Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=O)[NH:16][CH:17]=[N:18]3)=[C:13]([O:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:12]=2)[CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O.C(N(C(C)C)CC)(C)C.[Cl:43][C:44]1[C:49]([NH2:50])=[C:48]2[O:51][CH2:52][O:53][C:47]2=[CH:46][CH:45]=1>C1(C)C=CC=CC=1>[Cl:43][C:44]1[C:49]([NH:50][C:15]2[C:14]3[C:19](=[CH:20][C:11]([O:10][CH2:9][CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:12][C:13]=3[O:22][CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:18]=[CH:17][N:16]=2)=[C:48]2[O:51][CH2:52][O:53][C:47]2=[CH:46][CH:45]=1
Reactant: Nc1c(Cl)ccc2c1OCO2
Reactant: CN1CCN(CCOc2cc(OC3CCOCC3)c3c(=O)[nH]cnc3c2)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCOc2cc(OC3CCOCC3)c3c(Nc4c(Cl)ccc5c4OCO5)ncnc3c2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A first portion of 7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (0.19 g) in toluene (3 ml) was added to a stirred mixture of phosphoryl chloride (0.059 ml), diisopropylethylamine (0.13 ml) and toluene (3 ml) that was heated to 80° C. and the resultant mixture was heated to 80° C. for 6 hours. The mixture was allowed to cool to ambient temperature and was stirred overnight. The mixture was re-heated to 80° C. and a solution of 6-chloro-2,3-methylenedioxyaniline (0.088 g) in toluene (2 ml) was added. The resultant mixture was stirred and heated to 80° C. for 1.5 hours. The mixture was cooled to ambient temperature and the solvent was decanted from the oily gum that had been deposited. The oily gum was suspended in DMF (3 ml), a second portion of 7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (0.088 g) was added and the reaction mixture was heated to 100° C. for 9 hours. The mixture was allowed to cool to ambient temperature and partitioned between ethyl acetate and a 2M aqueous hydrochloric acid solution (10 ml). The aqueous solution was basified by the addition of 10M aqueous sodium hydroxide solution (10 ml) and extracted with methylene chloride. The organic solution was dried over magnesium sulphate and evaporated. The resultant oil was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.008 g); NMR Spectrum: (DMSOd6) 1.85-1.95 (m, 2H), 2.1-2.2 (m, 2H), 2.2 (s, 3H), 2.2-2.4 (m, 4H), 2.4-2.6 (m, 4H), 2.87 (m, 2H), 3.5-3.6 (m, 2H), 3.8-3.9 (m, 2H), 4.2 (m, 2H), 5.1 (m, 1H), 6.1 (s, 2H), 6.85 (s, 1H), 6.9 (s, 1H), 6.95 (d, 1H), 7.05 (d, 1H), 8.35 (s, 1H), 9.2 (s, 1H).
Reaction SMILES: CO[C:3]([O:15][CH3:16])([OH:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=1.[C:17](=[O:20])([O-])[O-].[K+].[K+].[CH3:23]I>CN(C=O)C>[CH3:17][O:20][CH:12]([O:13][CH3:23])[C:9]1[CH:8]=[CH:7][C:6](/[CH:5]=[CH:4]/[C:3]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: COC(O)(C=Cc1ccc(C=O)cc1)OC
Reactant: CI
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(C(OC)OC)cc1
Temperature: 40 °C
Yield: 89 %

Procedure:
4-Formylcinnamic acid dimethyl acetal (Cleeland, Jr., et al., U.S. Pat. No. 3,969,373; Jul. 13, 1976) (20.00 g, 90.00 mmol) and anhydrous potassium carbonate (12.44 g, 90.00 mmol) were stirred in anhydrous DMF (189 mL) for 5 minutes. Methyl iodide (12.8 g, 90.0 mmol) was added and the resulting mixture was stirred vigorously with gentle heating (oil bath at 40° C.) for 18 h. Volatiles were evaporated in vacuo and the residue partitioned between hexanes (400 mL) and water (100 mL). The hexanes layer was dried (magnesium sulfate) and evaporated to give (E)-methyl 4-(dimethoxymethyl)cinnamate as a pale yellow oil (18.98 g, 89%);
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6]C)=[O:5].[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Li+].[OH-]>C(Cl)Cl.O>[CH3:9][N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2](=[O:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CC(=O)Cl
Reactant: CNc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of methyl 3-chloro-3-oxopropanoate (1 mL, 9.32 mmol) and N-methyl aniline (1.01 mL, 9.32 mmol) in DCM (18.6 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue (N-methyl-N-phenyl-malonamic acid methyl ester, 2.55 g) was dissolved in THF (9 mL). A solution of LiOH×H2O (0.782 g, 18.64 mmol) in water (9 mL) was added and the mixture stirred for 1 h at room temperature. The THF was removed under reduced pressure and the remaining aqueous solution was acidified with 1N HCl (until pH-3) then extracted with EtOAc. The organic phase was concentrated under reduced pressure to afford the acid 31 (1.67 g, 93% yield) as a brown foam. MS (m/z): 194.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24](O)[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.S(Cl)([Cl:32])=O.CN(C)C=O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([Cl:32])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: FC(F)(F)C(Cl)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A mixture of 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (325 mg, 0.670 mmol), thionyl chloride (0.0978 mL, 1.34 mmol) and catalytic amount of dimethylformamide in tetrahydrofuran (6.7 mL) was stirred at room temperature for 2 h. The mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (297 mg, 0.590 mmol, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:24][N:25]([CH:32]([CH3:34])[CH3:33])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:29](=[O:30])/[CH:28]=[CH:27]/[CH2:26][N:25]([CH3:24])[CH:32]([CH3:34])[CH3:33])[CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)N(C)C/C=C/C(=O)O
Reactant: Fc1ccc(Nc2ncnc3oc4c(c23)CCNC4)cc1Cl
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2c(oc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3-chloro-4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]furo[2,3-d]pyrimidin-4-amine from Example 39A (100 mg, 0.314 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (85 mg, 0.44 mmol) to yield 80 mg (53%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(O)(=O)/C=C/C1C=CC(O)C=C1.C(N(CC)CC)C.[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>CN(C=O)C.ClCCl>[C:10]([NH:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)(=[O:12])/[CH:9]=[CH:8]/[CH:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH2:6]1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: NCCc1ccc(O)cc1
Agent: O=C(O)/C=C/C1C=CC(O)C=C1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(/C=C/C1C=CC(O)=CC1)NCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of 3-(4-hydroxyphenyl)propionic acid or p-dihydrocoumaric acid (1 g; 6.02 mmol) and of triethylamine (1.5 eq; 9.03 mmol) in DMF (10 mL) is cooled to 4° C. using an ice bath. An amine, tyramine (1 eq; 6.02 mmol) is added to the medium, followed by addition of a solution of BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1 eq; 6.02 mmol) in dichloromethane (10 mL); the mixture is stirred for about thirty minutes in the ice bath and then for 20 hours at room temperature. Stirring is then stopped and the dichloromethane is evaporated off under vacuum. 100 mL of water are added to the remaining solution and the mixture obtained is extracted with ethyl acetate (3×75 mL). The organic phase is successively washed with 100 mL of 1N HCl solution, 100 mL of water and 100 mL of 1M sodium bicarbonate (NaHCO3) solution. It is then dried over sodium sulfate and evaporated to dryness. The product is obtained in the form of a white precipitate after purification by chromatography on a column of silica gel.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2].[CH2:24]([I:27])[CH2:25][CH3:26]>>[I-:27].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:24][CH2:25][CH3:26])[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1C(C)=O)C2=O
Reactant: CCCI
Product: CCC[n+]1ccc(CC2CCc3cc(OC)ccc3C2=O)c(C(C)=O)c1
Product: [I-]

Procedure:
The title compound 135 is prepared according to the procedure reported in Example 38.1 with compound 103 (100.0 mg, 0.323 mmol) and propyl iodide (63 μL, 2 equiv) as reactants. Yellow solid. (Yield 116.2 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[F:10][C:11]([F:20])([F:19])[C:12]([OH:18])([CH3:17])[CH2:13][C:14](O)=[O:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O.CN(C=O)C>[NH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:14](=[O:15])[CH2:13][C:12]([OH:18])([CH3:17])[C:11]([F:20])([F:19])[F:10]
Reactant: CC(O)(CC(=O)O)C(F)(F)F
Reactant: Nc1ccc(Cl)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(CC(=O)Nc1ccc(Cl)cc1N)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A mixture of 4-chlorobenzene-1,2-diamine (1.32 g, 9.3 mmol), 4,4,4-trifluoro-3-hydroxy-3-methylbutanoic acid (1.6 g, 9.3 mmol), HATU (4.24 g, 11.2 mmol), DIPEA (3.1 mL, 18.6 mmol) and DMF (25 mL) was stirred at room temperature overnight. The mixture was diluted with water (150 mL), and then extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL), and then dried over Na2SO4, then filtered and concentrated. The residue was purified with flash column (30% EtOAc in PE to EtOAc) to give N-(2-amino-4-chlorophenyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide as brown oil (2.1 g, 76%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1>[OH-].[Na+]>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Oc1ccc(CCCc2ccncc2)cc1
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Product: CCCCOc1ccc(CCCc2ccncc2)cc1

Procedure:
Excess 1-bromobutane was added to a mixture of 0.9 g of 4-[3-(4-hydroxyphenyl)propyl]pyridine in 10 mL of 2N NaOH, and the mixture was refluxed for several hours. Then the mixture was cooled and the pH adjusted to 10. The product was extracted with CH2Cl2. The CH2Cl2 layer was then separated, washed with fresh water, filtered through phase separating paper, and concentrated. The residue was adsorbed onto silica gel and chromatographed over silica gel eluting with CH2Cl2 >15% EtOAc/CH2Cl2. Yield 0.45 g.
Reaction SMILES: [CH3:1][C:2]1[C:12]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.Cl.CNC.C=O.[CH3:23]C(C)=O.[C:27]([O:30]C(=O)C)(=[O:29])C>>[O:16]=[C:13]([C:12]1[C:2]([CH3:1])=[CH:3][C:4]2[O:9][CH2:8][C:7](=[O:10])[NH:6][C:5]=2[CH:11]=1)[CH:14]([CH3:23])[CH2:15][C:27]([OH:30])=[O:29]
Reactant: CC(C)=O
Reactant: CC(=O)OC(C)=O
Reactant: CCC(=O)c1cc2c(cc1C)OCC(=O)N2
Agent: C=O
Agent: CNC
Agent: Cl
Product: Cc1cc2c(cc1C(=O)C(C)CC(=O)O)NC(=O)CO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
3,4-Dihydro-7-methyl-6-(1-oxopropyl)-3-oxo-1,4(2H)-benzoxazine (23.7 g) was added to a mixture of 13 g of dimethylamine hydrochloride and 15 ml of 37% aqueous formaldehyde solution in 68 ml of acetic anhydride. After heating on a steam bath for three hours, 50 ml of acetone was added and heating was continued for 15 minutes. The solvents were removed by evaporation at reduced pressure and the residue was dissolved in 1N HCl and washed with ethyl acetate. The aqueous layer was basified with sodium hydroxide and the resultant crystals were collected by filtration. This product was dissolved in 500 ml of acetone and 10 ml of iodomethane were added. After heating at reflux overnight, the solid which formed was collected by filtration and washed with acetone. The product was dissolved in 400 ml of 50% aqueous methanol and 18 g of potassium cyanide in 200 ml of water was added. After stirring overnight at room temperature, the solid was collected and washed with water. The damp filter cake was suspended in 500 ml of 6N HCl and heated at reflux for 1.5 hours. Upon cooling a white precipitate formed which was collected by filtration and washed with water to give 19.4 g (81% yield) of the title compound, mp 169.5°-172° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C:12]34[C:15]5[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:16]=5[O:17][C:11]3=[CH:10][CH:9]=[CH:8][CH:7]4[C:6]2=[O:24])[CH2:3][CH2:2]1.[H][H]>>[CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C:12]34[C:15]5[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:16]=5[O:17][CH:11]3[CH2:10][CH2:9][CH:8]=[C:7]4[C:6]2=[O:24])[CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: COc1cccc2c1OC1=CC=CC3C(=O)N(CC4CC4)CCC123
Product: COc1cccc2c1OC1CCC=C3C(=O)N(CC4CC4)CCC321

Procedure:
Catalytic hydrogenation of 3-cyclopropylmethyl 9-methoxy-2,3-dihydro-1H-benzo[4,5]furo[3,2-e]isoquinolin-4[4H]-one (Example 4c) is carried out as in Example 4d but the reaction is stopped after one mole equivalent of hydrogen has been taken up, giving 3-cyclopropylmethyl-9-methoxy-2,6,7,7a-tetrahydro-1H-benzo[4,5]furo[3,2-e]isoquinolin-4[3H]-one. This, on treatment with m-chloroperbenzoic acid gives 3-cyclopropylmethyl-4a,5-epoxy-9-methoxy-2,4a,5,6,7,7a-hexahydro-1H-benzo[4,5]furo[3,2-e]isoquinolin-4[3H]-one which is reduced with lithium aluminum hydride to 3-cyclopropylmethyl-9-methoxy-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinolin-4a-ol.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:15][CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CC(O)C1)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC1CC(NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 65 h
Yield: 94.2 %

Procedure:
N-(Benzyloxycarbonyl)-3-amino-1-cyclobutanol (2.22 g, 10 mmol) from Step B and t-butyldimethylsilyl chloride (4.8 g, 32 mmol) were combined in 25 mL of anhydrous pyridine and the cloudy suspension was stirred over the weekend at ambient temperature, under a nitrogen atmosphere. After 65 h, the solution was concentrated in vacuo at 35°-40° C. The concentrate was diluted with 250 mL of methylene chloride and the methylene chloride solution was washed with 3×100 mL of water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue (3.9 g) was purified on a 1.0×45 cm silica gel column eluted @5 psi with 100 mL of hexane, followed by 200 mL of 10% acetone in hexane to give 3.16 g (88% yield) of the title compound; MS DCI-NH3M/Z: 336 (M+H)+, 353 (M+NH4)+ ; 1H NMR (CDCl3) δ - 0.03 (s, 6H), 0.83 (s, 9H), 1.75 (m, 2H), 2.68 (m, 2H), 3.69 (m, 1H), 3.93 (m, 1H), 5.06 (s, 2H), 7.30 (m, 5H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[P:13]([O-:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[K+].[I-].[Na+]>CN(C=O)C.CCOCC>[C:21]([O:20][P:13]([O:25][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 4-(bromomethyl)benzoate (1200 mg, 5.24 mmol), potassium di-tert-butyl phosphate (1431 mg, 5.76 mmol) and sodium iodide (785 mg, 5.24 mmol) were combined in DMF (3.00 mL) under nitrogen. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ether, washed with 10% LiCl solution and brine, then dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane/EtOAc) to provide Preparation 55A (571 mg, 1.593 mmol, 30%): 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.4 Hz, 2H), 7.53-7.37 (m, 2H), 5.05 (d, J=7.5 Hz, 2H), 3.92 (s, 3H), 1.48 (d, J=0.4 Hz, 18H).
Reaction SMILES: B(Br)(Br)Br.C([O:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:26]([CH3:32])[NH:27][C:28](=[O:31])[NH:29][N:30]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:16]1=[O:33])C1C=CC=CC=1.CO>C(Cl)Cl>[OH:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:26]([CH3:32])[NH:27][C:28](=[O:31])[NH:29][N:30]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:16]1=[O:33]
Reactant: CC1NC(=O)NN=C1c1ccc2c(c1)CCC(=O)N2CCOCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC1NC(=O)NN=C1c1ccc2c(c1)CCC(=O)N2CCO
Yield: 49.6 %

Procedure:
A solution of boron tribromide (4.59 g) in methylenechloride (5 ml) was added dropwise to a stirred suspension of 6-[1-(2-benzyloxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.38 g) in methylene chloride (200 ml) at -40° C. over a period of 10 minutes. After being stirred for 40 minutes at the same temperature, methanol (0.6 ml) was added to the suspension and evaporated in vacuo. The residue was dissolved in n-butanol, washed with brine, and evaporated in vacuo. The residual solid was washed with ethyl acetate and recrystallized from methanol to give 6-[1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.91 g), mp 237° to 243° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.O.[NH2:27][NH2:28]>CO>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:5]([CH2:4][C:3]([NH:27][NH2:28])=[O:2])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)(=[O:15])=[O:14])=[CH:17][CH:18]=1)[CH3:24]
Reactant: NN
Reactant: CCOc1ccc(S(=O)(=O)N(CC(=O)OC)c2ccc(C)cc2)cc1
Solvent: O
Solvent: CO
Product: CCOc1ccc(S(=O)(=O)N(CC(=O)NN)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
The crude carboxylic acid methyl ester, e.g. methyl{[(4-ethoxyphenyl)sulfonyl]-4-methylanilino}acetate (3.816 g, 10.5 mmol), was dissolved in MeOH (30 mL). Hydrazine hydrate was added (3.3 mL). The reaction mixture was stirred overnight at room temperature. A white precipitate was formed. It was isolated by filtration and rinsed with cold MeOH. From mother liquors some more compound could be recovered, affording the desired product, e.g. 4-ethoxy-N-(2-hydrazino-2-oxoethyl)-N-(4-methylphenyl)benzenesulfonamide (2.745 g, 72%) as a colorless solid in 99.8% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[C:4]([CH3:11])[CH:3]=1.Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:9]2=[S:10])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1N=C=S
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1N1C(=O)CN(C)C1=S
Yield: 58.9 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 9.18 g of 4-chloro-2-methylphenyl-isothiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from diethyl ether afforded the title compound (7.5 g) as an off-white solid, m.p. 113°-115° C. Anal. Calcd. for C11H11Cl N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.72; H, 4.17; N, 10.88. Mass spectrum (El, M.+) m/z 254/256.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH2:6]([NH:10][C:11](=[O:22])[CH2:12][CH2:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH3:9].Cl.O>CO>[CH2:6]([NH:10][C:11](=[O:22])[CH2:12][CH2:13][C:14](=[N:1][NH:2][C:3]([NH2:5])=[S:4])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:7][CH2:8][CH3:9]
Reactant: NNC(N)=S
Reactant: CCCCNC(=O)CCC(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCCNC(=O)CCC(=NNC(N)=S)c1ccccc1
Yield: 68.5 %

Procedure:
Thiosemicarbazide (1.95 g, 21.4 mmol) was added to a solution of N-butyl-4-oxo-4-phenyl-butyramide (5.0 g, 21.4 mmol), prepared in the previous step, in 75 ml of methanol plus 5.8 ml of 1 N HCl plus 5.8 ml of water and the reaction stirred at room temperature for 22 hours. The reaction was concentrated under reduced pressure at which time a solid formed. The solid was collected by filtration and dried to give 4.49 g of an off-white solid. Recrystallization of the solid from isopropyl alcohol gave 3.16 g (48%) of the title compound as a white solid, mp 64-68° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C.O>[O:1]1[CH2:2][CH2:3][C:4]2[CH:9]=[C:8]3[C:7](=[CH:6][C:5]1=2)[C:13](=[N:17][OH:18])[CH2:12][CH2:11][CH2:10]3
Reactant: O=C(O)CCCc1ccc2c(c1)CCO2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCCc2cc3c(cc21)OCC3

Procedure:
A mixture containing 46 g of the compound of Example 1, 60 g of hydroxylamine hydrochloride and 60 g of anhydrous sodium acetate in 410 ml of ethanol is brought to reflux for 5 hours. The mixture is then cooled and diluted with water, extracted with methylene chloride, dried and evaporated to dryness. The dry residue is recrystallized in ethanol.