Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:14][CH2:15][Cl:16])[P:5]1(=[O:13])[NH:10][CH:9](O)[CH2:8][CH:7]([CH3:12])[O:6]1.[CH:17]1([NH3+:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[SH:24][CH2:25][CH2:26][S:27]([O-:30])(=[O:29])=[O:28].ClC(Cl)(Cl)C(O)=O>O.CC(C)=O>[CH:17]1([NH3+:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl:1][CH2:2][CH2:3][N:4]([CH2:14][CH2:15][Cl:16])[P:5]1(=[O:13])[NH:10][CH:9]([S:24][CH2:25][CH2:26][S:27]([O-:30])(=[O:29])=[O:28])[CH2:8][CH:7]([CH3:12])[O:6]1
Reactant: CC1CC(O)NP(=O)(N(CCCl)CCCl)O1
Reactant: O=S(=O)([O-])CCS
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH3+]C1CCCCC1
Solvent: CC(C)=O
Solvent: O
Product: CC1CC(SCCS(=O)(=O)[O-])NP(=O)(N(CCCl)CCCl)O1
Reaction time: 20 h

Procedure:
1.45 g (5 mmol) of 2-(bis-(2-chloroethyl)-amino)-4-hydroxy-6-methyl-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide and 1.2 g (5 mmol) of cyclohexylammonium-2-mercaptoethanesulphonate were dissolved in 5 ml of water and in 5 ml of acetone, acidified with trichloroacetic acid and left to stand for 20 hours at 0° C. The mixture was then filtered, the filtrate was carefully concentrated under vacuum, the residue was taken up twice in acetone and was concentrated. The residue was then dissolved in acetone, precipitated with ether, and washed with ether and dried.
Reaction SMILES: [C:1]1(=O)O[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.ClC(C)CCC(Cl)=O.[Cl:20][C:21]1[CH:30]=[C:25]([C:26]([NH:28][OH:29])=[O:27])[C:24]([OH:31])=[CH:23][CH:22]=1>[Cl-].[Zn+2].[Cl-]>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[O:31][CH:1]3[CH2:2][CH2:3][CH:4]([CH3:5])[O:29][N:28]3[C:26](=[O:27])[C:25]=2[CH:30]=1
Reactant: O=C1CCCCO1
Reactant: O=C(NO)c1cc(Cl)ccc1O
Agent: CC(Cl)CCC(=O)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=S(Cl)Cl
Product: CC1CCC2Oc3ccc(Cl)cc3C(=O)N2O1

Procedure:
A mixture of 30 g. of γ -valerolactone, 30 ml. of distilled thionyl chloride and 0.5 g. of zinc chloride was heated on a steam bath overnight and then distilled at 15 mm. The distillate was redistilled at 69- 70° and 15 mm. giving 34 g. of 4-chlorovaleryl chloride. The acid chloride was reduced catalytically, reacted with 5-chlorosalicylhydroxamic acid and the resulting intermediate was ring-closed according to the method described in Example 3. The product after recrystallization from trichloroethylene weighed 8.5 g. and melted at 210- 213° C.
Reaction SMILES: [Cl:1][C:2]1C=C[C:5]([NH:8]N=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][CH:3]=1.[C:23]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+].[CH2:47](O)[CH3:48]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:47][CH:48]=1)[NH:8][C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]2=1
Reactant: Clc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Reactant: CCO
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Clc1ccc2[nH]c3c(c2c1)CCCC3
Temperature: 25 °C
Yield: 91 %

Procedure:
N-(4-Chlorophenyl)benzophenone hydrazone (1.0 equiv., 0.5 mmol, 153 mg), cyclohexanone (1.5 equiv., 0.75 mmol, 0.078 mL), and TsOH.H2O (2 equiv., 1.0 mmol, 190 mg) were dissolved in ethanol (3 mL) and heated to reflux for 41 hours. The reaction mixture was then cooled to room temperature, diluted with Et2O (5 mL), neutralized with a saturated NaHCO3 solution, and extracted with Et2O (3×10 mL). The organic extracts were then dried over K2CO3, filtered and concentrated under vacuum. Purification by flash column chromatography (10% EtOAc/Hex) gave the title product as a white solid (94 mg, 0.46 mmol, 91% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:13][C@H:12]2[CH2:14][CH2:15][OH:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>C1COCC1>[Si:21]([O:16][CH2:15][CH2:14][C@@H:12]1[CH2:13][N:11]1[S:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=S(=O)(c1ccc(F)cc1)N1C[C@H]1CCO
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC[C@@H]1CN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To the 2-{(2R)-1-[(4-fluorophenyl)sulfonyl]aziridin-2-yl}ethanol from Step 3 dissolved in THF (0.2 M) was added TBSCl (1.1 equiv.) followed by imidazole (2.2 equiv.). The reaction mixture was stirred 1 h at rt, then filtered with washing of the solids with MTBE. The combined organics were washed (2×) with 1M HCl, brine (2×), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with EtOAc/Hex (1:9) to give the title compound (85%) as a white solid.
Reaction SMILES: C([N:5]([CH:10]1[C:16]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=2[O:14][CH2:13][CH2:12][CH2:11]1)[S:6]([CH3:9])(=[O:8])=[O:7])CCC.[H-].[Na+].ICCCC>CN(C=O)C>[CH3:9][S:6]([NH:5][CH:10]1[C:16]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=2[O:14][CH2:13][CH2:12][CH2:11]1)(=[O:7])=[O:8]
Reactant: CCCCN(C1CCCOc2ccc([N+](=O)[O-])cc21)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCI
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC1CCCOc2ccc([N+](=O)[O-])cc21

Procedure:
From 0.5 g of 5-methylsulfonylamino-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine 0.6 g of 5-(N-butyl-N-methylsulfonylamino)-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine were obtained by reaction with sodium hydride and iodobutane in DMF analogously to Example 11, m.p. 96-98° C.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27](=[O:28])[O:26]1>C(Cl)(Cl)Cl>[C:1]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([O:10][CH:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:27](=[O:28])[O:26]2)=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C1OC(Br)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccc(-c2ccccc2)cc1)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 6.3 g of 4-biphenylylacetic acid in 30 ml of chloroform and 3.4 g of triethylamine is added a solution of 6.2 g of 3-bromophthalide in 20 ml of chloroform. The solution thus obtained is stirred 24 hours at room temperature, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness. The residue, crystallized from petroleum ether, gives the phthalidyl 4-biphenylylacetate.
Reaction SMILES: [Na].[O:2]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4]P(=O)(OC)OC.[C:16]([O:19][CH:20]1[CH2:27][CH2:26][CH:25]2[CH:21]1[CH2:22][CH2:23][CH:24]2[CH:28]=O)(=[O:18])[CH3:17].C(O)(=O)C>O1CCCC1.C(OCC)C>[C:16]([O:19][CH:20]1[CH2:27][CH2:26][CH:25]2[CH:21]1[CH2:22][CH2:23][CH:24]2/[CH:28]=[CH:4]/[C:3](=[O:2])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:18])[CH3:17]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: CC(=O)OC1CCC2C(C=O)CCC12
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(=O)/C=C/C1CCC2C(OC(C)=O)CCC12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of the sodium salt of dimethyl (2-oxoheptyl)phosphonate (0.105 g; prepared as described in Reference Example 55) in tetrahydrofuran (5.3 ml) at 0° C. was treated dropwise with a solution of 6-acetoxy-2-formylbicyclo[3,3,0]octane (70 mg; prepared as described in Reference Example 21 and predominantly in the 2β-configuration) in tetrahydrofuran (1.0 ml) with stirring. The resulting mixture was stirred for 18 hours at ambient temperature under an atmosphere of argon. The mixture was then treated dropwise with a solution of glacial acetic acid (200 mg) in diethyl ether (1 ml), and then the solution was concentrated in vacuo. The residue was treated with diethyl ether (20 ml) and water (20 ml) and the organic layer was separated. The aqueous layer was extracted with diethyl ether (3×20 ml). The combined extracts were washed with water and then with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo, to give an oil which was subjected to chromatography on a silica gel column, to give (E)-6-acetoxy-2-(3-oxooct-1-enyl)bicyclo[3,3,0]octane (65.7 mg), predominantly in the 2β-configuration.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C@H:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:12]=2)[CH:7]=[CH:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:34](Cl)(=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[CH2:9][C@H:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([N:21]3[CH2:22][CH2:23][N:24]([C:34]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:43])[CH2:25][CH2:26]3)[N:12]=2)[CH:7]=[CH:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C=C[C@@H](Oc2nc(N3CCNCC3)nc3ccccc23)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1C=C[C@@H](Oc2nc(N3CCN(C(=O)OCc4ccccc4)CC3)nc3ccccc23)C1

Procedure:
To a solution of 4-[(1S,4R)-(4-acetoxycyclopent-2-en-1-yl)oxy]-2-(1-piperazinyl)quinazoline (2.07 g) in dry methylene chloride (15 ml) is added triethylamine (1.63 ml) with stirring under ice-cooling, and thereto is further added dropwise a solution of benzyl chlorocarbonate (0.92 ml) in dry methylene chloride (5 ml). The mixture is stirred under ice-cooling for 2 hours, and the reaction mixture is diluted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform) to give 4-[(1S,4R)-(4-acetoxycyclopent-2-en-1-yl)oxy]-2-[4-(benzyloxycarbonyl)piperazin-1-yl]quinazoline (2.36 g) as crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:20][Si](C(C)C)(C(C)C)C(C)C)[CH:5]=[C:6]([CH3:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[CH3:19][C:6]1[CH:5]=[C:4]([OH:20])[CH:3]=[C:2]([CH3:1])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([CH:16]([CH3:17])[CH3:18])[CH:10]=1
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1Cc1ccc(F)c(C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(O)cc(C)c1Cc1ccc(F)c(C(C)C)c1
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 3,5-dimethyl-4-(4′-fluoro-3′-iso-propylbenzyl)triisopropylsilanoxybenzene in THF (10 mL) at 0° C. was added TBAF (1 M, 4.0 mL). The reaction mixture was stirred for 3 h, diluted with ethyl acetate 920 mL) and quenched with water (10 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:9) to afford 3,5-dimethyl-4-(4′-fluoro-3′-iso-propylbenzyl)phenol (450 mg, 61% for two steps): 1H NMR (300 MHz, CDCl3): δ 6.97 (d, J=7.4 Hz, 1 H), 6.86 (m, 1 H), 6.69 (m, 1 H), 6.60 (s, 2 H), 3.95 (s, 2 H), 3.20 (m, 1 H), 2.22 (s, 6 H), 1.25 (d, J=6.4 Hz, 6 H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:9); Rf=0.50.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:17])[NH:6][C:7]1[CH:8]=[N:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=1.[C:20]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:14]([NH:13][C:10]1[N:9]=[CH:8][C:7]([NH:6][C:5]([N:29]2[CH2:30][CH2:31][N:26]([C:22]3[CH:21]=[C:20]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)=[O:17])=[CH:12][CH:11]=1)(=[O:16])[CH3:15]
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3cccc(-c4ccccc4)c3)CC2)cn1
Yield: 18 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl[6-(acetylamino)pyridin-3-yl]carbamate (301 mg, 0.923 mmol), 1-biphenyl-3-ylpiperazine (200 mg, 0.839 mmol) and diisopropylethylamine (0.292 ml, 1.68 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 14 hours. To the reaction solution was added water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the titled compound (62.6 mg, 18.0%) as solid product.
Reaction SMILES: C1CCCCC1.[Li]CCCC.[N+:12]([CH3:14])#[C-:13].C[O:16][S:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=O.[NH4+].[Cl-]>C1COCC1>[N+:12]([CH2:14][S:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:16])#[C-:13]
Reactant: COS(=O)c1ccccn1
Reactant: [C-]#[N+]C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: [C-]#[N+]CS(=O)c1ccccn1
Yield: 64.7 %

Procedure:
Two moles of a cyclohexane solution of BuLi (1.218 mmol, 1 equiv.) was added to 4 mL of a tetrahydrofuran solution of isocyanomethane (50 mg, 1.218 mmol, 10 equiv.) at a temperature of −78° C. After ten minutes, 0.5 mL of a THF solution of methylpyridine-2-sulfinate (210 mg, 1.34 mmol, 11 equiv.) was added at once. After thirty minutes, 5 mL of saturated, aqueous NH4Cl was added. A crude product was extracted with CH2 Cl2 (2×15 mL), dried (NaSO4), and concentrated. The crude product was purified by radial chromatography (1 mm alumina plate, 30:70 ethylacetate/hexanes) to produce 131 mg (65% yield) of 2-((isocyanomethyl)sulfinyl)pyridine as a white solid having M.P. 91-93° C.; IR (film) 542, 776, 960, 992, 1038, 1053, 1427, 1452, 1578, 2139, 2923, 2997 cm−1; NMR: δ 4.73 (ABq, Δv=83.3 Hz, J=14.3 Hz, 2H), 7.49-7.52 (m, 1H), 8.04-8.12 (m, 2H), 8.67-8.68 (m, 1H); 13C NMR: δ 60.33, 125.65, 125.82, 138.56, 150.02, 160.58, 165.10.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([S:39](Cl)(=[O:41])=[O:40])[CH2:36][CH2:37][CH3:38]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:39]([CH2:35][CH2:36][CH2:37][CH3:38])(=[O:41])=[O:40])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: CCCCS(=O)(=O)Cl
Product: CCCCS(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, 1-butanesulfonyl chloride.
Reaction SMILES: C(Cl)(Cl)[Cl:2].Cl.Cl.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[CH2:18][CH2:19][N:20]([CH2:22][CH2:23]Cl)[CH2:21][CH:16]3[CH2:15][N:14]=[C:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:12]=2[CH:31]=1.[OH2:32]>C(O)(C)C>[ClH:2].[ClH:7].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[CH2:18][CH2:19][N:20]([CH2:22][CH2:23][OH:32])[CH2:21][CH:16]3[CH2:15][N:14]=[C:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:12]=2[CH:31]=1
Reactant: ClCCN1CCN2c3ccc(Cl)cc3C(c3ccccc3)=NCC2C1
Reactant: O
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CC(C)O
Product: OCCN1CCN2c3ccc(Cl)cc3C(c3ccccc3)=NCC2C1

Procedure:
2.5 mole H2O are heated under reflux with 15 ml thionylchloride for 20 minutes. The solvent is subsequently removed and the base yielded with dilute water sodium hydroxide solution under cooling with ice and subsequently isolated from chloroform. 3.2 g of 1,2,3,4,4a,5-hexahydro-9-chloro-3-(β-chlorethyl)7-phenyl-pyrazino[1,2-a][1,4]benzodiazepinedihydrochloride.1.0 mole H2O.0.6 mole Isopropanol has been crystallized from isopropanol said compound having a freezing point of 220° C. (decomposing).
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][NH:4][CH2:5][CH:6]([OH:8])[CH3:7].C1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=C[C:19](S(O)(=O)=O)=[CH:18][CH:17]=1>O.C(C(C)=O)C(C)C>[CH3:19][C:18]1([CH2:17][CH:16]([CH3:26])[CH3:21])[N:4]([CH2:5][CH:6]([OH:8])[CH3:7])[CH2:3][CH:2]([CH3:1])[O:9]1
Reactant: CC(O)CNCC(C)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CC(C)CC1(C)OC(C)CN1CC(C)O

Procedure:
A reaction vessel equipped with a thermometer, a stirrer and a condenser having a water separator was charged with 133 g of diisopropanolamine, 100 g of benzene, 120 g of methyl isobutyl ketone and p-toluenesulfonic acid. The content was heated to reflux and reacted for another 5 hours with removing water. Benzene was removed under a reduced pressure and then distilled at 75° to 79° C./1 mmHg to obtain 152 g of 2-methyl-2-isobutyl-3-(2-hydroxypropyl)-5-methyloxazolidine.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]1)C1C=CC=CC=1>ClCCCl>[Cl:27][C:22]1[CH:21]=[C:20]([C@@H:18]2[CH2:19][NH:15][CH2:16][C@H:17]2[C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: COC(=O)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 98.3 %

Procedure:
1-Chloroethyl chloroformate (1.5 mL, 13.9 mmol) was added to a solution of (3S,4R)-methyl 1-benzyl-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylate (4.20 g, 11.5 mmol) in DCE (50 mL) at 0° C. The mixture was refluxed for 1 hour. After cooling, the solvent was removed under vacuum at 65° C. for 1 hour. MeOH (50 mL) was added to the residue and refluxed for 1 hour. The MeOH was removed. The solid was re-dissolved in CHCl3 and treated with saturated Na2CO3. The aqueous portion was separated and extracted with CHCl3 (2×30 mL). The organic phase was combined and dried. The solvent was removed to afford (3S,4R)-methyl 4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylate (3.1 g, 98%). (LCMS (APCI+) [M+H]+274.1; Rt: 2.25 min.).
Reaction SMILES: [NH2:1][C:2](=[O:22])[CH:3]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[CH2:4][C:5]([O:7]CC1C=CC=CC=1)=[O:6]>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[NH2:1][C:2](=[O:22])[CH:3]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[CH2:4][C:5]([OH:7])=[O:6]
Reactant: NC(=O)C(CC(=O)OCc1ccccc1)c1ccc(Br)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(=O)C(CC(=O)O)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 78 %

Procedure:
A suspension of benzyl 4-amino-3-(4-bromophenyl)-4-oxobutanoate (1.14 g, 3.16 mmol) and platinum(IV) oxide (30 mg) in ethanol/ethyl acetate (5:1; 120 mL) was stirred under an hydrogen atmosphere for 2 h. After replacement of hydrogen with nitrogen the crude reaction mixture was filtered through a thin pad of celite and the filtrate evaporated to dryness to give the title compound as a white solid (671 mg, 78%). LC/MS: 2.41 min; z/e 271 and 273, calcd (M+1) 271 and 271. 1H NMR (400 MHz: DMSO-d6): 7.50 (2H), 7.25 (2H), 3.95 (1H), 2.95 (1H), 2.45 (1H).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[P:30](Cl)(Cl)(=[O:42])[O:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C.[Cl:52]CCl>>[Cl:52][C:33]1[CH:34]=[CH:35][C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:32]=1[O:31][P:30](=[N:12][C@@H:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:42]
Reactant: ClCCl
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: N[C@H](C(=O)OCc1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates the tosylate salt of (S)-benzyl 2-amino-2-phenylacetate (1.11 mg, 2.69 mmol) was dissolved with the naphthalen-1-yl phosphorodichloridate (0.72 mg, 2.74 mmol) in 5 mL anhydrous dichloromethane. The solution was cooled down to −78° C. at which 0.76 mL of triethylamine (5.45 mmol) was added dropwise. Then the mixture was left stirring for 1 h at −78° C. and then 30 min at room temperature. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using Hexane/Ethyl acetate (1:1) as eluents, to provide (2S)-benzyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate in 74% yield.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[O-:11][CH2:12][CH3:13].[Na+].[Cl-].[NH4+].[CH3:17]N(C)C=O>C(O)C>[N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]([CH:17]=[CH:13][CH:12]=[O:11])[CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: CC[O-]
Reactant: Nc1ncnc2nc[nH]c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: Nc1ncnc2c1ncn2C=CC=O
Reaction time: 0.17 h
Yield: 52.9 %

Procedure:
To a suspension of adenine (135 mg; 1 mmole) in dimethylformamide (2 ml) at -40° there is added a solution of sodium ethoxide (prepared from 15 mg of sodium hydride) in ethanol (1 ml) and the mixture is stirred for 10 min. Propargyl aldehyde (59 mg; 1.1 mmole) is added in one portion and stirring is continued at -40° for 1 hr. The pale brown reaction mixture is then allowed to come to room temperature and neutralized by the addition of aqueous ammonium chloride. The precipitated solid (100 mg) is removed by filtration. It is recrystallized by dissolution in boiling water (240 ml) followed by cooling. This affords to the pure title compound (100 mg., 52.9%) m.p. 258°-60° C. The NMR spectrum of the material is in agreement with the postulated structure and shows absorption peaks at (DMSO) 7.17 (q,J,=7.8 HzJ2 =14.4 Hz, 1H, --CH=CH--CHO) 7.55 (S, 2H, NH2) 8.28 (S, 1H) 8.54 (d, J, J=14.4 Hz, 1H CH=CH--CHO) 8.64 (S, 1H) 9.68 (d, J-7.9 Hz, CHO). Mass spectrum m/z (intensity, % of base peak), ion: 189 (55.7)M+, 161 (98) (M-CO)+, 160 (32) (M-HCO)+, 134 (100) (MC3H∂)M+, 161 (98) (M-CO)+, 160 (32) (M-HCO)+, 134 (100) (MC3H3O)+, 118 (93).