Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:38])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1>O1CCCC1>[CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:38])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccccc1CCN(CCCCC(=O)c1ccc2c(c1)CCN2)C(=O)OC(C)(C)C
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)N1CCc2cc(C(=O)CCCCN(CCc3ccccc3OC)C(=O)OC(C)(C)C)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
Ethyl isocyanate (85 mg) was added to a solution of tert-butyl 5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate (362 mg) obtained in Reference Example 50 in tetrahydrofuran (2 ml), and the mixture was stirred at 60° C. for 2 hours. The solvent was evaporated under reduced pressure, water was added to the resulting residue, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting solvent; hexane:ethyl acetate=1:1) to give the title compound as a pale yellow oil (254 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]=[C:27]=[S:28]>O1CCCC1.[Na].[H][H].C(=O)([O-])[O-]>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:27](=[S:28])[NH:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[Cl:18]
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: [H][H]
Agent: O=C([O-])[O-]
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCO
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.7 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (13.1 g, 50.6 mmol) and 2,4-dichloro-1-isothiocyanatobenzene (13.4 g, 65.8 mmol) in tetrahydrofuran (150 mL) was stirred at room temperature for 3 days. The mixture was diluted with saturated aqueous sodium hydrogen, carbonate, concentrated in vacuo, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give methyl 4-chloro-3-{[(2,4-dichlorophenyl)carbamothioyl]amino}-2-[(3-hydroxypropyl)amino]benzoate as a colorless powder (19.6 g)
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16]([NH:18]C)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].Cl.N[C@H:36](C(N)=O)C>>[NH2:18][C:16]([C@@H:15]([NH:14][C:12](=[O:13])[C:11]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Br:1])=[C:3]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])[N:4]=[CH:5]2)[CH:10]=1)[CH3:36])=[O:17]
Reactant: C[C@H](N)C(N)=O
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Agent: Cl
Product: Cc1ccc(C(=O)N[C@@H](C)C(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 40 %

Procedure:
The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide using L-alaninamide HCl (0.33 g 2.5 mmol) as the amine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (370 mg, 40%) as beige solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.95 (m, 1H), 7.83 (dd, 1H, J=2 Hz), 7.62 (m, 1H), 7.54 (d, 1H, J=8.4 Hz), 7.01 (m, 2H), 5.60 (q, 2H, J=12.4 Hz), 4.55 (m, 1H), 2.19 (s, 3H), 1.46 (dd, 3H J=1.2) ES-HRMS m/z 521.0598 (M+H C22H20BrF2N4O4 requires 521.0630).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7][C:6]2=O.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2
Reactant: COc1ccc2[nH]ccc(=O)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2nccc(Cl)c2n1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To the intermediate 6-methoxy-1,5-naphthyridin-4(1H)-one (15.0 g, 0.085 mol) was added POCl3 (300 mL) dropwise under nitrogen atmosphere at RT. The reaction mixture was heated to 110° C. with constant stirring. After 12 h, the mixture was concentrated in vacuo and azeotroped with toluene (2×100 mL). The residue was dissolved in ice-water (100 mL) and adjusted pH of the solution to 7 using 10% NaHCO3 solution, and extracted with EtOAc (4×100 mL). The combined organic extracts were washed with water (2×100 mL), saturated NaCl solution (100 mL), dried (Na2SO4), filtered and concentrated in vacuo.
Reaction SMILES: C([Li])(C)(C)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][N:8]=1.[I:17]I>C1COCC1.C(OCC)(=O)C.O>[Cl:6][C:7]1[CH:12]=[C:11]([I:17])[C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][N:8]=1
Reactant: COCOc1ccc(Cl)nc1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1cnc(Cl)cc1I
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
Add tert-buty lithium (1.7 M in pentane, 72 mL, 123 mmol) to a solution of 2-chloro-5-methoxymethoxy-pyridine (10.8 g, 62 mmol) in THF (300 mL) at −70° C. dropwise over 10 min. Stir the resulting solution at −70° C. for 30 min. Add a solution of iodine (23 g, 92 mmol) in THF (150 mL) dropwise over 30 min. Stir the resulting solution at −70° C. for 1 hour. Remove the ice bath and allow the reaction to warm to room temperature. Dilute the mixture with ethyl acetate and water and isolate the phases. Extract the aqueous phase with two portions of ethyl acetate. Combine the organic extracts and wash with two portions of aqueous sodium thiosulfate, one portion of water, one portion of saturated aqueous sodium chloride, dry over sodium sulfate, filter and concentrate in vacuo. Triturate the resulting solid with hexane. Collect the solid by vacuum filtration and wash the solid with hexane. Dry the solid under vacuum to give the title compound (10.8 g, 58%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.98 (s, 1H), 5.43 (s, 2H), 3.40 (s, 3H).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.[CH2:21]([O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])[CH3:22].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:21]([O:23][C:24](=[O:31])[C@@H:25]([NH:26][C:16]([C@@H:11]1[CH2:12][S:13][CH2:14][CH2:15][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=1)(=[O:8])=[O:9])=[O:18])[CH2:27][CH:28]([CH3:29])[CH3:30])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CSCCN1S(=O)(=O)c1ccc(C)cc1

Procedure:
6 ml (0.042 mol) of TEA was added to a mixture of 4.2 g (0.14 mol) of (3R)-4-(Toluene-4-sulfonyl)-thiomorpholine-3-carboxylic acid, 3.0 g (0.017 mol) of L-leucine ethyl ester hydrochloride, 3.2 g (0.014 mol) of DCC, and 1.7 g (0.014 mol) of DMAP in 200 ml of CH2Cl2, and the mixture was reacted at room temperature for 24 h. After the reaction, the solid was removed by sucking filtration, the solvent was removed by evaporation, the residue was dissolved with an appropriate amount of ethyl acetate, filtered to remove the insoluble matter, diluted with ethyl acetate, successively washed with 10% of NaHCO3 solution and saturated NaCl solution, dried with Na2SO4. The drying agent was removed, ethyl acetate was removed by evaporation, the residue was separated by flash chromatographic column (eluent: CH2Cl2:CH3Cl=1:1), to obtain 4.0 g of oily matter. 1H-NMR (400 MHz, CDCl3): δ 7.77237-7.74077 (m, 2H), 7.36382 (d, 2H, J=7.988 Hz), 6.74090 (d, 1H, J=9.244 Hz), 4.80098-4.77466 (m, 1H), 4.68244-4.58898 (m, 1H), 4.28174-4.15708 (m, 3H), 3.53789-3.28674 (m, 1H), 3.13092 (d, 1H, J=13.676), 2.56954-2.42247 (m, 5H), 2.24620-2.20545 (m, 1H), 1.66352-1.53450 (m, 3H), 1.30702-1.26745 (m, 3H), 0.96159-0.91891 (m, 6H); MS (EI) m/z: 443.1, 397.1, 369.1, 287.1, 256.0, 213.1, 155.0, 139.0, 112.0, 91.0, 65.0.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][C:12](=[O:22])[CH2:13][C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])[O:8][C@@H:7]([N:23]2[CH:30]=[C:29]([CH2:31][CH3:32])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:6]1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(COC)OC>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][CH:12]([OH:22])[CH2:13][C:14]2[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])[O:8][C@@H:7]([N:23]2[CH:30]=[C:29]([CH2:31][CH3:32])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](CCC(=O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](CCC(O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O

Procedure:
A solution of 149 mg of 3'-O-acetyl-5'-[3-(2,6-dichlorophenyl)-2-oxopropyl]-2',5'-dideoxy-5-ethyluridine and 26 mg of sodium borohydride in 7 ml of dimethoxyethane was stirred at room temperature for 2.5 hours. The solvent was removed by evaporation and the residue was taken up in 22 ml of 5% ammonium chloride solution and extracted twice with 20 ml of ethyl acetate each time. The extracts were washed with 20 ml of water, dried over anhydrous sodium sulphate and evaporated to give 3'-O-acetyl-5'-[3-(2,6-dichlorophenyl)-2(RS)-hydroxypropyl]-2',5'-dideoxy-5-ethyluridine in the form of a colourless gum. This was dissolved in 3 ml of 0.1M sodium methoxide solution and stirred at room temperature for 1 hour. The solution was then diluted with 150 ml of methanol, stirred with a cross-linked polystyrene/divinyl benzene cation exchange resin containing sulphonic acid groups (H+ form) and then filtered. The filtrate was evaporated and the residue was crystallized from ethanol to give 45 mg of 5'-[3-(2,6-dichlorophenyl)-2(RS)-hydroxypropyl]-2' ,5'-dideoxy-5-ethyluridine, mp 185°-186° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C.CCCCCC.CCOCC>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)c1ccc(F)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)C(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-fluorophenyl glyoxylic acid (100 mg, 0.595 mmol) in ethyl ether (5 ml) was added trimethylsilyl diazomethane (2 M/hexane, 1 ml) at 0° C. TLC showed reaction was complete after 1 h. The ether was evaporated to leave a yellow oil. Chromatography with hexane/ether (95:5) gave methyl 4-fluorophenylglyoxalate as a pale yellow oil (75 mg). 500 MHz 13C NMR (CDCl3): δ 184.11; 167.85; 165.79; 163.59; 133.04; 132.96; 128.97; 116.33; 116.16; 115.90; 115.72; 52.85.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:8][CH2:7][C:6]=2[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:28].FC1C=CC(CN2CCC3C(C(OCC)=O)=NC=C(OC)C=3C2=O)=CC=1>>[CH3:28][O:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH2:8][CH2:7][C:6]=2[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(OC)cc1)C2=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: CCOC(=O)c1ncc(OC)c2c1CCN(Cc1ccc(F)cc1)C2=O
Product: CCOC(=O)c1ncc(OC)c2c1CCN(Cc1ccc(OC)cc1)C2=O

Procedure:
The title product was prepared by treating ethyl 4-hydroxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate with TMS-diazomethane, using a method set forth in Step 5 of Example 8 for the preparation of ethyl 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate, except that after quenching with HOAc the reaction was concentrated in vacuo and partitioned between sat aq NaHCO3 and CHCl3. LRMS (M+1)=371.0
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][C:8]([N+:15]#[C-:16])([CH3:14])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11].[CH3:17][C:18]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:19]=1[CH:20]=O>Cl(O)(=O)(=O)=O>[CH3:17][C:18]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:19]=1[C:20]1[N:1]=[C:2]2[N:6]=[CH:5][NH:4][N:3]2[C:16]=1[NH:15][C:8]([CH3:14])([CH3:7])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: Nc1nc[nH]n1
Reactant: Cc1ccc(C)c(C=O)c1
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1ccc(C)c(-c2nc3nc[nH]n3c2NC(C)(C)CC(C)(C)C)c1

Procedure:
Compound 54 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) 1,1,3,3-tetramethylbutylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2,5-dimethylbenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:18])=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C>O>[Cl:19][CH2:20][C:21]([N:11]1[C:5]2[CH:4]=[C:3]([Br:18])[C:2]([Br:1])=[CH:17][C:6]=2[NH:7][C:8](=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[N:12][C:10]1=2)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: O=C1Nc2cc(Br)c(Br)cc2Nc2ncccc21
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1Nc2cc(Br)c(Br)cc2N(C(=O)CCl)c2ncccc21

Procedure:
6,11-Dihydro-8,9-dibromo-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one (0.1 mol) in 300 ml. of water-free dioxane is dissolved by heating to reflux. To the boiling solution is added, dropwise over 30 minutes, a solution of 15. g. (0.14 mol) of chloroacetyl chloride, dissolved in 40 ml. of water-free dioxane, and simultaneously 14.4 (0.14 mol) of triethylamine, dissolved in 30 ml. of water-free dioxane. The mixture is refluxed for 8 hours and then filtered while hot. The filtrate is evaporated in vacuo, and the resulting residue is recrystallized from acetonitrile to give 11-chloroacetyl-8,9-dibromo-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][CH2:5][C@H:6]([NH:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][OH:8].Cl[C:30]1[C:34]2[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:33]=2[O:32][N:31]=1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]2[O:32][N:31]=[C:30]([O:8][CH2:7][C@@H:6]([NH:9][C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][S:4][CH3:3])[C:34]=2[CH:35]=1
Reactant: Clc1ccc2onc(Cl)c2c1
Reactant: CSC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CSC[C@@H](COc1noc2ccc(Cl)cc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 77.6 %

Procedure:
To a suspension of 0.44 g of 60% (w/w) sodium hydride in 6 ml of N,N-dimethylformamide is dropwise added 15 ml of an N,N-dimethylformamide solution of 4.0 g of (R)-3-methylthio-2-tritylamino-1-propanol over 15 minutes with ice-cooling, and the temperature is gradually elevated to 80° C., after which this is added to a solution of 2.07 g of 3,5-dichloro-1,2-benzoisoxazole in 10 ml of N,N-dimethylformamide. They are subjected to reaction at the same temperature for one hour. After cooling, water and ethyl acetate are added and shaken, and the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluant:n-hexane:ethyl acetate=20:1], to obtain 4.4 g of oily (R)-5-chloro-3-(3-methylthio-2-tritylaminopropoxy)-1,2-benzoisoxazole.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH3:10].[Cl-].[CH2:12]([O:14][C:15](=[O:19])[C:16]([OH:18])=[O:17])[CH3:13].C(N([CH2:25][CH3:26])CC)C>CCOCC>[C:16]([O:18][C:16]([C:15]([O:19][CH2:25][CH3:26])=[O:14])=[CH:10][C:3]1[N:2]([CH3:1])[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=1)(=[O:17])[C:15]([O:14][CH2:12][CH3:13])=[O:19]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C(=O)O
Reactant: Cc1ncc([N+](=O)[O-])n1C
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(=O)OC(=Cc1ncc([N+](=O)[O-])n1C)C(=O)OCC
Yield: 54 %

Procedure:
The reaction of 1,2-dimethyl-5-nitroimidazole with oxalic acid ethyl ester chloride in the course of 22 hours in the presence of triethylamine and of substantial amounts of ether gives 1-carbethoxy-2-(1-methyl-5-nitro-imidazol-2-yl)-vinyl ethyl oxalate in 54 percent yield; the latter compound, on treatment with ethanol, gives 1-methyl-5-nitro-imidazol-2-yl-pyruvic acid ethyl ester in 43 percent yield (J. Heterocycl., loc. cit., 904 and 905). ##STR4##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:24])[C@H:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](=N)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:24])[C@H:15]([N:23]=[C:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1[C@@H](O)[C@H](N)Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCNC[C@@H]1[C@@H](O)[C@@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
Dissolve 2-(R)-(2-(R)-amino-1-(S)-hydroxy-3-phenylpropyl)-piperazine-1-carboxylic acid tert-butyl ester (98 mg, 0.29 mmol) in dry dichloromethane and add benzophenoneimine (0.083 ml, 0.49 mmol) by syringe, stir overnight, and purify (silica gel chromatography, eluting with ethyl acetate and 98:2 ethyl acetate:triethylamine) to obtain (144 mg, 95% yield) of the title compound (144 mg, 95%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=3)[O:9]2)=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)OC(c1ccc(Cl)cc1)CC2=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: COc1ccc2c(=O)cc(-c3ccc(Cl)cc3)oc2c1
Yield: 79 %

Procedure:
50 mg (0.17 mmol) of 2-(4-chloro-phenyl)-7-methoxy-chroman-4-one synthesized in Preparation 4 and 3.0 molar equivalents (0.12 g, 0.51 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was refuxed in benzene solvent for a day, and then benzene was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethylacetate=5/1, v/v) to give the title compound in a yield of 79%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)([O-:3])=[O:2].[C:13](=O)([O:19]C(C)(C)C)[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[N:10]=[CH:9]2)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cccc2cn[nH]c12
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1ncc2cccc([N+](=O)[O-])c21
Yield: 59 %

Procedure:
A solution of 7-nitro-1H-indazole (2.81 g, 17.23 mmol), di-tertbutyl carbonate (7.52 g, 34.5 mmol), triethylamine (4.81 mL, 34.5 mmol) and 4-dimethylamino-pyridine (2.11 g, 17.2 mmol) in anhydrous acetonitrile (100 mL) is stirred under nitrogen at ambient temperature for approximately 3 hrs. After removing the solvent in vacuo, the residue is partitioned between ethyl acetate and aqueous sodium hydrogen sulfate (1N). The organic layer is separated, washed with saturated aqueous brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by chromatography on flash grade silica gel using DCM. Fractions containing the product are combined, concentrated in vacuo to a solid and dried under high vacuum to provide the title compound as a yellow solid (2.674 g, 10.16 mmol). 1H NMR (300 MHz, d6-DMSO) δ=1.55 (s, 9H); 7.58 (t, J=8.0 Hz, 1H); 8.20 (d, J=7.4 Hz, 1H); 8.30 (d, J=7.7 Hz, 1H); 8.67 (s, 1H), TLC: Rf =0.5 (DCM).
Reaction SMILES: [Na].[CH:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([OH:11])[CH:3]=1.[Br:12][CH:13](Br)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:12][CH2:13][CH2:14][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[CH:2][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCCBr)cc1

Procedure:
1.97 g of the sodium salt of p-nitrophenol(0.01 mol), 2.16 ml of dibromoethane (0.025 mol) and 0.5g of potassium carbonate were taken in 50 ml of dry acetone (4A activated molecular sieves) and refluxed overnight. Potassium carbonate was filtered and the solvent was removed by rotary evaporation to yield 4-(2-bromoethoxy)nitrobenzene (L) in almost quantitative yield. 1H-NMR: CDCl w: 365 (t,2H), 44 (t,2H), 70-83 (ABq,4H)/
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].II.[CH2:12]1[CH:16]2[CH2:17][C:18](=[O:19])[CH:14]([CH2:15]2)[CH2:13]1>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2([OH:19])[CH2:17][CH:16]3[CH2:15][CH:14]2[CH2:13][CH2:12]3)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=C1CC2CCC1C2
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CC2CCC1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-bromo-4-fluorobenzene (5.00 ml, 45.5 mmol), magnesium turnings (3.32 g, 137 mmol), and a few iodine crystals in 70 ml dry THF were vigorously stirred for 4 hours under the protection of nitrogen and cooling with ice/water. Norcamphor (5.00 g, 45.5 mmol) dissolved in 10 ml dry THF was added drop-wise, and the reaction was allowed to warm up to room temperature and stirred overnight. The reaction was carefully quenched with water and decanted from the excess magnesium turnings. The reaction mixture in THF and water was adjusted to pH 7 with 2N HCl solution and extracted with chloroform (3×50 ml). The extract was dried over anhydrous sodium sulfate and the solvent was removed by vacuum evaporator. This resulted in an alcohol intermediate (III) appearing as a faintly yellow oil (9.4 g, 99%).