Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH:12]([N:15](CC)C(C)C)(C)C.CN>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:12][NH2:15]
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: C1CCOC1
Product: NCc1c(Br)cccc1[N+](=O)[O-]

Procedure:
A solution of 3-bromo-2-fluoronitrobenzene (1 g) in THF (8.3 ml) is heated in the presence of N,N-diisopropylethylamine (690 μA) and of methylamine (2.54 ml) in a microwave reactor (105° C., 30 min). The reaction medium is concentrated and then taken up in ethyl acetate, and then washed with water and then with brine. The organic extracts are combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure. (2-Bromo-6-nitrophenyl)methylamine (1 g) is isolated in the form of an orange solid, and is used as it is in the next stage.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11]C(=O)C)[CH:5]=[N:4][C:3]=1[C:15]([NH2:17])=[O:16].C([N:26]=[C:27]=[S:28])(=O)C1C=CC=CC=1.CO.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O.C(O)(=O)C>[OH:11][CH2:10][CH2:9][O:8][CH2:7][N:6]1[C:2]([NH:1][C:27](=[S:28])[NH2:26])=[C:3]([C:15]([NH2:17])=[O:16])[N:4]=[CH:5]1
Reactant: CC(=O)OCCOCn1cnc(C(N)=O)c1N
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: NC(=O)c1ncn(COCCO)c1NC(N)=S
Yield: 83.2 %

Procedure:
5-Amino-1-[[2-(acetyloxy)ethoxy]methyl]-1H-imidazole-4-carboxamide (44.0 g, 182 mM) and benzoylisothiocyanate (29.7 g, 182 mM) were refluxed in acetone (430 ml) for 1 hour. To the resulting solution were added methanol (430 ml) and potassium carbonate (14.9 g, 108 mM) dissolved in water (45 ml) whereafter the mixture was refluxed for 4 hours. After cooling to room temperature acetic acid was added to a pH-value of 8. The formed product was filtered off at 0° C., washed and dried. Hereby 39.2 g (83%) of the title compound was isolated as a white powder, mp. 181°-182° C. (dec.). A sample crystallized from water had mp. 182°-183° C. (dec.). 13C-NMR(DMSO-d6) δppm: 183.9; 163.7; 134.9; 129.3; 127.9; 74.0; 70.4; 59.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:28][C@H:27]([OH:29])[CH2:26][C@H:25]4[C:30](O)=[O:31])[C:17]4[S:22](=[O:23])[CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([N:36](C(C)C)CC)(C)C.N.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:28][C@H:27]([OH:29])[CH2:26][C@H:25]4[C:30]([NH2:36])=[O:31])[C:17]4[S:22](=[O:23])[CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)[C@@H]1C[C@@H](O)CN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
80 mg (2S,4R)-1-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl }-4-hydroxy-pyrrolidine-2-carboxylic acid are placed in 2.00 ml N,N-dimethylformamide and combined with 86.77 mg diisopropylethylamine and 76.20 mg O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluronium-hexafluoro-phosphate (HATU). The mixture is stirred for 0.25 hours at ambient temperature, then 334 μl ammonia solution (0.5 M in dioxane) are added. The reaction mixture is stirred for 3 hours at ambient temperature, then acidified and water is added. The diastereomers are separated by preparative HPLC (method B). 11.7 mg of Diastereomer 1 and 15.3 mg of Diastereomer 2 (Example 128) are obtained as powders. Analytical HPLC-MS (method A): Diastereomer 1, RT=1.49 min, Diastereomer 2, RT=1.49 min.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[F:26][C:27]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:28]=1[NH2:29].CC(C)([O-])C.[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:29][C:28]3[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:27]=3[F:26])[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccc(N)c(F)c1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c(F)c1
Temperature: 140 °C
Yield: 52.4 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol), 2-fluoro-4-methylaniline (65.9 mg, 526 μmol), BINAP (10.9 mg, 17.5 μmol), palladium (II) acetate (19.7 mg, 87.7 μmol) and sodium tert-butoxide (84.3 mg, 877 μmol) in DMF (1 mL) and toluene (500 μL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was diluted with water then extracted into ethyl acetate (3×). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (silica, 20-50% ethyl acetate/hexanes) gave N-tert-butyl-2-(2-fluoro-4-methylphenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (87 mg, 184 μmol, 53%) as an off-white solid. MS (EI/CI) m/z: 470.1 [M−H].
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=[CH:9][C:10]=2[CH3:14])[NH:5][CH:4]=1.S(Cl)(Cl)=O.Cl[CH2:23]Cl>>[CH3:23][O:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=[CH:9][C:10]=2[CH3:14])[NH:5][CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])c2[nH]cc(CO)c(=O)c12
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COCc1c[nH]c2c([N+](=O)[O-])ccc(C)c2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1,4-dihydro-3-hydroxymethyl-5-methyl-8-nitro-4-oxoquinoline (1.12 g) in dichloromethane (10 ml) was dropwise added a solution of thionyl chloride (569 mg) in dichloromethane (5 ml) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature and for 2 hours at ambient temperature. The mixture was concentrated in vacuo, suspended in dichloromethane-methanol and refluxed for 2 hours. The mixture was evaporated in vacuo, and the residue was recrystalized from methanol to give 1,4-dihydro-3-methoxymethyl-5-methyl-8-nitro-4-oxoquinoline (889 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)=[O:17])=[CH:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28]1COCC1.C[Mg]Br>Cl.O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)([OH:17])[CH3:28])=[CH:14][N:15]=3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCOC1
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(-c3ccccc3)nn12
Agent: C[Mg]Br
Agent: Cl
Solvent: O
Product: CC(O)(c1ccc2ncccc2c1)c1cnc2ccc(-c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.3 %

Procedure:
A 25 mL RB flask was charged with (6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.200 g, 0.57 mmol) and THF (2.00 ml, 24 mmol), then cooled to 0° C. methylmagnesium bromide (0.76 ml, 2.2 mmol) was added dropwise and the mixture was stirred at room temperature for 5 hours. This was diluted with 2 N HCl (1 mL) and water (25 mL), then extracted with DCM (25 mL×2) and EtOAc (25 mL). The combined organics were washed with brine and dried with MgSO4, filtered, and concentrated. The resulting oil was purified by MPLC using a 40 g RediSep column, eluting with 2-6% MeOH/DCM over 40 minutes. 1-(6-phenylimidazo[1,2-b]pyridazin-3-yl)-1-(quinolin-6-yl)ethanol (0.082 g, 39% yield) was isolated as a tan solid. MS (ESI pos. ion) m/z: 367 (MH+). Calc'd exact mass for C23H18N4O: 366.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:19]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[NH+:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2>C([O-])([O-])=O.[Na+].[Na+]>[CH3:2][N:3]1[C:19]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: Cn1c2ccccc2c2[nH+]c3ccccc3cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1c2ccccc2c2nc3ccccc3cc21
Yield: 45.5 %

Procedure:
The 10-methylquindolinium hydrochloride obtained above (250 mg, 0.9 mmol) was shaken with an aqueous 5% Na2CO3 solution (50 mL), extracted with ethyl ether (2×50 mL) and purified by HPLC (ethyl acetate-hexane 1:6) to give 100 mg (45.5%) of 10-methylquindoline; 1H NMR (CDCl3) δ 8.56 (d, J=7.6, H, H8), 8.34 (d, J=8.4, 1H, H4), 7.94 (d, J=8.0, 1H, H1), 7.85 (s, 1H, H11), 7.69-7.61 (m, 2H, H3 and H6), 7.56 (t, J=7.2, 1H, H2), 7.37 (d, J=8.4, 1H, H9), 7.33 (t, J=7.6, 1H, H7), 3.82 (s, 3H, CH3); 13C NMR (CDCl3) δ 145.89, 144.84, 143.92, 133.98, 129.60, 129.12, 127.08, 126.75, 126.12, 125.14, 121.96, 121.47, 119.58, 110.58, 108.34, 28.98; MS (EI, m/z) 232.1 (M+)
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:23]1([C:29](=[N:31]O)[NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[CH2:7]([C:8]1[O:10][N:31]=[C:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:30]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=NO)c1ccccc1
Reactant: O=C(O)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Cc2nc(-c3ccccc3)no2)cc1
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
To a solution of phenylacetic acid (2.04 g) in 50 mL of DMF was added carbonyldiimidazole (2.7 g). The mixture was stirred for 20 min and then benzene amidoxime (2.04 g) was added. The resulting mixture was stirred for 20 min at r.t. and 18 h at 75 ° C. After cooling, the reaction mixture was poured in to 50 mL of water and extracted with 2×50 mL of 1:1 hexane/EtOAc. The extract was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography, eluting with 1:5 EtOAc/hexane to give 2 g of the title compound as a yellow syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:25](Cl)=[O:26])[C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3.[NH4+:28].[OH-].C(OCC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:25]([NH2:28])=[O:26])[C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3
Reactant: [NH4+]
Reactant: COc1ccc(C2Cc3c(C(=O)Cl)cc(OC)cc3C3CCCCC23)cc1
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1ccc(C2Cc3c(C(N)=O)cc(OC)cc3C3CCCCC23)cc1

Procedure:
Combine 3-Methoxy-9-(4-methoxy-phenyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthrene-1-carbonyl chloride (0.08 g, 0.18 mmol), NH4OH (2 ml), and diethyl ether (1 ml) at 0-5° C. and stir as such 2 hours. Dilute with ethyl acetate and wash with water. Dry over anhydrous sodium sulfate, and remove solvent in vacuo at 40° C. to yield preparation 121 (0.069 g, 100%). MS m/z 366 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16]CC)=[O:15])[CH2:4][CH2:3]1.O.[OH-].[Li+].O>C(O)C>[C:10]([O:9][C:7]([N:6]1[C@@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]1[C:14]([OH:16])=[O:15])=[O:8])([CH3:11])([CH3:12])[CH3:13]
Reactant: CCOC(=O)[C@@H]1CC[C@H](C)N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
To a solution of (2S,5S)-1-tert-butyl 2-ethyl 5-methylpyrrolidine-1,2-dicarboxylate (6.46 g, 25.1 mmol) in ethanol (20 mL) was added lithium hydroxide mono hydrate (2.11 g, 50.2 mmol) and deionized water (12 mL). The mixture was allowed to stir for 16 hours then partitioned between ethylacetate and a 1:1 mixture of saturated brine and 1N HCl. The aqueous layer was extracted an additional time with ethyl acetate. The organic layers were combined, dried with sodium sulfate and the solvent was removed in vacuo to yield (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid as a white solid (quant.) and was used directly in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([NH:20][CH2:21][CH:22](OC)OC)=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:35][O:36][NH2:37].C(OCC)(=O)C>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([NH:20][CH2:21][CH:22]=[N:37][O:36][CH3:35])=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CON
Reactant: COC(CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)OC
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CON=CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Yield: 69.4 %

Procedure:
In a solution of 152 mg of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-N-(2,2-dimethoxyethyl)-2-methyl benzoic acid amide (Compound of the present invention No. 5-083) synthesized similarly to Synthetic Example 5 in 14 ml of methanol-water (6:1) mixed solvent, 38 mg of methoxyamine hydrochloride was added, and stirred under reflux with heat for 8 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, diluted by adding 80 ml of ethyl acetate, washed with water (30 ml×2), and dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethylacetate-hexane (1:1), and 102 mg of the aimed product was obtained as colorless resinous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.C(O)(=O)CC.[BH4-].[Na+].[CH3:16][C:17](=O)[CH2:18][CH3:19]>>[CH:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1)([CH2:18][CH3:19])[CH3:16]
Reactant: Cc1cccc(N)c1
Reactant: CCC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCC(=O)O
Product: CCC(C)Nc1cccc(C)c1
Temperature: 0 °C

Procedure:
3-Toluidine (107.16 g), 2-butanone (72.11 g) and propionic acid (74.08 g) were stirred and cooled to 0° C. Sodium borohydride (37.83 g) was then added in portions keeping the temperature below 5° C. After allowing to warm to room temperature the reaction mixture was carefully poured onto ice/water. The product was extracted into ethyl acetate, washed with water, 2% hydrochloric acid and finally water again before drying over magnesium sulphate. Evaporation of the solvent under reduced pressure gave a brown oil which was purified by chromatography on silica gel.
Reaction SMILES: [OH-].[Na+].[N:3]#[C:4][NH2:5].[CH3:6][S:7][CH:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][CH:15]=1)[CH3:9].Cl[O-].[Na+]>>[C:4]([N:5]=[S:7]([CH3:6])[CH:8]([C:10]1[CH:15]=[N:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:11]=1)[CH3:9])#[N:3]
Reactant: N#CN
Reactant: CSC(C)c1ccc(C(F)(F)F)nc1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)=NC#N
Reaction time: 0.08 h

Procedure:
A sulfide feed stream known to include acidic impurities was titrated with dilute NaOH and found to contain about 3.2×10−5 moles of acid/gram. The cyanamide was titrated with dilute NaOH and found to contain about 2.01×10−5 moles of acid/gram. Thus, for the oxidation reaction of 5-[1-(methylthio)ethyl]-2-trifluoromethylpyridine with cyanamide and sodium hypochlorite (13%) conducted on a 0.047 mole scale, the total moles of acid in the mixture was 0.00041 moles. The effect of adding NaOH to the mixture to neutralize the acidity in the sulfide feed stream and the cyanamide was determined. The NaOH was added as a 25% aqueous solution and stirred for about 5 minutes before adding the sodium hypochlorite. The results are summarized in Table 2.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[N:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=3)[CH2:9][C@@H:4]2[CH2:3]1.[H-].[Na+].[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)#[N:21]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:1][C@@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[N:11]=[CH:12][C:13]([F:16])=[CH:14][N:15]=3)[CH2:9][C@@H:4]2[CH2:3]1)#[N:21]
Reactant: O[C@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Reactant: N#Cc1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: N#Cc1cccc(CO[C@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 12.5 %

Procedure:
A solution of 0.60 g (2.5 mmol) of (7S,8aS)-7-hydroxy-2-(5-fluoropyrimidin -2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]-pyrazine (Preparation 15) in 30 mL of THF was treated with 0.41 g (10 mmol) of sodium hydride (60% oil dispersion), followed by 0.75 g (3.8 mmol) of 3-cyanobenzyl bromide and 30 mg (0.1 mmol) of tetra-n-butylammonium iodide. The mixture was stirred 50° C. for 16 h, cooled to room temperature, the solvent was evaporated, and the residue partitioned between ethyl acetate and water. The layers were separated, the organic phase was washed with water and brine, dried (magnesium sulfate), filtered and evaporated. Purification by MPLC silica gel chromatography with ethyl acetate gave 0.11 g (12%) of the title compound. mp (.HCl) 95°-100° C. HRMS calcd for C19H21FN5O (MH+): 345.1730; found: 345.1739.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:11])[CH:3]=1.[C:12](=[NH:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[Na+].[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:12](=[N:25][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:11])[CH:3]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(Br)c2occc2c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1cc(N=C(c2ccccc2)c2ccccc2)c2occc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 125 %

Procedure:
To a 7-bromo-5-methylbenzofuran (9.71 g, 46 mmol) toluene solution (100 ml) were added a benzophenone imine (10.25 g, 56 mmol) toluene solution (55 ml), tris(dibenzylideneacetone)dipalladium (1.1 g, 1 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 2.1 g, 3.45 mmol), and sodium t-butoxide (3.1 g, 31 mmol). The resulting mixture was then stirred for 4 hours while heating under reflux in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water and saturated ammonium chloride solution were added thereto, followed by extraction using ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure. The residue was purified using silica gel column chromatography (n-hexane:ethyl acetate=10:1). The solvent was removed under a reduced pressure, giving a yellow oily substance of benzhydrylidene(5-methylbenzofuran-7-yl) amine (17.9 g, yield: 81%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:21]([NH:23][CH2:24][CH:25]3[O:30][CH2:29][CH2:28][N:27]([C:31]4[CH:43]=[CH:42][CH:41]=[CH:40][C:32]=4[C:33]([O:35]C(C)(C)C)=[O:34])[CH2:26]3)=[O:22])=[C:18]([CH3:20])[N:19]=2)=[CH:11][CH:10]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:21]([NH:23][CH2:24][CH:25]3[O:30][CH2:29][CH2:28][N:27]([C:31]4[CH:43]=[CH:42][CH:41]=[CH:40][C:32]=4[C:33]([OH:35])=[O:34])[CH2:26]3)=[O:22])=[C:18]([CH3:20])[N:19]=2)=[CH:11][CH:10]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CN(c2ccccc2C(=O)OC(C)(C)C)CCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CN(c2ccccc2C(=O)O)CCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Trifluoroacetic acid (1 mL) was added to tert-butyl 2-[2-[[2-(4-chlorophenyl)-4-methylthiazole-5-carbonyl]aminomethyl]morpholin-4-yl]benzoate (113 mg, 0.214 mmol) in dichloromethane (1 mL). The mixture was stirred at room temperature for 2 hours. Subsequently, the solvent was removed and a 1 mol/L aqueous potassium hydroxide solution was added to the residue to make it basic. The mixture was then made acidic by the addition of 2 mol/L hydrochloric acid. The crystallized powdery product was collected by filtration and washed with water to give 78.2 mg (78%) of the desired compound as a colorless powder.
Reaction SMILES: [Mg].II.[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([Mg]Br)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH3:5].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]>C1COCC1>[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([CH:23]([C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[C:20]([N+:27]([O-:29])=[O:28])[CH:21]=2)[OH:24])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH3:5]
Reactant: CCOc1cc([Mg]Br)ccc1OC
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1cc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)ccc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Grignard reagent was prepared in an oven-dried three necked flask outfitted with a reflux condenser, dropping funnel, and magnetic stirrer. Approximately ¼ of a solution of (3-ethoxy-4-methoxy-bromo)-benzene (10 g, 43.3 mmol) in anhydrous THF (60 mL) was added to a mixture of magnesium turnings (1.05 g, 43.3 mmol) in THF (10 mL) with a small piece of iodine. As soon as the solution became colorless (heating sometimes necessary), the remaining (3-ethoxy-4-methoxy-bromo)-benzene solution was added dropwise to the reaction mixture under mild reflux, over 30 min. The resulting mixture was refluxed for 3 h then cooled to room temperature for 30 min. The (3-ethoxy-4-methoxy-phenyl) magnesium bromide was then added slowly to a stirred solution of 4-methoxy-3-nitro-benzaldehyde (6.53 g, 36.1 mmol) in THF (60 mL) at 0° C. After complete addition, the reaction mixture was stirred at cold for 10 min and then at room temperature for 2 h. The solution was cooled to 0° C. and quenched with saturated NH4Cl solution (90 mL). The aqueous layer was extracted with ether (3×90 mL). The combined organic layers were washed with water (2×120 mL), brine (120 mL) and dried (MgSO4). Removal of solvent gave the crude (3-ethoxy-4-methoxy-phenyl)-(4-methoxy-3-nitro-phenyl) -methanol, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C@@H:8]([CH3:9])[C:7](=[O:10])[NH:6][C:5]2[CH:11]=[C:12]([C:15](OC)=[O:16])[CH:13]=[N:14][C:4]1=2)[CH3:2].[H-].[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:3]1[C@@H:8]([CH3:9])[C:7](=[O:10])[NH:6][C:5]2[CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=[N:14][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncc(C(=O)OC)cc2NC(=O)[C@@H]1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1c2ncc(CO)cc2NC(=O)[C@@H]1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
(S)-methyl 4-ethyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate (0.560 g, 2.25 mmol) was dissolved in THF (5 mL) and cooled to 0° C. under nitrogen atmosphere. Sodium hydride (60% susp. in mineral oil, 0.135 g, 3.38 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. It was then cooled to −50° C. and LiAlH4 (2M in THF, 3.40 mL, 6.80 mmol) was added dropwise over 10 min. The reaction mixture was kept at −30-(−20)° C. for 1 h, cooled to below −50° C. and slowly quenched with MeOH (5 mL). The resulting solution was warmed to room temperature and subjected to preparative HPLC (1-30% acetonitrile in water, TFA buffered) to afford the title compound as a dark oil (TFA salt, 0.587 mg, 78%). [M+H] calc'd for C11H15N3O2, 222; found, 222.