Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=[N:13][NH:14][C:15]([NH2:17])=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1.[P:18]([O:23]C)([O:21][CH3:22])[O:19][CH3:20]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[N:13][NH:14][C:15]([NH2:17])=[O:16])[CH2:2][P:18](=[O:23])([O:21][CH3:22])[O:19][CH3:20])=[N:7][CH:8]=1
Reactant: COP(OC)OC
Reactant: NC(=O)NN=C(CCl)COc1ccc(Cl)cn1
Product: COP(=O)(CC(COc1ccc(Cl)cn1)=NNC(N)=O)OC
Reaction time: 2 h

Procedure:
1-Chloro-3-(5-chloropyrid-2-yloxy)-2-semicarbazonopropane (322 mg.) and trimethyl phosphite (720 mg.) were mixed and heated at 70°-100° C., with stirring, for 11/2 hours. The mixture was evaporated to dryness, finally under high vacuum, to give dimethyl 3-(5-chloropyrid-2-yloxy)-2-semicarbazonopropylphosphonate, RF = 0.15 (5% v/v methanol in ethyl acetate), the required starting material.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[C:24]3[C:19](=[C:20]([O:25][CH3:26])[N:21]=[CH:22][CH:23]=3)[N:18]([CH3:27])[CH:17]=2)[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:31]>CN(C)C=O>[CH:1]1([CH2:4][N:5]([CH3:31])[C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[C:24]3[C:19](=[C:20]([O:25][CH3:26])[N:21]=[CH:22][CH:23]=3)[N:18]([CH3:27])[CH:17]=2)[CH2:3][CH2:2]1
Reactant: CI
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3NCC3CC3)cn(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3N(C)CC3CC3)cn(C)c12
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
A solution of the product from Example 44B (0.116 g, 0.301 mmol) in dimethylformamide (2 mL) under nitrogen was treated with sodium hydride (0.018 g, 0.451 mmol) at ambient temperature, stirred for 30 minutes, treated with iodomethane (0.038 mL, 0.602 mmol), stirred for 30 minutes at ambient temperature and quenched into cold water. The mixture was extracted into ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated to afford the title compound (0.12 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([C:10]([OH:12])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:13]([NH:20][CH2:21]/[C:22](/[CH3:25])=[CH:23]/[CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.[O-]P1(OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)O1)=O.[Na+].[Na+].[Na+].[Na+].C(OCC)(=O)C>C(Cl)Cl>[CH2:13]([N:20]([CH2:21]/[C:22](/[CH3:25])=[CH:23]/[CH3:24])[C:10]([CH:9]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=2[CH2:8]1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C1Cc2c(Cl)cccc21
Reactant: C/C=C(\C)CNCc1ccccc1
Agent: O=P1([O-])OP(=O)([O-])OP(=O)([O-])OP(=O)([O-])O1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C(\C)CN(Cc1ccccc1)C(=O)C1Cc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
3-Chloro-1,2-dihydrocyclobutabenzene-1-carboxylic acid (3.78 mmol, 690 mg) was dissolved in DCM (10 ml). (E)-N-benzyl-2-methylbut-2-en-1-amine (5.67 mmol, 993 mg) and triethylamine (7.56 mmol, 1.050 ml, 765 mg) were added, followed by cyclophos 50% in ethyl acetate (4.53 mmol, 2.70 ml, 2886 mg). The reaction mixture was stirred overnight at room temperature and then diluted with DCM (5 ml) and washed in turn with 2 N HCl (10 ml), 2 N NaOH (10 ml) and brine (10 ml). The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a crude residue that was purified by silica column chromatography (eluting with heptane—50% ethyl acetate:heptane) to give (E)-N-benzyl-3-chloro-N-(2-methylbut-2-enyl)-1,2-dihydrocyclobutabenzene-1-carboxamide (430 mg). m/z: 340.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([Br:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:14]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([Br:12])=[C:10]([Cl:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1c(Br)ccc(N)c1C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1c(C)c(N)cc(Cl)c1Br
Temperature: 60 °C
Reaction time: 15 h
Yield: 95.9 %

Procedure:
To a solution of methyl 3-amino-6-bromo-2-methylbenzoate (960 mg, 3.93 mmol) in acetonitrile (40 mL) was added N-chlorosuccinimide (525 mg, 3.93 mmol) under ice-cooling, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→30/70) to give the title compound (1.05 g, yield 96%).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][NH:13][C:14]3[C:19]([N+:20]([O-])=O)=[CH:18][C:17]([C:23]([F:26])([F:25])[F:24])=[CH:16][N:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.CC(O)=O.CO>C(Cl)Cl.[Zn]>[CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][NH:13][C:14]3[C:19]([NH2:20])=[CH:18][C:17]([C:23]([F:26])([F:24])[F:25])=[CH:16][N:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1nc2ccc(CNc3ncc(C(F)(F)F)cc3[N+](=O)[O-])cc2s1
Agent: [Zn]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CSc1nc2ccc(CNc3ncc(C(F)(F)F)cc3N)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a mixture of N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitro-5-(trifluoromethyl)pyridin-2-amine (0.97 g, 2.42 mmol), HOAc (4 mL), and MeOH (4 mL) in DCM (30 mL) cooled in ice-water bath was slowly added zinc dust (1.6 g, 24.2 mmol). The reaction mixture was stirred at 0° C. for 2 h. The mixture was filtered and the filtrate was diluted with DCM and then washed with water and aq NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford N2-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-5-(trifluoromethyl)pyridine-2,3-diamine (0.89 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.44-7.41 (m, 1H), 7.03 (d, J=1.8 Hz, 1H), 4.84 (br s, 1H), 4.78 (d, J=5.1 Hz, 2H), 3.29 (br s, 2H), 2.79 (s, 3H). LCMS (ESI) m/z 371 (M+H)+.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]3[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=3)=[CH:3][CH:2]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C1(C)C=CC=CC=1.CO>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]3[CH:12]=[C:11]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:10]=[CH:9][C:8]2=3)=[CH:3][CH:2]=1
Reactant: Brc1ccc2c(c1)Cc1ccccc1N2c1ccc(-c2ccccc2)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: c1ccc(-c2ccc(N3c4ccccc4Cc4cc(-c5ccccc5)ccc43)cc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
10-(biphenyl-4-yl)-2-bromo-9,10-dihydroacridine compound (10 g, 24.3 mmol) was dissolved in toluene (300 mL) under a nitrogen atmosphere. Then, phenyl boronic acid (3.6 g, 29.2 mmol) was added thereto. To the resultant mixture solution, tetrakis triphenyl phosphine palladium (1.1 g, 0.97 mmol) and potassium carbonate (10.1 g, 72.9 mmol) were added. Then, distilled water (40 mL) was added thereto, followed by reflux-stirring for 3 hours. The resultant solution was cooled to about 60° C., and purified by silica gel. Then, a toluene layer was extracted. The extracted organic solvent was concentrated and removed, and methanol was added to produce a solid. Through filtration, a yellowish brown solid was obtained. It was dissolved by methylene chloride, and added with methanol in small amounts so as to obtain required 10-(biphenyl-4-yl)-2-phenyl-9,10-dihydroacridine compound (7.8 g, yield 78%, pale yellow solid).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](OCC)(=O)[CH:12]=[O:13].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:12](=[O:13])[CH:11]=[N:10]2
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=c1cnc2cc(Cl)c(Cl)cc2[nH]1

Procedure:
4,5-Dichlorophenylenediamine (26.0 g, 147 mmol) and 50% ethyl glyoxylate in toluene (32 mL, 161 mmol) in ethanol (250 mL) was refluxed for 18 h. The reaction was cooled and the crystallized brown product was collected by filtration, then washed with ethanol (50 mL). The obtained product (25.5 g, 81%) was 96% pure via LC/MS. MS (ES) m/e 215[M+H]+.
Reaction SMILES: [N+:1]1([O-])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13][CH3:14])=[O:12])[C:2]=1[C:15]([O:17][CH3:18])=[O:16].P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13][CH3:14])=[O:12])[C:2]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc2ccccc2[n+]([O-])c1C(=O)OC
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: COC(=O)c1cc2ccccc2nc1C(=O)OC

Procedure:
A solution of N-oxide 3 (10 mM) and phosphorus trichloride (30 mM) in anhydrous chloroform (100 ml) was refluxed for 7 h. Solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate and then evaporated under reduced pressure. The residue was recrystallized from isopropanol to provide the title dimethyl quinoline-2,3-dicarboxylate 7 as an off white (or light yellow) powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:18]=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:13]([F:24])=[CH:12][N:11]=1>>[Cl:23][C:20]1[N:19]=[CH:18][C:17]([NH:16][C:14]2[C:13]([F:24])=[CH:12][N:11]=[C:10]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=3)[N:15]=2)=[CH:22][CH:21]=1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(Cl)nc1
Product: Oc1cccc(Nc2ncc(F)c(Nc3ccc(Cl)nc3)n2)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro -N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-N4-(6-chloropyridin-3-yl)-5-fluoro-4-pyrimidineamine gave N4-(6-chloropyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.10 (bs, 1H), 9.64 (bs, 1H), 8.85 (m, 1H), 8.30 (m, 2H), 8.22 (d, 1H, J=4.2 Hz), 7.43 (d, 1H, J=8.7 Hz), 7.01 (m, 3H), 6.42 (bd, 1H, J=8.4 Hz); LCMS: purity: 93%; MS (m/e): 332 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H][H]>[Ni].O.C(O)C>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1cnc2cc[nH]c2c1
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: c1cnc2c(c1)NCC2
Yield: 11.8 %

Procedure:
1.49 g of Raney nickel at 50% in water are added to a solution of 1.5 g of 4-azaindole in 45 ml of absolute ethanol, in an autoclave under argon. The mixture is hydrogenated under 100 bar of hydrogen at a temperature of 95° C. for 41 h. After a return to ambient temperature, the catalyst is filtered off through Clarcel and the filtrate is concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g 15-40 μm silica cartridge, elution being carried out with pure dichloromethane and then with a 99/1 v/v mixture of dichloromethanemethanol with a flow rate of 80 ml/min, and then on a 30 g 15-40 μm silica cartridge, elution being carried out with pure dichloromethane with a flow rate of 30 ml/min. 0.18 g of 4-azaindoline is thus obtained in the form of a pale yellow solid which melts at 63° C. (Kofler bench).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:24](=[O:25])[C@@H:23]([NH:26][C:27](=[O:39])[C@@H:28]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29])[C:17]3([CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[O:16][C:15]3[CH:40]=[CH:41][CH:42]=[CH:43][C:14]1=3)=[C:7]([O:44][CH3:45])[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2[C:66]3[O:65][C:64]4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C[OH:89]>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:33]([O:32][C:31]([N:30]([CH3:38])[C@@H:28]([CH3:29])[C:27]([NH:26][C@H:23]1[C:17]2([CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[O:16][C:15]2[CH:40]=[CH:41][CH:42]=[CH:43][C:14]=2[N:13]([CH2:12][C:8]2[C:7]([O:44][CH3:45])=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([C:64]([O:65][CH3:66])=[O:89])=[CH:3]3)[C:24]1=[O:25])=[O:39])=[O:37])([CH3:34])([CH3:35])[CH3:36]
Reactant: CO
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C2(CCOCC2)Oc2ccccc21
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COC(=O)c1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C4(CCOCC4)Oc4ccccc43)c(OC)ccc2c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
tert-butyl (S)-1-((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (0.17 g, 249 μmol, Eq: 1.00), Pd(OAc)2 (2.24 mg, 9.96 μmol, Eq: 0.04) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (11.5 mg, 19.9 μmol, Eq: 0.08) were combined in a 5 mL microwave tube, the vessel was evacuated and purged with N2. MeOH (79.8 mg, 101 μl, 2.49 mmol, Eq: 10) and TEA (0.5 mL) were added, the vessel was purged with CO gas for approximately 30 sec and placed in an oil bath heated to 70° C. After 18 h, the mixture was cooled, diluted with EtOAc, washed with 1 N HCl, H2O, and brine. The organic mixture was dried over Na2SO4, concentrated and the residue purified by flash chromatography to afford methyl 5-(((S)-3-((S)-2-(tert-butoxycarbonyl (methyl)amino)propanamido)-4-oxo-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-5 (4H)-yl)methyl)-6-methoxy-2-naphthoate (110.5 mg, 67% as a light yellow foam.) MS m/z 662.3 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13][C:14](Cl)(Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)(Cl)Cl.Cl>C1(C)C(C)=CC=CC=1>[ClH:13].[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:14](=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: ClC(Cl)(Cl)c1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(N=C(Nc2ccc(C(=O)OCC)cc2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
To a stirred suspension of ethyl 4-aminobenzoate (165.0 g; 1.0 mole) in xylene (465 mL) was added α,α,α-trichlorotoluene (100.7 g; 0.52 mole). The mixture was allowed to reflux for 18 h, then was cooled to 0° C. and filtered. The resultant precipitate was washed with ice-cold xylene (2×70 mL), triturated with hot toluene and dried to yield the salt (89.8 g; 39.7%) as white crystals: mp 214.0°-215.5° C. 1H-NMR (CDCl3) 8.0-6.9 (m, 14H), 4.3 (q, 4H, J=7 Hz), 1.4 (t, 6H, J=7 Hz); IR (CHCl3) 1715, 1600; MS (m/e) 416 (M+ -HCl), 252 (base).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:33]([C:34]#[C:35][CH2:36][NH:37][C:38](=[O:43])[C:39]([F:42])([F:41])[F:40])=[CH:32][N:13]([C@@H:14]2[O:31][C@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@@H:16]([O:17][CH2:18]SC)[CH2:15]2)[C:12](=[O:44])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC=1.[N-:51]=[N+:52]=[N-:53].[Na+]>C(Cl)Cl.CN(C=O)C>[C:1]([NH:9][C:10]1[C:33]([C:34]#[C:35][CH2:36][NH:37][C:38](=[O:43])[C:39]([F:42])([F:41])[F:40])=[CH:32][N:13]([C@@H:14]2[O:31][C@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@@H:16]([O:17][CH2:18][N:51]=[N+:52]=[N-:53])[CH2:15]2)[C:12](=[O:44])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CSCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: [Na+]
Solvent: C1=CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)C[C@@H]1OCN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
The starting material (14) (1.65 g, 2.99 mmol) was dissolved in DCM (18 ml) and cooled to 0° C. Cyclohexene (1.5 ml, 14.95 mmol) and SO2Cl2 (0.72 ml, 8.97 mmol) were added and stirred 1 h in ice bath. TLC indicated starting material still to be present whereupon a further aliquot of SO2Cl2 (0.24 ml) was added and the mixture stirred for 1 h at 0° C. Volatiles were removed by evaporation to yield a light brown solid that was redissolved in 18 ml of dry DMF (18 ml) under N2. Sodium azide (0.97 g, 14.95 mmol) was then added to the solution and stirred for 2.5 h at room temperature. The reaction mixture was passed through a pad of silica and eluted with EtOAc and the volatiles removed by high vacuum evaporation. The resulting brown gel was purified by flash chromatography (petroleum ether:EtOAc 4:1 to 2:1) to yield the desired product as a white crystalline solid (15) (0.9 g, 55%). 1H NMR (d6 DMSO): δ 0.00 (s, 6H, CH3), 0.78 (s, 9H, tBu), 2.16 (m, 1H, H-2′), 2.22 (m, 1H, H-2′), 3.70 (d, 1H, J=11.5 Hz, H-5′), 3.75 (d, 1H, J=11.3 Hz, H-5′), 4.01 (m, 1H, H-4′), 4.10 (m, 1H, CH2NH), 4.23 (m, 1H, H-3′), 4.76 (s, 2H, CH2S), 5.99 (m, 1H, H-1′), 7.37 (m, 2H, Ph), 7.50 (m, 2H, Ph), 7.81 (d, 1H, J=7.4 Hz, Ph), 7.95 (s, 1H, H-6), 9.78 (br s, 1H, NHCH2), 12.64 (br s, 1H, NH). Mass (−ve electrospray) calcd for C28H34F3N7O6Si 649.71. found 648.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[O:8][CH:7]([C:15]([Cl:18])([Cl:17])[Cl:16])[C:6]=2[CH:19]=1.[C:20](Cl)(=[O:22])[CH3:21].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:20]([N:1]([C:24](=[O:26])[CH3:25])[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:12])([Cl:13])[Cl:14])[O:8][CH:7]([C:15]([Cl:18])([Cl:17])[Cl:16])[C:6]=2[CH:19]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reactant: CC(=O)Cl
Product: CC(=O)N(C(C)=O)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2

Procedure:
A mixture of 6-amino-2,4-bis(trichloromethyl)benzo[1,3]dioxin (1.0 g.), acetyl chloride (1 ml.) and acetic anhydride (25 ml.) was warmed on a steam bath for 5 hours. The reaction mixture was cooled and evaporated to dryness under reduced pressure. Trituration of the oily residue with aqueous ethanol gave a solid product, which was crystallised from ethanol to give 6-diacetylamino-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 147°-148° C.
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:12]=[N+:13]=[N-:14].[Na+].C(OC)=O.CO>O>[O:1]([CH2:8][CH:9]([OH:10])[CH2:11][N:12]=[N+:13]=[N-:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: COC=O
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCC(O)COc1ccccc1
Yield: 101 %

Procedure:
A procedure similar to that described in preparation 12 was repeated, except that 1.00 g of phenoxymethyloxirane, 1.94 g of sodium azide, 10 ml of methyl formate and 45 ml of an 8:1 by volume mixture of methanol and water were used, to give 1.30 g of the title compound as a pale yellow oil having an Rf value of 0.26 (on silica gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:10]([C:12]1[S:13][C:14]([Cl:17])=[CH:15][CH:16]=1)=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Cl:17][C:14]1[S:13][C:12]([C:10](=[O:11])[CH:3]([NH:2][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=2)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(N)C(=O)c1ccc(Cl)s1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A mixture of ethyl 3-amino-4-(5-chlorothiophen-2-yl)-4-oxobutyrate hydrochloride (596 mg), 4-fluorobenzoyl chloride (380 mg) and sodium hydrogen carbonate (1.0 g) in ethyl acetate (10 ml) and water (10 ml) was stirred at room temperature for 2 hours. To the reaction mixture were added ethyl acetate (30 ml) and water (30 ml), and the organic layer was collected. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with hexane to obtain a crude product of ethyl 4-(5-chlorothiophen-2-yl)-3-[(4-fluorobenzoyl)amino]-4-oxobutyrate (732 mg) as colorless powder.
Reaction SMILES: [CH3:1][N:2]([CH2:30][CH3:31])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[N:17]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[C:16](=[O:29])[CH2:15][S:14]1.[H][H]>C(O)C.[Pd]>[CH3:1][N:2]([CH2:30][CH3:31])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[N:17]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)[C:16](=[O:29])[CH2:15][S:14]1
Reactant: CCN(C)CCCOc1ccccc1C1SCC(=O)N1CCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCN(C)CCCOc1ccccc1C1SCC(=O)N1CCc1ccc(N)cc1

Procedure:
A suspension of 10 parts of 2-[2-[3-(methylethylamino)propoxy]phenyl]-3-[2-(4-nitrophenyl)ethyl]-4-thiazolidinone (see Example 19) in 100 ml of ethanol is treated with 1 part of 5% palladium on carbon and placed under 3 atmospheres of gaseous hydrogen. The mixture is shaken until one equivalent of hydrogen is consumed, filtered and the solvent evaporated under reduced pressure to give the title compound.
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([C:15]2([CH:21]=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[F:14].C1C[O:26][CH2:25][CH2:24]1>CCOC(C)=O>[F:7][C:8]1[CH:9]=[C:10]([C:15]2(/[CH:21]=[CH:24]/[C:25]([O:4][CH2:2][CH3:5])=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Reactant: O=CC1(c2ccc(F)c(F)c2)CCCCC1
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/C1(c2ccc(F)c(F)c2)CCCCC1
Reaction time: 0.25 h
Yield: 45.9 %

Procedure:
To a solution of triethyl phosphonoacetate (1.802 mL, 9.00 mmol) in THF (20 mL) at 0° C. was added 1M potassium t-butoxide (9.00 mL, 9.00 mmol) dropwise, and the mixture was stirred at the same temperature. After 15 mins, a solution of 1-(3,4-difluorophenyl)cyclohexanecarbaldehyde (Int. 3-B, 1.009 g, 4 5 mmol) in 10 mL of THF was added, and the mixture was stirred at room temperature for 2 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and evaporated to give an oily residue. The residue was purified by Combiflash (80 g silica gel) eluting with 5:95 EtOAc-hexane to give (E)-ethyl 3-(1-(3,4-difluorophenyl)cyclohexyl)acrylate (Int. 3-C, 608 mg, 45.9% yield for 2 steps) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 6.98-7.16 (3 H, m), 6.91 (1 H, d, J=15.82 Hz), 5.60 (1 H, d, J=16.26 Hz), 4.17 (2 H, q, J=7.18 Hz), 1.83-2.06 (4 H, m), 1.40-1.61 (6 H, m), 1.27 (3 H, t, J=7.03 Hz).