Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:54])[C@@H:24]([NH:25][C:26](=[O:53])/[C:27](/[C:40]4[N:41]=[C:42]([NH:45]C(OC(C)(C)C)=O)[S:43][CH:44]=4)=[N:28]\[O:29][C:30]([C:33]([O:35]C(C)(C)C)=[O:34])([CH3:32])[CH3:31])[C@H:21]3[S:20][CH2:19][C:18]=2[S:55][CH:56](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:57][C:58]2[N:59]=[N:60][NH:61][CH:62]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.O>[NH2:45][C:42]1[S:43][CH:44]=[C:40](/[C:27](=[N:28]/[O:29][C:30]([C:33]([OH:35])=[O:34])([CH3:31])[CH3:32])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:54])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:55][CH2:56][S:57][C:58]4[N:59]=[N:60][NH:61][CH:62]=4)[CH2:19][S:20][C@H:21]23)=[O:53])[N:41]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SC(Sc4c[nH]nn4)C(c4ccccc4)(c4ccccc4)c4ccccc4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: COc1ccccc1
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCSc3c[nH]nn3)CS[C@H]12)c1csc(N)n1)C(=O)O
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-(1-t-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (822 mg: 0.706 mMol.) in a mixture of anisole (3 ml) and nitro- methane (12 ml) at -40° C. is added a solution of aluminum chloride (0.75 g: 5.64 mMol.) in anisole (3 ml), and the mixture is stirred at -30° to -40° C. for 1 hour. The reaction mixture is mixed with 1N-hydrochloric acid (5.7 ml), diluted with water, washed with ethyl acetate, and concentrated under reduced pressure to remove remaining organic solvents. The residual solution is subjected to chromatography over styrene-divinylbenzene copolymer (methanol: water=4:1) and resulting powder is washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid (299 mg) as pale yellowish white powder. Yield: 71%.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[CH2:7]([C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH2:10][CH3:11].Cl>CO>[CH2:7]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:2][OH:3])=[O:17])=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NO
Reactant: CCCCCc1ccc(C(=O)OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCc1ccc(C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Hydroxylamine hydrochloride (17.4 g, 250 mmol.) was dissolved in AR Grade methanol (50 mL) under argon, then added to NaOMe (25% w/w in MeOH) 132 mL, 580 mmol) under argon with ice cooling. A solution of methyl 4-pentylbenzoate, prepared above (25.15 g. 123 mmol) in methanol was then added, and the reaction stirred at room temperature under N2 for 3 days. The reaction mixture was acidified to pH 6 with conc. HCl (caution!). The mixture was filtered and the filtrate evaporated to give a precipitate. This was extracted with CHCl3, the combined extracts dried (MgSO4) and the solvent evaporated. The residue was recrystallised from EtOH to give 4-pentylbenzohydroxamic acid acid as crystals, m.p. 89.9°-90.1° C. (12.35 g, 49%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH:22]=4)[C:20]#[N:21])[O:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.CCOC(C)=O>[C:20]([C:19]1[CH:22]=[C:15]([C:13]2[O:12][N:11]=[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[N:1]([CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:2]=[CH:3]4)[N:14]=2)[CH:16]=[CH:17][C:18]=1[O:23][CH:24]([CH3:26])[CH3:25])#[N:21]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1C#N
Reactant: CCOC(=O)C(C)(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 48 h
Yield: 17.2 %

Procedure:
To a solution of 5-[3-(1H-indazol-5-yl)-1,2,4-oxadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile (D43) (85 mg, 0.246 mmol) in N,N-Dimethylformamide (DMF) (5 ml) was added ethyl 3-bromo-2,2-dimethylpropanoate (D98) (103 mg, 0.492 mmol) and Cs2CO3 (120 mg, 0.369 mmol). The resulting mixture was stirred at 80° C. for 48 h then cooled to room temperature and diluted with EtOAc. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [30-50% EtOAc/cyclohexene] gave the title compound (20 mg, 16%) as a yellow solid. MS (ES) C26H27N5O4 requires 473, found 474 [M+H]+
Reaction SMILES: C(OP([CH2:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])(OCC)=O)C.[H-].[Na+].[NH2:20][C:21]1[C:35]([Cl:36])=[CH:34][C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=O)=[CH:23][C:22]=1[Cl:37].O>O1CCCC1>[NH2:20][C:21]1[C:22]([Cl:37])=[CH:23][C:24]([C:25]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[CH:9][C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])=[CH:34][C:35]=1[Cl:36]
Reactant: CCOP(=O)(CC(=O)N1CCOCC1)OCC
Reactant: Nc1c(Cl)cc(C(=O)c2ccc(Cl)cc2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(Cl)cc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1Cl
Reaction time: 0.17 h

Procedure:
A solution of 5.3 g (0.02 mol) of diethylphosphonoacetic acid morpholide in 100 ml of dry tetrahydrofuran was slowly added dropwise, while stirring, to a suspension of 1 g of sodium hydride (0.02 mol, 50% in oil) in 50 ml of dry tetrahydrofuran. Slight heating and strong foaming occurred. After all had been added, the mixture was stirred for 10 minutes more. A solution of 3 g (0.01 mol) of 4-amino-3,4',5-trichlorobenzophenone in 20 ml of dry tetrahydrofuran was added dropwise to the resulting clear solution, and the mixture was heated for 16 hours at reflux temperature. After cooling, the solution was poured into water, and the aqueous mixture was extracted exhaustively with methylene chloride. The methylene chloride phase was dried with sodium sulfate and evaporated by evaporation in vacuo. The residue was crystallized from isopropanol/petroleum ether. The colorless crystals thus obtained, melting point 150°-155° C., contained the cis/trans isomers in a ratio of 1:3.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:40](=[N:43]O)([NH2:42])[CH3:41].[H-].[Na+]>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C@H:12]2[CH2:13][CH2:14][C@H:15]([O:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]4[O:24][N:43]=[C:40]([CH3:41])[N:42]=4)=[CH:26][CH:27]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)O)cc3)CC2)CC1
Reactant: CC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(O[C@H]3CC[C@H](C(=O)N4CCN(C(C)C)CC4)CC3)cc2)n1

Procedure:
A mixture of 0.1 g (0.22 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid and 59 mg (0.36 mmol) of 1,1′-carbonyl-diimidazole in 2 ml THF was refluxed for 16 hr. After cooling down, 79 mg (1.1 mmol) of acetamide oxime was added and the mixture was refluxed for 48 hr. To the mixture, 29 mg (0.66 mmol, 55% purity) of sodium hydride was added and the mixture was refluxed for 16 hr. The mixture was evaporated. The mixture was diluted with AcOEt, washed with saturated NaHCO3 solution, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica eluting with dichloromethane and methanol=from 98:2 to 9:1. The combined product fractions were evaporated to dryness to yield 40 mg (44%) of the title compound. MS (m/e): 413.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=2)[N:8]=1.[NH3:25]>CCO>[F:1][C:2]([F:24])([F:23])[CH2:3][N:4]=[C:5]([NH2:25])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=2)[N:8]=1
Reactant: N
Reactant: NC(=O)c1ccc(Cn2ccc(NC(=S)NCC(F)(F)F)n2)cc1
Solvent: CCO
Product: NC(=O)c1ccc(Cn2ccc(NC(N)=NCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-(3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazol-1-ylmethyl)benzamide (180 mg.) in EtOH saturated with ammonia (5 ml.) was added yellow mercuric oxide (380 mg.). The mixture was stirred at room temperature for 17 hours. The mixture was centrifuged, then the supernatant liquor was evaporated in vacuo to give 4-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-ylmethyl]benzamide, m.p. 192° (from EtOH/petroleum ether (b.p. 60°-80°)).
Reaction SMILES: [CH2:1]1[S:9](=[O:11])(=[O:10])[O:8][CH2:7][CH2:6][O:5][S:2]1(=[O:4])=[O:3].[H-].[Na+].Cl[CH2:15][C:16]1[C:25]2[C:20](=CC=C[CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[Na+].[I-].[CH2:28]([CH2:31]OC)OC>>[CH:24]1[C:25]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:6][C:7]=1[O:8][S:9]([CH:1]([S:2]([OH:5])(=[O:4])=[O:3])[CH3:28])(=[O:11])=[O:10].[CH2:28]=[CH2:31]
Reactant: COCCOC
Reactant: O=S1(=O)CS(=O)(=O)OCCO1
Reactant: ClCc1cccc2ccccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: C=C
Product: CC(S(=O)(=O)O)S(=O)(=O)Oc1ccc2ccccc2c1
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 3.5 g of ethylene methanedisulfonate in 60 mL of glyme and 0.9 g of NaH was added 3.4 g of 1-chloromethylnaphthalene followed by 2.6 g of NaI. The solution was stirred overnight and the glyme removed by the rotary evaporator at 20 mm pressure. The residue was taken up in an acid solution and CH2Cl2. The CH2Cl2 was rinsed with a NaHSO3 solution, dried, concentrated, and cyclohexane was added to give 3.9 g (86%) of ethylene 2-naphthyl-1,1-ethanedisulfonate, m.p. 179-183° C. (94-2).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[O:29][C:28]([CH3:31])([CH3:30])[O:27][C:26](=[O:32])[C:25]=2[CH:33]=1>>[CH3:30][C:28]1([CH3:31])[O:29][C:24]2[CH:23]=[CH:22][C:21]([NH:20][CH2:16][C:15]3[CH:18]=[CH:19][C:12]([C:11]#[C:10][C:7]4[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=4)=[CH:13][CH:14]=3)=[CH:33][C:25]=2[C:26](=[O:32])[O:27]1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Reactant: CCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Product: CCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Yield: 25.2 %

Procedure:
The title compound was prepared following procedure described in Example 1, step c) from 4-[(4-propylphenyl)ethynyl]benzaldehyde (1.53 g; 6.16 mmol) and 6-amino-2,2-dimethyl-benzo[1,3]dioxin-4-one (1.19 g; 6.16 mmol). Purification of the yellow solid (2.4 g) obtained by flash chromatography using silica gel (EtOAc:c-Hex 10:90 to 20:80) gave 660 mg (25%) of the title compound as a yellow solid. HPLC, Rt: 5.48 min (purity: 72.4%), 1H NMR (CDCl3) δ: 7.47 (d, J=7.5 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H),: 7.31 (d, J=8.1 Hz, 2H), 7.08 (m, 3H), 6.70-6.79 (m, 2H), 4.25 (s, 2H), 2.57 (t, J=7.6 Hz, 2H), 1.62 (s, 6H), 1.55 (m, 2H), 0.86 (t, J=7.3 Hz, 3H).
Reaction SMILES: CN(C)CCN(C)C.C([Li])(CC)C.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[C:18]([OH:20])=[O:19].[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.C(OCC)C.O>[Cl:25][C:16]1[C:15]([F:14])=[C:23]([F:24])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1ccc(F)c(F)c1Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
A solution of N,N,N′,N′-tetramethylethylenediamine (39.6 ml, 264 mmol) in tetrahydrofuran (170 ml) was cooled under argon to −70° C. before the addition of sec-butyl lithium (205 ml, 288 mmol). To the mixture 3,4-difluorobenzoic acid (19 g, 120 mmol) was then added as a solution in tetrahydrofuran (80 ml) over a period of 40 minutes ensuring that the temperature of the mixture did not rise above −60° C. The mixture was then stirred at a temperature of −68° C. to −70° C. for 1 hr before adding a solution of hexachloroethane (100 g, 422 mmol) in tetrahydrofuran (170 ml) over a period of 35 minutes whilst keeping the temperature of the mixture below −60° C. The mixture was stirred at a temperature of −65° C. to −70° C. for 2 hrs. The mixture was allowed to warm to −10° C. and then water (500 ml) was added to quench the reaction. The mixture was diluted with diethyl ether (250 ml) and the two resulting layers were separated. The aqueous layer was acidified to pH1 using concentrated aqueous hydrogen chloride and then extracted with 2×500 ml aliquots of diethyl ether. The combined organic extracts were passed through a hydrophobic frit and reduced in vacuo to give a yellow solid. This was recrystallised from ethyl acetate to give two crops (8.35 g and 4.47 g) of pure 2-chloro-3,4-difluorobenzoic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]2[N:11]=[C:12]([S:15][CH2:16][C:17]([OH:19])=O)[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1.CN(C(ON1N=N[C:30]2[CH:31]=[CH:32][CH:33]=[N:34][C:29]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:34]1([C:17](=[O:19])[CH2:16][S:15][C:12]2[CH:13]=[CH:14][C:9]3[N:10]([C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:7][N:8]=3)[N:11]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)CSc1ccc2nnc(-c3cccs3)n2n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Product: O=C(CSc1ccc2nnc(-c3cccs3)n2n1)N1CCCCC1
Reaction time: 0.25 h

Procedure:
To 2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)acetic acid (100 mg, 0.34 mmol) dissolved in DMF (3 mL) was added HATU (150 mg), and after 15 minutes stirring, piperidine (40 mg) was added followed by DIPEA (200 μL). The mixture was stirred for room temperature overnight and then evaporated to dryness. 1-(Piperidin-1-yl)-2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)ethanone was then isolated by preparative TLC (silica gel plates, 9:1 CHCl3/MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[F:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:26]1[O:29][CH:27]1[CH3:28]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:12]2[C:13]([F:20])=[CH:14][CH:15]=[C:16]([F:19])[C:17]=2[F:18])[CH2:26][CH:27]([OH:29])[CH3:28])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC1CO1
Reactant: O=S(=O)(Cc1c(F)ccc(F)c1F)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)CC(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2-(4-Chloro-benzenesulfonylmethyl)-1,3,4-trifluoro-benzene (Example 8, step 2, 305 mg, 0.95 mmol) was dissolved in 4 mL THF. The solution was cooled to −78° C. and butyllithium (2.5M in hexane, 0.4 mL) was added slowly. The solution was stirred at −78° C. for 2 h then warmed to 0° C. and stirred for 0.5 h. The solution was then cooled to −78° C. again and propylene oxide (178.0 mg, 3.1 mmol) in 3.25 mL of THF was added slowly and the reaction mixture was allowed to stir and warm to room temperature overnight. The reaction mixture was quenched with a saturated NH4Cl solution (50 mL). The reaction mixture was extracted three times with EtOAc (50 mL each) and the combined organics were washed with water (100 mL) and brine (100 mL). The organic layer was then dried over Na2SO4 and concentrated. The product was purified using column chromatography (hex./EtOAc 100/0 to 70/30 in 60 min. 0.19 g, 52%). 1H NMR (CDCl3 400 MHz) δ 7.59 (m, 2H), 7.42 (m, 2H), 7.10 (m, 1H), 6.81 (m, 0.5H), 6.66 (m, 0.5H), 4.83-4.99 (m, 1H), 4.06 (m, 0.5H), 3.51 (m, 0.5H), 2.50-2.74 (m, 1H), 2.26 (m, 1H), 1.03-2.24 (m, 3H). The product is a mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:13][CH2:12][S:11][C:10]([NH2:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CN(C)CC.[CH:21]([OH:24])(C)[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH3:15])[CH2:13][CH2:12][S:11][C:10]([NH:14][C:21](=[O:24])[CH3:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(c2cccc(Br)c2)CCSC(N)=N1
Reactant: CC(C)O
Agent: CCN(C)C
Product: CC(=O)NC1=N[C@](C)(c2cccc(Br)c2)CCS1
Yield: 35 %

Procedure:
4-(3-bromo-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine (20 g, 61 mmole) is purified by HPLC chiral separation [Column: 8×32 cm chiralpak AD; Eluent: 60:40:0.2 (isopropyl alcohol: heptanes: dimethylethylamine); Flow: 350 mL/min at UV 260 nm]. The second eluting isomer is isolated to provide the enantiomerically enriched title compound (35% Yield): MS (m/z): 327, 329 (M+1)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]([C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(O)(=O)C.O.[NH2:29][NH2:30].O>C(O)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:29][NH:30][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: NN
Reactant: CCOC(=O)CC(C(=O)c1ccccc1)C(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a solution of 15 grams 3,3-dibenzoyl-propionic acid ethyl ester and 3 grams glacial acetic acid in 90 milliliters ethanol was added at room temperature drop by drop a solution of 3.0 grams hydrazine hydrate in 10 milliliters ethanol followed by stirring at room temperature for 3 hours. The reaction mixture was then clarified by treatment with activiated carbon, and 150 milliliters water were added to the clear solution followed by cooling in an ice bath. The precipitate formed thereby was filtered off by suction, dried and taken up in 400 milliliters benzene. The benzene solution was extracted first with a saturated aqueous solution of sodium bicarbonate and thereafter with water. The benzene solution was dried and benzene distilled off. By the addition of about three times this volume of cyclohexane, a precipitate representing the ester reaction product was formed which was separated by filtration. 13.1 grams 3,5-diphenyl-1H-pyrazol-4-acetic acid-ethyl ester melting at 117°-118° C. were obtained, representing a yield of 86%.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].C(=O)(O)O.[NH2:14][NH:15][C:16]([NH2:18])=[NH:17].C(=O)=O>O>[C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[NH2:14][NH:15][C:16]([NH2:18])=[NH2+:17].[NH2:14][NH:15][C:16]([NH2:18])=[NH2+:17]
Reactant: N=C(N)NN
Reactant: O=C(O)CC(O)C(=O)O
Agent: O=C(O)O
Agent: O=C=O
Solvent: O
Product: NNC(N)=[NH2+]
Product: O=C([O-])CC(O)C(=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
DL-Malic acid (2.0 g, 14.92 mmol) was dissolved in 5 ml of distilled water. Aminoguanidine bicarbonate (4.06 g, 29.83 mmol) was added in portions at room temperature (carbon dioxide gas was evolved) and the reaction was stirred at room temperature for 18 hours. The water was removed in vacuo with heating to approximately 90° C. for 4 hours. The product was isolated as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][S:9]([O:12][CH2:13][CH:14]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[O:15]C1CCCCO1)(=[O:11])=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:8][S:9]([O:12][CH2:13][C@@H:14]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[OH:15])(=[O:10])=[O:11]
Reactant: CS(=O)(=O)OCC(OC1CCCCO1)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)OC[C@H](O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Into toluene (10 ml) were added 2-(4-chlorophenyl)-2-(3,4,5,6-tetrahydro-[2H]-pyran-2-yloxy)ethyl methanesulfonate (3.0 g), p-toluenesulfonic acid monohydrate (1.7 g) and methanol (0.5 g), and the resulting mixture was stirred at 50° C. for 1 hour. The reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, then with a saturated aqueous sodium chloride solution, and dried with anhydrous magnesium sulfate. The desiccant was filtered off and then the solvent was distilled off under reduced pressure to obtain a colorless oily compound mentioned above (2.0 g, 89.0%).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)=[O:13].Cl.N1C=CC=CC=1>O>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[O:13][C:3]3[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=3[CH:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)Cc2cc(OC)ccc2OC)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc(-c2cc3cc(O)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
A mixture of 74 (1.5 g, 5.2 mmol) and Pyridine HCl (10 g) was heated to 200° C. After 1.5 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc and the organic layer was dried, concentrated to give a solid which was triturated with CH2Cl2 to give a solid (0.6 g, 51%): Mp=275–278° C.; 1H NMR (DMSO-d6) δ 9.81 (br s, 1 H), 9.12 (br s, 1 H), 7.66 (d, 2 H, J=2.5 Hz), 7.32 (d, 1 H, J=8.5 Hz), 7.00 (s, 1 H), 6.90–6.83 (m, 3 H), 6.65 (dd, 1 H, J=8.6 Hz, 2.6 Hz); MS 225 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:23][OH:24].O.[NH2:26][NH2:27]>CN1CCCC1=O.C(OCC)(=O)C>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][C:3]([CH2:23][OH:24])=[C:2]2[NH:26][NH2:27])=[O:22].[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([NH:12][C:7]1[C:6]2[N:5]=[CH:4][C:3]3[CH:23]=[N:26][NH:27][C:2]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:22]
Reactant: NN
Reactant: O=C(Nc1cccc2c(Cl)c(CO)cnc12)c1c(Cl)cccc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: NNc1c(CO)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Product: O=C(Nc1cccc2c1ncc1cn[nH]c12)c1c(Cl)cccc1Cl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-8-(2,6-dichlorobenzoylamino)-3-hydroxymethylquinoline (297 mg) in N-methylpyrrolidone (4 ml) was added hydrazine monohydrate (390 mg), and the mixture was stirred for 3 hours at 90° C. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel and by preparative thin layer chromatography to give 8-(2,6-dichlorobenzoylamino)-4-hydrazino-3-hydroxymethylquinoline (127 mg) and 6-(2,6-dichlorobenzoylamino)-1H-pyrazolo[4,3-c]-quinoline (90 mg). 8-(2,6-Dichlorobenzoylamino)-4-hydrazino-3-hydroxymethylquinoline NMR (DMSO-d6, δ): 4.70 (2H, d, J=6 Hz), 5.19 (2H, s), 5.35 (1H, t, J=6 Hz), 7.39 (1H, dd, J=8, 8 Hz), 7.49-7.63 (3H, m), 8.15 (1H, d, J=8 Hz), 8.28 (1H, s), 8.40 (1H, s), 8.56 (1H, d, J=8 Hz), 10.46 (1H, s) 6-(2,6-Dichlorobenzoylamino)-1H-pyrazolo[4,3-c]quinoline NMR (DMSO-d6, δ): 7.49-7.63 (3H, m), 7.77 (1H, dd, J=8, 8 Hz), 8.20 (1H, d, J=8 Hz), 8.46 (1H, br s), 8.78 (1H, d, J=8 Hz), 9.25 (1H, s), 10.76 (1H, s)