=[CH2:14])[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:5][CH2:4][CH2:3][CH:2]=1>C(OCC)(=O)C.C(O)C.[Pd]>[CH:1]1([C:6]2([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C)CC1(C2=CCCC2)CCCC1=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)CC1(C2CCCC2)CCCC1=O
Reaction time: 2 h
Yield: 83.1 %

Procedure:
A solution of the compound of Embodiment 4 (2-cyclopent-1-enyl-2-(2-methylprop-2-enyl)cyclopentan-1-one, 5.0 g, 0.02 moles) in ethyl acetate/ethanol (9:1, 100 mL) was added to a Parr reaction bottle. To this vessel was added 5% Pd—C (0.5 g) in one portion. The reaction vessel was placed in a Parr hydrogenation apparatus and H2 gas (40 psi) was introduced. The apparatus was agitated for 2 hours, and it was determined by TLC and GC that the reaction was complete. The resulting organic slurry was filtered through celite and concentrated. The pale yellow oil was distilled under vacuum to give 2-cyclopentyl-2-(2-methylpropyl)-cyclopentan-1-one (4.24 g, 83.1% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([S:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])=[CH:17][C:16]([CH:29]=O)=[CH:15]2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].CO.[CH3:33][NH2:34].[BH4-].[Na+].[ClH:37].C(=O)([O-])O.[Na+]>CO>[ClH:37].[CH3:33][NH:34][CH2:29][C:16]1[CH:17]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[N:14]([S:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)(=[O:13])=[O:12])[CH:15]=1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2C(F)(F)F)c1
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2C(F)(F)F)n(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
1-{[3-(Methylsulfonyl)phenyl]sulfonyl}-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde (300 mg) was dissolved in methanol (30 mL), 40% methylamine methanol solution (510 mg) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (75 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (30 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0→7:3), and dissolved in methanol (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 214 mg, 64%).
Reaction SMILES: [OH:1]O.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[C:7]([CH3:14])[N:6]=1.O>ClCCl>[CH3:3][O:4][C:5]1[N:6]=[C:7]([CH3:14])[C:8]([OH:1])=[CH:9][CH:10]=1
Reactant: OO
Reactant: COc1ccc(B(O)O)c(C)n1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(O)c(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
Add hydrogen peroxide (7.69 mL, 89.8 mmol) to a stirred mixture of 2-methoxy-6-methyl-5-pyridylboronic acid (5.0 g, 30 mmol) in dichloromethane (100 mL) kept under nitrogen at room temperature. Stir overnight at ambient temperature, add water and extract the mixture with dichloromethane. Combine the organic phases, dry (MgSO4), filter and concentrate to afford 2.6 g (62%) of the title compound. MS (m/z)=140 [M+1]
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH2:18][NH:19][C:20]([NH2:22])=[S:21])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].Br[CH:29]([CH:32]=O)[CH:30]=[O:31]>C1COCC1.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH2:18][NH:19][C:20]1[S:21][C:29]([CH:30]=[O:31])=[CH:32][N:22]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=CC(Br)C=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNC(N)=S)C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCNc1ncc(C=O)s1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a solution of material from Example 48 (5.25 g, 15.75 mmol) in a mixture of THF (178 mL) and acetic acid (29.6 mL), is added sequentially sodium acetate (1.55 g, 18.91 mmol) and 2-bromomalonaldehyde (2.75 g, 17.33 mmol) and the reaction is stirred at room temp. for 2 h. The solvent is removed in vacuo and the residue is partitioned between water (25 mL) and CH2Cl2 (40 mL). The aqueous phase is extracted with CH2Cl2 (2×20 mL), neutralized to pH 8 with solid sodium bicarbonate and extracted again with CH2Cl2 (3×25 mL). The organic layers are combined, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue is purified by BIOTAGE® Silica gel chromatography on a 160 g Thompson Single Step silica cartridge using a linear gradient from 60% Hexanes/Ethyl Acetate to 50% Hexanes/Ethyl Acetate over 5 column volumes to give 3.8 g (62.6%) of the title compound as a yellow foam. LC/MS (Condition A): ret. T=3.52 min, (M+Na) 408.15. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.64 (1 H, s), 8.94 (1 H, br. s.), 8.06 (1 H, s), 7.28 (1 H, d, J=7.78 Hz), 3.79-3.96 (1 H, m), 1.92-2.05 (1 H, m), 1.75-1.92 (1 H, m), 1.43 (3 H, br. s.), 1.40 (18 H, d, J=1.76 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]=[C:16]2[C:19]2([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[O:30][CH3:31])[CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>Br.C(O)(=O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:19]2([C:16]3[C:17]4[C:12](=[CH:11][CH:10]=[C:9]([OH:8])[CH:18]=4)[CH2:13][CH2:14][N:15]=3)[CH2:20][CH2:21][CH2:22]2)=[C:24]([O:30][CH3:31])[CH:25]=1
Reactant: COc1cc(Cl)ccc1C1(C2=NCCc3ccc(OCc4ccccc4)cc32)CCC1
Agent: Br
Solvent: CC(=O)O
Product: COc1cc(Cl)ccc1C1(C2=NCCc3ccc(O)cc32)CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
7-(benzyloxy)-1-[1-(4-chloro-2-methoxyphenyl)cyclobutyl]-3,4-dihydroisoquinoline (460 mg, 1.065 mmol) were dissolved in 33% hydrobromic acid in acetic acid. The reaction mixture was stirred at room temperature for 15 min. The solvent was evaporated in vacuo. Toluene was added and evaporated in vacuo (repeated three times). The crude product was purified by flash chromatography (silica, dichloromethane then dichloromethane:methanol=4:1). Yield: 322 mg (0.942 mmol, 88%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:15]O>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cccc(I)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(I)c1
Reaction time: 16 h
Yield: 93 %

Procedure:
3-iodobenzoic acid (7.44 g, 30 mmol) was suspended in dry MeOH (40 mL) under nitrogen at 0° C. SOCl2 (3.3 mL) was added over 5 minutes. Stirring continued at room temperature for 16 hours, after which the reaction mixture was concentrated. The residue was dissolved in EtOAc and was washed twice with NaHCO3 (conc.). The organic solution was dried over MgSO4, filtered and concentrated to yield a white crystalline solid (7.32 g, 93%). NMR 1H (ppm, CDCl3): 8.36 (t, J4=1.6 Hz, 1H), 7.98 (d, J3=7.8 Hz, 1H), 7.86 (d, J3=7.9 Hz, 1H), 7.16 (t, J3=7.8 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [O:1]([C@H:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:41][CH2:42][C:43]1[C:44]([OH:51])=[N:45][C:46]([CH3:50])=[CH:47][C:48]=1[CH3:49]>O.ClCCl.C(N(CC)CC)C>[OH:51][C:44]1[C:43]([CH2:42][NH:41][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([C@@H:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:48]([CH3:49])[CH:47]=[C:46]([CH3:50])[N:45]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: C[C@H](Oc1ccccc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc([C@H](C)Oc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A mixture of (S)-4-(1-phenoxyethyl)benzoic acid (121 mg, 0.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 1 mmol), N-hydroxybenzotriazole (135 mg, 1 mmol), triethylamine (0.2 mL) and dichloromethane (5 mL) were stirred at 25° C. for half an hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (20 mL) was added and the mixture was extracted with dichloromethane (30 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give (S)—N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenoxyethyl)benzamide as a white solid (100 mg, 53%). LRMS (M+H+) m/z: calcd. 376.18. found 376. HPLC purity (214 nm): 100%. 1H NMR (300 MHz, d6-DMSO): δ 11.44 (s, 1H), 8.29-8.27 (m, 1H), 7.77 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 7.20-7.15 (m, 2H), 6.87-6.83 (m, 3H), 5.83 (s, 1H), 5.53-5.51 (m, 1H), 4.26 (d, J=5.1 Hz, 2H), 2.14 (s, 3H), 2.10 (s, 3H), 1.53 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[C:23]1([CH3:26])[CH:24]=[CH:25][C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:21][CH:22]=1
Reactant: Cc1ccc(N)cc1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1
Yield: 64 %

Procedure:
Prepared from VII and 4-toluidine. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 64%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3016, 2853, 2228, 1731, 1641, 1605, 1581, 1554, 1505, 1458, 1376, 1353, 1304, 1268, 1215, 1165, 1130, 976, 831, 811; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H, J=9.0 Hz), 8.07 (s, 1H), 7.76 (d, 1H, J=9.0 Hz), 7.20-7.17 (m, 2H), 7.12-7.05 (m, 2H), 2.32 (s, 3H); HRMS calcd for C17H12N5S (M+H+): 318.0813, found 318.0811.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([NH:13][C:14](=[O:18])[CH2:15][CH2:16]Cl)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:13]2[CH2:16][CH2:15][C:14]2=[O:18])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(NC(=O)CCCl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(N2CCC2=O)cc1OC
Reaction time: 8 h

Procedure:
Sodium hydride (0.1 mole; 57% dispersion in mineral oil) is charged into a glass reaction flask. The mineral oil is removed by washing the sodium hydride with benzene, and dimethyl sulfoxide (50 ml) is thereafter slowly added with stirring. The mixture is stirred until no more hydrogen gas evolves. A solution of N-(3,4-dimethoxyphenyl)-β-chloropropionamide (0.08 mole) in carbon tetrachloride (50 ml) is added dropwise to the reaction flask with stirring while maintaining the temperature of the reaction mixture below about 30°C. After the addition is completed the reaction mixture is allowed to stand at room temperature for a period of about 8 hours. After this time benzene is added and the reaction mixture is washed with water and aqueous sodium bicarbonate. The washed mixture is then dried over anhydrous magnesium sulfate, is filtered, and is stripped of solvents under reduced pressure to yield the desired product N-(3,4-dimethoxyphenyl)-2-azetidinone as the residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:12]
Reactant: O=C1NC(Cc2ccc(F)cc2)C(c2ccc(F)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1
Yield: 86.4 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((4-fluorophenyl)methyl)-1,3-oxazolidin-2-one (11.87 g, 41.0 mmol) in ethanol (200 ml) was added 8N aqueous sodium hydroxide solution (25.6 ml, 205 mmol) and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated, diluted with water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-1,3-bis(4-fluorophenyl)-1-propanol (9.33 g, 86%).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]=1[OH:20])([CH3:6])([CH3:5])[CH3:4].O>CO.Cl[Ni]Cl>[NH2:13][C:12]1[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])=[C:8]([OH:20])[C:9]([C:16]([CH3:17])([CH3:18])[CH3:19])=[CH:10][CH:11]=1
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])c(C(C)(C)C)c1O
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(N)c(C(C)(C)C)c1O
Reaction time: 0.01 h
Yield: 77.7 %

Procedure:
NaBH4 (433 mg, 11.45 mmol) was added to a solution of 2,6-di-tert-butyl-3-nitrophenol (950 mg, 3.780 mmol) and NiCl2 (1.24 g, 9.568 mmol) in methanol (15 mL) at −15° C. After the addition was complete, the reaction mixture was stirred for 20 seconds and water was added immediately and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and evaporated in vacuo to afford 3-amino-2,6-di-tert-butyl-phenol (650 mg, 78%). 1H NMR (300 MHz, CDCl3) δ 6.92 (d, J=8.4 Hz, 1H), 6.24 (d, J=8.4 Hz, 1H), 5.39 (s, 1H), 1.62 (s, 9H), 1.39 (s, 9H); MS (ESI) m/z: 222.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]([N:12]([CH2:17][CH3:18])[S:13]([CH3:16])(=[O:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:19])[CH:8]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([O:29][CH2:30][CH2:31][CH2:32]Br)[CH3:28]>CC(N(C)C)=O>[CH2:27]([O:29][CH2:30][CH2:31][CH2:32][O:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:1])([CH3:20])[CH2:11][CH:10]2[N:12]([CH2:17][CH3:18])[S:13]([CH3:16])(=[O:15])=[O:14])[CH3:28]
Reactant: CCN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O
Reactant: CCOCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOCCCOc1ccc2c(c1)C(N(CC)S(C)(=O)=O)CC(C)(C)O2
Temperature: 110 °C

Procedure:
1.5 g (5 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-ethyl-methanesulfonamide were heated to 80° C. for 30 min with 1.38 g (10 mmol) of powdered potassium carbonate in 60 ml of DMA. 4 ml of 3-ethoxy-1-bromopropane were then added dropwise at 50-60° C., the mixture was heated to 110° C. for 2 h and concentrated in vac. after cooling, the residue was treated with water and aqueous hydrochloric acid, the mixture was extracted with EA, the organic phase was dried and concentrated, and the oily residue was chromatographed on silica gel using n-heptane/EA (2:1). 0.9 g of N-[6-(3-ethoxypropoxy)-2,2-dimethylchroman-4-yl]-N-ethyl-methanesulfonamide was crystallized from appropriate fractions using petroleum ether, m.p. 72-74° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=2)O)=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:46]=[N+:47]=[N-:48])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.CN(C)C=O.[Br-].[Li+]>[N:46]([CH:21]([C:23]1[O:24][C:25]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=1)[CH2:20][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[C:12]([Cl:19])[CH:11]=1)=[N+:47]=[N-:48]
Reactant: CN(C)Cc1ccc(C(O)Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)o1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)Cc1ccc(C(Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)N=[N+]=[N-])o1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 75.7 %

Procedure:
To a stirring solution of 2-[8-(benzyloxy)-5-chloroquinolin-7-yl]-1-{5-[(dimethylamino)methyl]-2-furyl}ethanol (2.18 mmol) in toluene (13.5 mL) and dimethylformamide (2.7 mL) at 0° C. was added diphenyl phosphoryl azide (5.46 mmol, 2.5 eq.) followed by dropwise addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (5.46 mmol, 2.5 eq.). The reaction mixture was stirred 5 min at 0° C. then warmed to room temperature and stirred 16 h. The mixture was next diluted with saturated aqueous lithium bromide solution (25 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to a dark brown syrup that was purified by column chromatography using 30% acetone/dichloromethane to give the product as a brown syrup (1.65 mmol, 76%). MS (ESI) m/z 462.4; HRMS: calcd for C25H24ClN5O2+H+, 462.16913; found (ESI, [M+H]+ Obs'd), 462.1693.