Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:20].[NH2:21][CH2:22][CH2:23][SH:24].C(N(CC)CC)C>C(#N)C>[NH2:21][CH2:22][CH2:23][S:24][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:20]
Reactant: CN1CCc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: NCCS
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCc2c(SCCN)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 49.8 %

Procedure:
100 mg of compound (8) obtained in Example 3 (1), 56 mg of 2-amino-ethanethiol and 109 mg of triethylamine were added to 2 ml of acetonitrile, and the solution was heated at reflux for 2 hours. After air-cooling, the solvent was removed by distillation. To the residue, ethanol was added, and the deposited solids were filtered off and washed with ether to obtain 60 mg of the subject compound (184).
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:14](=[O:15])[C:13]2[C:8](=[C:9]([CH3:20])[CH:10]=[CH:11][C:12]=2[NH:16]C(=O)C)[O:7][CH2:6]1)(=[O:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>>[C:1]([NH:4][CH:5]1[C:14](=[O:15])[C:13]2[C:8](=[C:9]([CH3:20])[CH:10]=[CH:11][C:12]=2[NH2:16])[O:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C)c2c1C(=O)C(NC(C)=O)CO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)NC1COc2c(C)ccc(N)c2C1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The compound prepared in (1) above (100 mg) was added to 3 ml of concentrated hydrochloric acid and heated at 80° C. with stirring for 1 hour. The mixture was cooled, alkalinized with the addition of sodium bicarbonate, and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography using chloroform-ethyl acetate (4:1) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 48 mg of the title compound.
Reaction SMILES: [CH3:1]/[C:2](/[CH:19]=[CH:20]/[CH:21]=[C:22](\[CH3:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])=[CH:3]\[CH:4]=[CH:5]\[CH:6]=[C:7](/[CH3:18])\[CH:8]=[CH:9]\[CH:10]=[C:11](/[CH3:17])\[CH:12]=[CH:13]\[C:14]([OH:16])=[O:15].[CH:29]1C=CC2C3(C4C=C(I)C(O)=C(I)C=4OC4C(I)=C(O)C(I)=CC3=4)OC(=O)C=2C=1.C1C=C(C2C3C(=C(I)C([O-])=C(I)C=3)OC3C=2C=C(I)C(C=3I)=O)C(C([O-])=O)=CC=1.[Na+].[Na+].CC1C(C(O)=O)=C(O)C=C2C(C3C(O)=C(O)C([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)=C(O)C=3C(=O)C=12)=O.CC1C(C(O)=O)=C(O)C=C2C(C3C(O)=C(O)C([C@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)=C(O)C=3C(=O)C=12)=O.CC1C=CC(N/N=C2/C3C(C=C(C([O-])=O)C/2=O)=CC=CC=3)=C(S([O-])(=O)=O)C=1.[Ca+2].C1C(Br)=C([O-])C(Br)=C2OC3C(C4(OC(=O)C5C(Cl)=C(Cl)C(Cl)=C(Cl)C4=5)C=12)=CC(Br)=C([O-])C=3Br.[Na+].[Na+].CCN(C1C=CC2C(C3C=CC=CC=3C(C)=O)=C3C(=CC(C=C3)=[N+](CC)CC)OC=2C=1)CC.CCN(C1C=CC2C(C3C(C(O)=O)=CC=CC=3)=C3C(OC=2C=1)=CC(=[N+](CC)CC)C=C3)CC.[Cl-].C1[C@@H](C(O)=O)NC(C(O)=O)=C/C/1=C/C=[N+]1C2C(=CC(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)=C(O)C=2)C[C@H]1C([O-])=O.C1C(/C=C/N2C3C(=CC(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)=C(O)C=3)C[C@H]2C([O-])=O)=CC(C(O)=O)=N[C@@H]1C([O-])=O.C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].C1C=C(C2C3C=CC([O-])=CC=3OC3C=2C=CC(C=3)=O)C(C([O-])=O)=CC=1.[Na+].[Na+].C1C=CC(C(O)=O)=C(C2C3C=CC(O)=CC=3OC3C=2C=CC(C=3)=O)C=1.C1C=C2C(OC3(C4C=CC(O)=CC=4OC4C=C(O)C=CC3=4)C2=CC=1)=O>>[CH3:18]/[C:7](/[CH:8]=[CH:9]/[CH:10]=[C:11](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])\[CH3:17])=[CH:6]\[CH:5]=[CH:4]\[CH:3]=[C:2](\[CH:19]=[CH:20]\[CH:21]=[C:22](/[CH:23]=[CH:24]/[C:25]([O:27][CH3:29])=[O:26])\[CH3:28])/[CH3:1]
Reactant: O=C1OC2(c3ccccc31)c1cc(I)c(O)c(I)c1Oc1c2cc(I)c(O)c1I
Reactant: CC(/C=C/C=C(C)/C=C/C(=O)O)=C\C=C\C=C(C)\C=C\C=C(C)\C=C\C(=O)O
Agent: CCN(CC)c1ccc2c(-c3ccccc3C(=O)O)c3ccc(=[N+](CC)CC)cc-3oc2c1
Agent: CCN(CC)c1ccc2c(-c3ccccc3C(C)=O)c3ccc(=[N+](CC)CC)cc-3oc2c1
Agent: Cc1c(C(=O)O)c(O)cc2c1C(=O)c1c(O)c([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(O)c(O)c1C2=O
Product: COC(=O)/C=C/C(C)=C\C=C\C(C)=C\C=C\C=C(C)\C=C\C=C(C)\C=C\C(=O)O

Procedure:
norbixin; apocarotinic acid ethyl ester, E160f, C.I. 40825; chlorophyll, E 140, C.I. 75810; erythrosine, E127, C.I. 45430; carmine, cochineal, E120, C.I. 75470; litholrubin BK, C.I. 15850:1; phloxin B, C.I. 45410; rhodamine B, C.I. 45170; red beet dye betanin, E162; tartrazine, E102, C.I. 19140; uranine, C.I. 45350 or fluorescein, C.I. 45350:1.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13](OC)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].C(O)(=O)C>C1COCC1.O>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COP(=O)(CC(=O)C(C)(C)C)OC
Temperature: -78 °C

Procedure:
Dimethyl methylphosphonate (13.6 g, 0.11 mol) was dissolved in anhydrous THF (100 ml) under argon atmosphere. To the solution stirred at -78° C. was added dropwise n-butyl lithium (1.61N, 68.3 ml, 0.11 mol) over 30 minutes, and then a solution of commercially available methyl pivalate (5.0 g, 0.043 mol) in anhydrous THF (10 ml) was also added dropwise over 30 minutes. The reaction mixture was warmed to room temperature. Under ice cooling, acetic acid (7 ml) and water (10 ml) were added. After concentrating, water (20 ml) was added to the resulting residue. The mixture was extracted with ethyl acetate (50 ml×2), and the ethyl acetate layers were washed with water (20 ml×1) and with brine (20 ml×1), dried over anhydrous soldium sulfate, concentrated. Distillation of the residue gave dimethyl 3,3-dimethyl-2-oxo-butylphosphonate as a colorless clear oil (6.53 g, 0.031 mol, 72.6%, b.p.=90°-93° C./0.35 mmHg). The structure was identified by the following data.
Reaction SMILES: [F:1][CH:2]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([N:5]1[CH2:9][CH2:8][C@H:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=O.CO>C1COCC1>[F:1][CH:2]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][N:5]1[CH2:9][CH2:8][C@H:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1
Reactant: O=C(C(F)CCc1ccccc1)N1CC[C@H](Sc2ccc(O)cc2)C1
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc(S[C@H]2CCN(CC(F)CCc3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 69.3 %

Procedure:
(2RS,3S)-2-Fluoro-1-[3-(4-hydroxy-phenylsulfanyl)-pyrrolidin-1-yl]-4-phenyl-butan-1-one (200 mg, 0.56 mmol) was dissolved in THF (4 ml). Borane-dimethylsulfide complex (170 μl, 1.67 mmol) was added. The mixture was refluxed for 7 hours and then cooled to 0° C. MeOH (0.7 ml) was added dropwise and the solvent was removed in vacuo. The residue was dissolved with THF (3.5 ml) and 5N HCl (1.1 ml) and was stirred at 60° C. for 12 hours. The solvent was removed in vacuo and the residue was taken up in saturated NaHCO3 (3 ml). The aqueous layer was extracted with CH2Cl2 (3 times). The combined organic phases were dried over Na2SO4, filtered and the solvent was evaporated. The residue was chromatographed over silica gel (CH2Cl—MeOH, 99:1) to provide (2RS,3S)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidin-3-ylsulfanyl]-phenol (134 mg, 70%) as colorless oil. MS: m/e 346.3 (M+H+).
Reaction SMILES: C1(N[N:8]=[C:9]2[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[N:11]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:10]2=[O:32])C=CC=CC=1>C(O)(=O)C.[Zn]>[NH2:8][CH:9]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[N:11]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]1=[O:32]
Reactant: CC(C)CCn1c(=O)c(=NNc2ccccc2)c(=O)n(-c2ccccc2)c2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)CCN1C(=O)C(N)C(=O)N(c2ccccc2)c2ccccc21
Yield: 74.5 %

Procedure:
Zinc dust (26 g) was added to a suspension of 1-(3-methylbutyl)-5-phenyl-1H-1,5-benzodiazepine-2,3,4-(5H)-trione 3-(phenylhydrazone) (20.2 g) in 97% acetic acid (260 ml) at 23° under nitrogen. After 1 h the mixture was filtered and the filtrate evaporated. The residue was redissolved with DCM (200 ml) and water (100 ml) and the mixture was cautiously neutralised by portionwise addition of solid sodium carbonate. The mixture was extracted with DCM and the combined organic extracts were washed with saturated brine, dried and evaporated. The residue was chromatographed with DCM-MeOH (1→8%) as eluent to give the title compound (11.9 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[OH:11]O>C(O)(=O)C>[CH3:1][C:2]1[NH:10][C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[N+:3]=1[O-:11]
Reactant: OO
Reactant: Cc1nc2cnccc2[nH]1
Solvent: CC(=O)O
Product: Cc1[nH]c2cnccc2[n+]1[O-]

Procedure:
Following the method of Chem. Pharm. Bull., 12, 866 (1964), a solution of 2-methylimidazo[4,5-c]pyridine (5.65 g, 42.5 mmol) in 30% aqueous hydrogen peroxide (15 ml) and glacial acetic acid was stirred at 60° C. for 6 days. The volatiles were removed under reduced pressure and the residue was dissolved in ethanol and treated with solid anhydrous potassium carbonate. The solid was filtered off, washed with ethanol, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 10-30% water in acetone. Fractions containing the product were concentrated under reduced pressure, redissolved in isopropanol/toluene, 1:1 (200 ml) and re-evaporated to give the title compound, as a hygroscopic solid, (2.94 g, 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:11])[CH2:9]O)=[CH:4][CH:3]=1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:11])[CH2:9][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@H](CO)c1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](CN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1
Reaction time: 72 h
Yield: 59.4 %

Procedure:
To a solution of (S)-2-(4-fluorophenyl)propan-1-ol (0.82 g, 5.35 mmol, 1.0 equiv), phthalimide (0.82 g, 5.6 mmol, 1.05 equiv), and triphenyl phosphine (2.1 g, 8.03 mmol, 1.5 equiv) in dry THF (18 mL) was added dropwise diethylazodicarboxylate (3.6 mL, 15% in toluene, 8.0 mmol, 1.5 equiv). The reaction mixture was stirred over 72 h and then concentrated in vacuo. Purification by silica gel chromatography (15-25% EtOAc/Hexanes) provided the title compound (0.9 g, 59%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH:16]=[C:17]([CH3:18])[C:11]=2[N:10]([CH3:27])[C:9]1=[O:28])(=O)C.O[Li].O>C1COCC1.O.C(Cl)Cl>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:15]2[C:12]3[C:13](=[O:14])[N:8]([CH2:7][CH2:6][CH2:5][OH:4])[C:9](=[O:28])[N:10]([CH3:27])[C:11]=3[C:17]([CH3:18])=[CH:16]2)=[CH:25][CH:24]=1
Reactant: CC(=O)OCCCn1c(=O)c2c(c(C)cn2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cn(Cc2ccc(Cl)cc2)c2c(=O)n(CCCO)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1,7-dimethyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3 (2H,4H,5H)-yl)propyl acetate (40 mg, 0.099 mmol) in THF (5 mL) and water (5 mL) was added LiOH.H2O (4.74 mg, 0.198 mmol). The reaction was stirred at RT for 30 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1,7-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (15 mg, 41.9% yield) as a white solid. 1H NMR (DMSO-d6) δ: 7.38 (d, J=8.4 Hz, 2H), 7.26 (s, 1H), 7.22 (d, J=8.4 Hz, 2H), 5.45 (s, 2H), 4.44 (t, J=5.3 Hz, 1H), 3.95-3.82 (m, 2H), 3.56 (s, 3H), 3.45-3.39 (m, 2H), 2.26 (s, 3H), 1.73-1.58 (m, 2H). LCMS: MH+ 362 and TR=2.343 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][C:6]=12.[NH:17](C(OC(C)(C)C)=O)[C@H:18]([C:22](O)=[O:23])[CH2:19][O:20][CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[NH2:17][C@@H:18]([CH2:19][O:20][CH3:21])[C:22]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:9]=[CH:10][N:5]3[N:4]=[CH:3][C:2]([Br:1])=[C:6]3[N:7]=2)[CH2:12][CH2:13]1)=[O:23]
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Brc1cnn2ccc(N3CCNCC3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC[C@H](N)C(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromo-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine (300 mg, 1.1 mmol) taken up in 10 mL DMF. Boc-Ser(Me)-OH (280 mg, 1.3 mmol), HATU (368 mg, 1.6 mmol), and triethylamine (590 uL, 4.25 mmol) was added and stirred at room temp overnight. Reaction was diluted with DCM and washed with water. DCM layer was dried over magnesium sulfate reduced in vacuo. This was then taken up in 30% TFA in DCM solution and stirred at room temperature for 2 hours. It was then cooled to 0° C. and conc Aq NaOH added slowly until aqueous layer remains basic. DCM layer extracted dried over magnesium sulfate, reduced in vacuo for 405 mg crude product for further reaction as is. LRMS (ESI) m/z 383/385 [(M+H)]+, calc'd for C14H19BrN6O2: 383.25.
Reaction SMILES: [CH:1]1([S:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:25].[Na+]>CO.O>[CH:1]1([S:6]([CH:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(Nc1nccs1)C(SC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(Nc1nccs1)C(c1ccc(Cl)c(Cl)c1)S(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.8 %

Procedure:
To a solution of rac-2-cyclopentylsulfanyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (Example 10; 34 mg, 0.088 mmol) in methanol (2 mL) was added a solution of sodium periodate (34 mg, 0.16 mmol) in water (1 mL) and the mixture was stirred at 25° C. After 6 h, the precipitate was filtered off and washed with dichloromethane (15 mL). The organic layer was set aside and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. Chromatography of the residue (Biotage Flash 12M column, 50/50 hexanes/ethyl acetate) afforded rac-2-cyclopentanesulfinyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (23 mg, 66% yield) as a colorless oil: EI-HRMS m/e calculated for C16H16N2O2S2Cl2 (M+) 402.0030, found 402.0035.
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][OH:13])=[C:10](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1>C1COCC1>[CH3:34][O:33][C:31](=[O:32])[C:28]1[CH:27]=[CH:26][C:25]([O:13][CH2:12][C:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][O:9][C:10]=2/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:30][CH:29]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OCc1c(-c2ccccc2)noc1/C=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2/C=C/c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A stirred solution of [3-phenyl-5-((E)-styryl)-isoxazol-4-yl]-methanol (1.50 g, 5.4 mmol) in THF (50 mL) was cooled in an ice bath. Sodium hydride (0.28 g of a 55% dispersion in mineral oil, 6.4 mmol) was added and the mixture was stirred for 30 min whilst allowing to warm to room temperature. To the resulting suspension was added methyl 6-chloropyridine-3-carboxylate (0.93 g, 5.4 mmol). After stirring for 2 h the reaction mixture was quenched with aqueous saturated sodium bicarbonate solution (20 mL). Evaporation of the organic solvent was followed by extraction with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, concentrated and purified by chromatography (silica, heptane:ethyl acetate=90:10 to 60:40) to afford the title compound as an off-white solid (0.78 g, 35%). MS: m/e=413.5 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([C:24]2[CH:25]=[C:26]([CH:32]=[CH:33][C:34]([O:36]CC)=[O:35])[CH:27]=[CH:28][C:29]=2[O:30][CH3:31])=[CH:12][C:13]2[C:14]([CH3:23])([CH3:22])[CH2:15][CH2:16][C:17]([CH3:21])([CH3:20])[C:18]=2[CH:19]=1)(O)=[O:2].C1([NH:45]C2CCCCC2)CCCCC1.S(Cl)(Cl)=O.C(N(CC)CC)C.N.Cl>ClCCl.C(OCC)C.C1COCC1.O>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([C:24]2[CH:25]=[C:26]([CH:32]=[CH:33][C:34]([OH:36])=[O:35])[CH:27]=[CH:28][C:29]=2[O:30][CH3:31])=[CH:12][C:13]2[C:14]([CH3:23])([CH3:22])[CH2:15][CH2:16][C:17]([CH3:21])([CH3:20])[C:18]=2[CH:19]=1)(=[O:2])[NH2:45]
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2OCCCCCC(=O)O)C(C)(C)CCC3(C)C)c1
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: O
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCCCCC(N)=O)C(C)(C)CCC2(C)C
Reaction time: 0.17 h
Yield: 62.5 %

Procedure:
A solution of 1.2-7 g (2.43 mmol) of ethyl 3-{3-[3-(5-carboxypentyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylate obtained in Example 24(a) dissolved in 35 ml of dichloromethane was introduced into a round-bottomed flask, 505 μl (2.55 mmol) of dicyclohexylamine were added, and the mixture was stirred for 10 minutes. Then 186 μl (2.55 mmol) of thionyl chloride were added dropwise and the mixture was stirred at room temperature for 10 minutes. The reaction medium was evaporated to dryness, the residue obtained was taken up in ethyl ether, the suspension was filtered and the filtrate was evaporated. The residue obtained was dissolved in 15 ml of THF and the solution was introduced dropwise under nitrogen into a three-necked flask containing 20 ml of THF, 405 μl (2.92 mmol) of triethylamine and 160 μl of a 34% aqueous ammonia solution (2.67 mmol). The mixture was stirred at room temperature for 30 minutes, the reaction medium was poured into water, acidified to a pH of 1 with 1N hydrochloric acid and extracted with ethyl ether, and the organic phase was decanted, dried over magnesium sulfate, filtered and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of heptane and ethyl acetate (80:20). After evaporation of the solvents, 750 mg (60%) of the expected compound were obtained in the form of a white powder having a melting point of 133°-135° C.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.Br[CH:24]([CH:32]=O)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C(=O)C>O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][C:24]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][N:13]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CCOC(=O)CCC(Br)C=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)CCc1cnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (4.00 g), ethyl 4-bromo-5-oxopentanoate (3.80 g) and N,N-dimethylacetamide (25 mL) was stirred at 90° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (3.79 g, yield 70%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:3, volume ratio). melting point 126-127° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=2)O1>>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:28][CH:29]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1c2n(c3c(-c4ccc(N)nc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light brown solid (13 mg, 16%), MS (ISP) m/z=318.5 [(M+H)+], mp 332° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-amine (71.5 mg, 0.325 mmol).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:15][N:16]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][N:18]=[C:17]1[SH:27]>>[N:5]1([C:3](=[O:4])[CH2:2][S:27][C:17]2[N:16]([CH3:15])[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][N:18]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: Cn1c(-c2ccccc2)cnc1S
Reactant: O=C(CCl)N1CCCc2ccccc21
Product: Cn1c(-c2ccccc2)cnc1SCC(=O)N1CCCc2ccccc21
Yield: 42 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 1-methyl-5-phenyl-1H-imidazole-2-thiol as the nucleophile to yield 28 as an off-white solid (42%): MS m/z: 364 (M+H)+. Anal. Calcd. For, C21H21N3OS: C, 69.39; H, 5.82; N, 11.56; S, 8.82. Found: C, 69.29; H, 5.83; N, 11.40; S, 8.83.
Reaction SMILES: [CH3:1][P:2]([C:7]1[CH:12]=[C:11](Cl)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:6])[O:3]CC.[CH2:17]([SH:19])[CH3:18].[OH-].[Na+]>CS(C)=O.O>[CH3:1][P:2]([C:7]1[CH:12]=[C:11]([S:19][CH2:17][CH3:18])[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:6])[OH:3]
Reactant: CCS
Reactant: CCOP(C)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1ccc([N+](=O)[O-])c(P(C)(=O)O)c1

Procedure:
To a solution of ethyl P-methyl-2-nitro-5-chlorophenylphosphinate (20.0 mmol) and ethanethiol (60.0 mmol) in dimethylsulfoxide (20 ml) is added a solution of sodium hydroxide (40.0 mmol) in 1 ml of water. The mixture is warmed to 60° overnight, after which it is poured into water and extracted with ether. The aqueous solution is acidified, extracted with methylene chloride, dried and evaporated to give P-methyl-2-nitro-5-ethylthiophenylphosphinic acid, which is then treated with diazomethane in methanol to give methyl P-methyl-2-nitro-5-ethylthiophenylphosphinate.