Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:37]=[CH:36][C:7]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH2:34][CH3:35])[C:15]4[C:20]([C:21]=3[CH:22]=2)=[CH:19][C:18]([CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)=[CH:17][CH:16]=4)=[CH:6][CH:5]=1)([O-])=O.Cl.O.C(=O)([O-])[O-].[Na+].[Na+]>[Fe].CN(C)C=O>[NH2:1][C:4]1[CH:37]=[CH:36][C:7]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH2:34][CH3:35])[C:15]4[C:20]([C:21]=3[CH:22]=2)=[CH:19][C:18]([CH:23]=[CH:24][C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=2)=[CH:17][CH:16]=4)=[CH:6][CH:5]=1
Reactant: CCn1c2ccc(C=Cc3ccc([N+](=O)[O-])cc3)cc2c2cc(C=Cc3ccc([N+](=O)[O-])cc3)ccc21
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2ccc(C=Cc3ccc(N)cc3)cc2c2cc(C=Cc3ccc(N)cc3)ccc21
Reaction time: 1.5 h
Yield: 94 %

Procedure:
20 g of 3,6-bis(4-nitrostyryl)-9-ethyl carbazole were added to a mixture consisting of 30 g of iron powder, 10 ml of concentrated hydrochloric acid, 50 ml of water and 600 ml of N,N-dimethylformamide and subjected to 1.5 hours' intense stirring at a temperature of 80° to 90° C. Thereafter, the pH value was adjusted to be 8 by means of 10% aqueous solution of sodium carbonate while thus heating, and the undissolved matter was filtered. The resulting filtrate, after treating with active carbon, was gradually poured in 600 ml of water, whereby there was obtained yellow crystals of 3,6-bis(4-aminostyryl)-9-ethyl carbazole. The yield of this crystal was 17 g (yield: 94%) and the melting point thereof was 260° C. or more.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].C(N(CC)C(C)C)(C)C.O>ClCCl>[N+:18]([C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9](=[O:10])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:17][CH:16]=1)([O-:20])=[O:19]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccccn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 g of 2-aminopyridine is dissolved in 10 ml of dichloromethane and then 1.18 g of 4-nitrophenyl chloroformate are added, as are 1.85 ml of N,N-diisopropylethylamine. The reaction mixture is stirred for one hour at ambient temperature. 50 ml of water are added to the reaction mixture and then the medium is extracted with 50 ml of dichloromethane. The solvents are evaporated off and then the solid is used in the next stage without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH:9]([CH3:19])[CH:8]=1)(=O)=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH2:10][CH:9]([CH3:19])[CH:8]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1ccc2c(c1)CC(C)C=C2OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)CC(C)C=C2c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 88.1 %

Procedure:
6-methoxy-3-methyl-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate (9.88 g, 30.7 mmol), 4-chlorophenylboronic acid (6.23 g, 39.9 mmol) and K2CO3 (12.7 g, 91.9 mmol) were combined in a mixture of toluene/ethanol/water (80 mL/40 mL/40 mL) at room temperature in a heavy walled pressure flask. Following sparging of the mixture with Ar for 30 minutes, PdCl2(dppf) (1.12 g, 1.53 mmol) was added in one portion and the flask was sealed and heated to 50° C. for 2.5 h. After returning to room temperature, the layers were separated and the aqueous layer was extracted with EtOAc and Hex (2×50 mL each). The combined organics were washed with brine, filtered through a pad of Celite, and dried over anhydrous MgSO4. The resulting solution was absorbed on silica gel in vacuo and purified via Yamazen column chromatography (0-15% EtOAc/Hex) to provide 7.7 g (88%) of the title compound as an amorphous white solid. 1H-NMR: 400 MHz, (CDCl3) δ: 7.32 (d, J=8 Hz, 2H); 7.26 (d, J=8 Hz, 2H); 6.87 (d, J=8.4 Hz, 1H); 6.57 (d, J=2.8 Hz, 1H); 6.62 (dd, J=8.4, 2.8 Hz, 1H); 5.74 (d, J=2.8 Hz, 1H); 3.79 (s, 3H); 2.81 (ABq, J=20.8, 12.4 Hz, 1H); 2.60 (m, 1H); 2.59 (ABq, J=8.4, 2.8 Hz, 1H); 1.14 (d, J=6.4 Hz, 3H).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([OH:10])[CH:8]=2)[CH:3]=[CH:2]1.CC1(C)C(C)(C)OB(C2C=C3[O:27][CH:26]=[CH:25][C:22]3=[N:23]C=2)O1>>[O:27]1[CH2:26][CH2:25][C:22]([O:10][C:7]2[CH:8]=[C:9]3[O:1][CH:2]=[CH:3][C:4]3=[N:5][CH:6]=2)=[N:23]1
Reactant: Oc1cnc2ccoc2c1
Reactant: CC1(C)OB(c2cnc3ccoc3c2)OC1(C)C
Product: c1cc2ncc(OC3=NOCC3)cc2o1

Procedure:
6-(4,5-dihydroisoxazol-3-yloxy)furo[3,2-b]pyridine I-69a and I-69b were prepared in 2 steps from racemic compound I-10 and furo[3,2-b]pyridin-6-ol using Method 5 after furo[3,2-b]pyridin-6-ol is prepared from 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine using Method 11. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=374.2 m/z. Activity: A
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])[CH3:3].C(N1C=CN=C1)([N:21]1C=CN=C1)=O.N>O1CCCC1>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([NH2:21])=[O:9])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(N)=O)cc(C(C)(C)C)c1O
Temperature: 26 °C
Reaction time: 2 h
Yield: 104.1 %

Procedure:
In a 22 L Morton flask, 749 g (3.0 mol) of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, 533 g (3.3 mol) carbonyldiimidazole and tetrahydrofuran (THF) were combined and heated slowly to reflux and allowed to reflux for 2.5 hours. The reaction mixture was cooled to 26° C. and concentrated aqueous ammonia was added. Stirring was continued for 2 hours and the reaction mixture was allowed to stand overnight. The contents were transferred to a flask and rinsed with tetrahydrofuran (250 mL). The mixture was stirred, layers were separated, and the aqueous layer was saved. The organic layer was washed with brine (2.5 L) followed by brine/deionized (DI) water (1 L/1.5 L). The organic layer was washed with 9.7 M hydrochloric acid (HCl)/deionized water (0.25 L/2.25 L), followed by 9.7 M hydrochloric acid/deionized water (0.5 L/2.8 L), and 9.7 M hydrochloric acid/deionized water/brine (0.5 L/1.5 L/1.5 L). The organic layer was set aside while the combined aqueous layers were washed with tetrahydrofuran. The combined organic layers were washed with brine, dried with sodium sulfate (855 g) and filtered. The filtrate was evaporated to 1011 g of a wet (water), white solid. Methylene chloride was added and removed in vacuo. This procedure was repeated with ethyl acetate (6 L, then 2 L) to produce a solid residue (779 g). The residue was slurried in ethyl acetate and heptane, filtered, and dried in a vacuum oven to yield the desired amide (736 g, 98.7%) as a white solid mp 257-260° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]CC3C=CC=CC=3)[CH:18]=2)[N:3]=1.C1CCCCC=1>C1COCC1.[Pd]>[NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[N:3]=1
Reactant: Cc1ccc(C(=O)n2nc(Nc3cccc(OCc4ccccc4)c3)nc2N)cc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)n2nc(Nc3cccc(O)c3)nc2N)cc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 12.4 %

Procedure:
To a solution of 5-amino-3-[3-(benzyloxy)phenylamino]-1-(4-(methyl)phenyl)carbonyl-1H-1,2,4-triazole (Ia-14) (0.50 g, 1.3 mmol) in THF (20 mL) was added cyclohexene (10 mL) and 10% Pd/C (0.10 g). The reaction was stirred at 90° C. under N2 for 48 h, then filtered through diatomaceous earth, washing with THF, and concentrated to give a yellow-orange solid. Purification by flash chromatography (95:5 CH2Cl2/CH3OH) followed by triturated in CH2Cl2 afforded 5-amino-3-[3-(hydroxy)phenylamino]-1-(4-(methyl)phenyl)carbonyl-1H-1,2,4-triazole (Ia-15) (0.05 g, 14%) as a yellow solid: Rf 0.22 (95:5 CH2Cl2/CH3OH); mp (DSC) 2 endothermic events, 214.7-217.5° C., 322.1-329.8° C., 1 exothermic event, 226.8-228.8° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.14 (d, J=8.1 Hz, 2H), 8.13 (d, J=8.2 Hz, 2H), 7.77 (s, 2H), 7.36 (d, J=8.1 Hz, 2H), 6.99-6.94 (m, 3H), 6.29-6.25 (m, 1H), 2.45 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.2, 158.2, 157.6, 157.3, 142.9, 142.0, 130.6,129.7, 129.1, 128.5, 107.8, 107.4, 104.0, 21.0; IR (ATR) 3363, 1668 cm−1; APCI MS m/z 310 [C16H15N5O2+H]+; HPLC (Method A) 96.9% (AUC), tR=11.5 min. Anal. Calcd for C16H15N5O2.0.50H2O: C, 60.47; H, 4.92; N, 22.03. Found: C, 60.87; H, 4.65; N, 21.75.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][C:5](=[O:7])[CH:4]=[C:3]1N1CCCC1.C[OH:15]>Cl>[OH:15][C:3]1[C:2]([CH3:13])([CH3:1])[O:6][C:5](=[O:7])[CH:4]=1
Reactant: CC1(C)OC(=O)C=C1N1CCCC1
Reactant: CO
Agent: Cl
Product: CC1(C)OC(=O)C=C1O
Temperature: 88 °C

Procedure:
A suspension of 5,5-dimethyl-4-pyrrolidin-1-ylfuran-2(5H)-one (535 mg) in a mixture of MeOH (2 mL) and 5M HCl (8 mL) was heated at 88° C. for 2 hours. The mixture was cooled to room temp., extracted with CHCl3 (10×15 mL), combined, dried over Na2SO4, and evaporated to dryness to give 4-hydroxy-5,5-dimethyl-5H-furan-2-one as light brown solid. Yield: 359 mg, 95%.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[C:10]1([C:16]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:24]3[CH:20]([CH2:21][NH:22][CH:23]3[C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:19](=[O:34])[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[C:27]1([CH2:26][C:25]([CH:23]2[CH:24]3[CH:20]([C:19]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([OH:34])[CH2:18][CH2:17][C:16]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:21][NH:22]2)=[O:33])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2C1CNC2C(=O)Cc1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)C1NCC2C1C(c1ccccc1)(c1ccccc1)CCC2(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
A solution of phenylmagnesium bromide (prepared starting from 3.14 g of bromobenzene and 0.48 [lacuna] of magnesium in 30 cm3 of ether) is added to a suspension of 4.09 g of (3aRS,7aRS)-7,7-diphenyl-2-phenylacetylperhydroisoindol-4-one in 50 cm3 of tetrahydrofuran. The reaction mixture is stirred at 25° C. for 1 hour and then heated under reflux for 2.5 hours, cooled and treated with 150 cm3 of a saturated solution of ammonium chloride. The organic phase is washed with water (2×100 cm3). The aqueous phases are extracted with 100 cm3 of ethyl acetate. The combined organic phases are washed with 100 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 30 cm3 of acetonitrile to give 2.9 g of (3aRS,4RS,7aRS)-2-phenylacetyl- 4,7,7-triphenylperhydroisoindol-4-ol in the form of white crystals which melt at 270° C.
Reaction SMILES: [CH:1]([C:9]1[C:17]2[C:12](=[CH:13][C:14](N)=[CH:15][CH:16]=2)[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N([O-])=O.[Na+].[I:31]I>CC(O)=O.O.Cl>[I:31][C:14]1[CH:13]=[C:12]2[C:17]([C:9]([CH:1]=[CH:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[N:10][N:11]2[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=1
Reactant: II
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(N)cc21
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Temperature: 2 °C
Reaction time: 0.5 h
Yield: 113.7 %

Procedure:
To a solution of 3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamine (1.58 g, 4 mmol) in AcOH (14 mL), water (3 mL) and concentrated HCl (1.67 mL) cooled to 2° C. was added a solution of NaNO2 (304 mg, 4.4 mmol) in water (0.5 mL) over 5 min. The resulting dark red solution was stirred at 2° C. for 0.5 h, then a solution of KI (797 mg, 4.8 mmol) and I2 (610 mg, 2.4 mmol) in water (1 mL) was added drop-wise so as to keep the internal temperature below 5° C. After 2 h at 2° C. the reaction was allowed to stir at 23° C. for 17 h. The reaction was quenched with 3 N NaOH (aq), diluted with EtOAc (50 mL) and H2O (15 mL), the phases were separated and the aqueous was extracted 2×15 mL EtOAc. The pooled organic phase was washed 3×20 mL 5% NaHSO3, brine (15 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. The crude reaction was purified by silica gel chromatography (eluting with 1:1 hexane:EtOAc) to give 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as a white solid (1.3 g, 68% yield). 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 7.79 (d, 1H, J=9.0 Hz), 7.30–7.60 (m, 8H), 5.73 (s, 2H), 3.63 (t, 2H, J=6.0 Hz), 0.96 (t, 2H, J=6.0 Hz), 0.0 (s, 9); 13C NMR (75 MHz, CDCl3) δ 143.6, 142.4, 137.2, 132.1, 130.8, 129.0, 128.3, 126.8, 122.5, 122.4, 119.6, 119.5, 92.9, 78.1, 66.9, 18.0, −1.2. Anal. Calc'd: C, 52.94; H, 5.29; N, 5.88. Found: C, 52.66; H, 5.29; N, 5.74.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=O)[NH:5][CH:6]=1.P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39]>CC(C)=O.CCOCC>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39].[CH3:1][C:2]1[N:3]=[C:4]2[CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[N:5]2[CH:6]=1
Reactant: Cc1c[nH]c(Cc2ccccc2NC(=O)N2CCN(C)CC2)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: Cc1cn2c(n1)Cc1ccccc1N=C2N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 10 g of 1-[2-(4-methyl-2-imidazolylmethyl)phenylcarbamoyl]-4-methylpiperazine, 86 ml of phosphorous oxychloride and 7.24 g of phosphorous pentachloride is stirred at room temperature for 4 hours and evaporated to dryness. The residue is suspended in 186 ml of methylene chloride and 55.2 ml of triethylamine is added dropwise at 0° over a period of 15 minutes. The mixture is stirred at room temperature overnight, poured into cold water, basified with 10% aqueous potassium carbonate and extracted with methylene chloride. The methylene chloride extracts are re-extracted with 2N hydrochloric acid. The acidic extracts are basified with 2N aqueous sodium hydroxide and extracted three times with methylene chloride. The organic extracts are dried over magnesium sulfate, decolorized with charcoal and evaporated to dryness. The residue is chromatographed from 180 g of silica gel using methylene chloride-methanol-ammonium hydroxide (300:50:1) as eluant to give a foamy material which is dissolved in acetone and treated with an equivalent amount of maleic acid to give on dilution with ether the 2-methyl-5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine mono-maleate, m.p. 195°-197°.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:34])=[C:11]([NH:13][C:14]([C:16]3[CH:33]=[CH:32][C:19]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:25]([C:26](OC)=[O:27])=[CH:24][N:23]=4)=[CH:18][CH:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:34])=[C:11]([NH:13][C:14](=[O:15])[C:16]3[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:25]([CH2:26][OH:27])=[CH:24][N:23]=4)=[CH:32][CH:33]=3)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(COc2ccc(C(=O)Nc3cc(C(=O)NC4CC4)ccc3C)cc2)nc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(CO)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
To a solution of methyl 6-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}methyl)nicotinate (200 mg, 0.436) in THF (10 mL) was added LiAlH4 (33 mg, 0.871 mmol). Extra THF (7 mL) was added and the mixture was stirred for 16 h at room temperature. Glauber's salt (Na2SO4.10H2O) (1.0 g, 3.11 mmol) was added and the reaction was stirred for a further 16 h. The mixture was filtered and the solid washed with methanol (40 mL). The filtrates were evaporated and the resulting crude material was purified by SCX cartridge to give the title compound as a white solid (150 mg, 80%); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.67 (m, 2H), 2.25 (s, 3H), 2.85 (m, 1H), 4.56 (d, 2H), 5.28 (s, 2H), 5.59 (t, 1H), 7.15 (d, 2H), 7.34 (d, 1H), 7.51 (d, 1H), 7.64 (m, 1H), 7.79 (m, 2H), 7.97 (m, 2H), 8.37 (d, 1H), 8.55 (s, 1H), 9.83 (s, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](Cl)(Cl)[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:9]([O:8][C:6](=[O:7])[C:5]([NH:4][C:1](=[O:3])[CH3:2])([CH:25]([C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)[C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: Fc1ccc(C(Cl)(Cl)c2ccc(F)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of diethyl acetamidomalonate (238 mg, 1.1 mmol) in N,N-dimethylformamide (1 mL) was added 55% sodium hydride (44 mg, 1.1 mmol), and the mixture was stirred at room temperature for 1 hr. Bis(4-fluorophenyl)methylene chloride (93 μL, 0.5 mmol) and tetra-n-butylammonium iodide (24 mg) were added, and the mixture was stirred at 50° C. for 16 hrs and then at 80° C. for 16 hrs. After completion of the reaction, HPLC quantitative analysis was performed to confirm 161 mg of the title compound (Inertsil ODS-2, 0.03 M phosphate buffer:acetonitrile=90:10-25:75 (20 min), 220 nm, 1.0 mL/min, rt).
Reaction SMILES: O[C@@H:2]([C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[C:23]=1[CH3:32])[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1.C1(P([N:47]=[N+:48]=[N-:49])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(C)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>ClCCl>[N:47]([C@H:2]([C:22]1[C:23]([CH3:32])=[C:24]2[C:25](=[CH:30][CH:31]=1)[C:26](=[O:29])[O:27][CH2:28]2)[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1)=[N+:48]=[N-:49]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC1=C(N2CCC3(CCN(C[C@@H](O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1=C(N2CCC3(CCN(C[C@H](N=[N+]=[N-])c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 35 °C
Reaction time: 20 h

Procedure:
To a suspension of 8-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (Example 8, 500 mg, 1.13 mmol) and diphenylphosphoryl azide (643 mg, 1.36 mmol) in a mixed solvent of toluene and dichloromethane (v:v, 10:1, 11 mL) was added DBU (343 mg, 2.26 mmol). The reaction mixture was stirred at 35° C. for 20 h. The solvent was removed by evaporation and the residue was purified by flash column chromatography (0-100% ethyl acetate in petroleum ether) to afford the title compound. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 5.26 (s, 2H), 5.23 (s, 2H), 4.99 (dd, J=4.0 Hz, 9.2 Hz, 1H), 4.00 (t, J=6.8 Hz, 2H), 2.95-2.87 (m, 2H), 2.78-2.73 (m, 1H), 2.60-2.57 (m, 1H), 2.48-2.43 (m, 1H), 2.33 (s, 3H), 2.10 (t, J=6.8 Hz, 2H), 2.03-1.86 (m, 6H), 1.51-1.48 (m, 2H); MS-ESI (m/z): 466 (M+1)+.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:16]=[CH:15][C:10]2[NH:11][CH2:12][CH2:13][O:14][C:9]=2[CH:8]=1)[CH3:6])C.[OH-].[Na+].CC(O)=O>C1COCC1.O>[O:14]1[C:9]2[CH:8]=[C:7]([CH:5]([CH3:6])[C:4]([OH:17])=[O:3])[CH:16]=[CH:15][C:10]=2[NH:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)C(C)c1ccc2c(c1)OCCN2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc2c(c1)OCCN2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 2-(3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-propionic acid ethyl ester (258 mg) in THF (3 mL) and H2O (3 mL) was added NaOH (134 mg) at room temperature. After being stirred for 20 h at room temperature, the reaction mixture was acidified with AcOH (pH=4) and diluted with water. The resulting mixture extracted with dichloromethane and the combined organic layer was dried magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (CH2Cl2:MeOH=15:1) to afford the product as a brown oil. (150 mg, 65.8%)
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:18])[CH2:4][CH:5]([CH3:17])[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[CH:10]=1)([OH:8])[CH3:7].[Cl:19]CCl.[OH-].[Na+].[H-].C([Al+]CC(C)C)C(C)C>CCOCC>[ClH:19].[CH3:18][N:3]([CH3:2])[CH2:4][CH:5]([CH3:17])[C:6]([C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)([OH:8])[CH3:7]
Reactant: ClCCl
Reactant: COc1cccc(C(C)(O)C(C)CN(C)C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Product: CC(CN(C)C)C(C)(O)c1cccc(O)c1
Yield: 71 %

Procedure:
Starting from (RS)-3-dimethylamino-1-(3-methoxy-phenyl)-2-methyl-propan-1-one and methyl iodide, (2RS,3SR)-4-dimethylamino-2-(3-methoxy-phenyl)-3-methyl-butan-2-ol hydrochloride (23) was obtained, under the conditions given in Example 1 (1st step) and using ether as a solvent, in a yield of 46% and with a melting point of 178°-179° C. The base was released from (23) with dichloromethane/sodium hydroxide solution. After drying the solvent, the dichloromethane was distilled off under vacuum. 23.7 g (0.1 mole) of the base were reacted with diisobutylaluminium hydride as in Example 2. In this manner, 18.5 g (71% theoretical) of hydrochloride (22) were obtained with a melting point of 183°-184° C.