Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Br-].[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=3)=[CH:38][CH:37]=2)=C(C=1)C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:52][C:53]1[CH:54]=[C:55]([CH2:71][CH:72](C=O)[CH2:73][CH2:74][CH2:75][CH2:76][C:77]([O:79][CH2:80][CH3:81])=[O:78])[CH:56]=[C:57]([F:70])[C:58]=1[O:59][Si:60]([CH:67]([CH3:69])[CH3:68])([CH:64]([CH3:66])[CH3:65])[CH:61]([CH3:63])[CH3:62].[Cl-].[NH4+]>CCCCCC.C1COCC1>[F:52][C:53]1[CH:54]=[C:55]([CH:56]=[C:57]([F:70])[C:58]=1[O:59][Si:60]([CH:61]([CH3:62])[CH3:63])([CH:67]([CH3:68])[CH3:69])[CH:64]([CH3:65])[CH3:66])[CH2:71][CH:72]([CH:4]=[CH:3][C:2]1[CH:1]=[C:8]([F:7])[CH:9]=[CH:10][C:11]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:49])([F:50])[F:51])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[CH2:73][CH2:74][CH2:75][CH2:76][C:77]([O:79][CH2:80][CH3:81])=[O:78]
Reactant: CCOC(=O)CCCCC(C=O)Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1
Reactant: [Li]CCCC
Reactant: Fc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CCCCC(C=Cc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1
Reaction time: 0.75 h

Procedure:
0.7 ml (1.12 mmol) of a 1.6 M solution of n-butyllithium in hexane is added dropwise to a suspension of 784 mg (1.06 mmol) of [5-fluoro-2-(4′-trifluoromethylbiphenyl-4-ylmethoxy)-benzyl]triphenylphosphonium bromide in 10 ml of THF at 0° C. and then stirred for 45 min. Subsequently, a solution of 500 mg (1.06 mmol) of ethyl 7-(3,5-difluoro-4-triisopropylsilanyloxy-phenyl)-6-formylheptanoate in 10 ml of THF is added dropwise at 0° C. and then stirred at this temperature for 2 h. The mixture is mixed with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The resulting crude product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:1). 813 mg (84% of theory) of the title compound are obtained as an E/Z mixture (2:1).
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]([N:7]1[CH2:19][C:18]2[S:17][C:16]3[N:15]=[CH:14][N:13]=[C:12]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=4)[C:11]=3[C:10]=2[CH2:9][CH2:8]1)=[O:6].[CH3:29][NH:30][CH3:31].CO.ClCCl>ClCCl>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C:12]2[C:11]3[C:10]4[CH2:9][CH2:8][N:7]([C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:30]([CH3:31])[CH3:29])[CH2:19][C:18]=4[S:17][C:16]=3[N:15]=[CH:14][N:13]=2)[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: O=C(C=CCBr)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Reactant: CNC
Solvent: ClCCl
Solvent: CO
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
To an ice-bathed cooled solution of 4-Bromo-1-[4-(3-chloro-4-fluoro-phenylamino)-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluoren-7-yl]-but-2-en-1-one (0.125 g, 0.00026 mol) in dichloromethane (1.25 ml) was added dimethylamine (2.0M solution in THF) (0.65 ml, 0.001 mol) over 1-2 min. The resulting mixture was stirred at RT for 2 hours. TLC (10% MeOH/Dichloromethane) indicates no SM present, a new polar spot seen. Conc. the reaction mixture to dryness under vacuum at 30° C. Purified by silica gel chromatography (ISCO system) using a gradient of dichloromethane—30% methanol/dichloromethane. The fractions combined, conc to dryness and the residue dissolved in 10% MeOH/DCM, filtered through a filter paper. The filterate was conc. to dryness and dried under vacuum at RT O/N to give 0.03 g (23%) of desired product. 1H-NMR (CD3OD-d3) δ 8.46 (m, 1H), 8.39 (s, 1H), 7.88 (m, 1H), 7.62 (m, 1H), 7.42 (t, 1H), 6.67 (m, 1H), 3.94 (m, 2H), 3.87 (m, 4H), 2.75 (m, 2H), 2.56 (s, 6H); LCMS RT=2.38 min, [M+H]+=446.0.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]3[C:17](=[O:18])[CH:16]=[CH:15][C:13](=[O:14])[C:10]=3[C:11](=[O:12])[C:4]2=[CH:3][CH:2]=1)=[O:8].[CH2:19]=[CH:20][C:21]([Cl:23])=[CH2:22]>C(O)(=O)C.CCOCC>[Cl:23][C:21]1[CH2:22][CH:16]2[CH:15]([C:13](=[O:14])[C:10]3[C:11](=[O:12])[C:4]4[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=4[C:7](=[O:8])[C:9]=3[C:17]2=[O:18])[CH2:19][CH:20]=1
Reactant: C=CC(=C)Cl
Reactant: O=c1ccc(=O)c2c(=O)c3ccccc3c(=O)c1=2
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1C2=C(C(=O)c3ccccc31)C(=O)C1CC(Cl)=CCC1C2=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 72 %

Procedure:
Quinizarinquinone (I) (1.0 g, 4.2 mmol) and chloroprene (1.12 g, 12.6 mmol) were dissolved in acetic acid (6 ml, glacial) and stirred at ambient temperature under nitrogen for 2.5 days. The reaction mixture was then diluted with ether (25 ml), the reaction mixture filtered, the retained precipitate washed with ether and dried under reduced pressure in the presence of phosphorus pentoxide to yield 9-chloro-6a,7,10,10atetrahydro-5,6,11,12-naphthacenetetraone (II) (988 mg, 72%). Recrystalization (chloroform-ether) gave the foregoing compound in analytical purity m.p. 221°-222° C.,
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[NH:21][C:22]([C:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH:25]=5)=[CH:23][C:16]=34)[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[NH:21][C:22]([C:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH:25]=5)=[CH:23][C:16]=34)[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4ccc5ncn(Cc6cccc(F)c6)c5c4)ccnc3[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(Cn2cnc3ccc(-c4ccnc5[nH]c(C6=CCNCC6)cc45)cc32)c1
Reaction time: 3 h

Procedure:
A solution of Example 14D (92.0 mg, 0.176 mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (0.14 mL, 1.8 mmol) and the mixture was stirred for 3 hours and concentrated. The residue was dissolved in 2 mL of methanol and slowly treated with 3 mL 2M hydrogen chloride in ether. The suspension was stirred for 15 minutes and diluted with ether. The solids were filtered, washed with ether, treated with aqueous sodium bicarbonate, filtered, washed with water and concentrated to give the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 2.23-2.29 (m, 2H), 2.92 (t, J=5.6 Hz, 2H), 3.38-3.46 (m, 1H), 5.64 (s, 2H), 6.33 (d, J=1.9 Hz, 1H), 6.53 (s, 1H), 7.11-7.17 (m, 3H), 7.19-7.25 (m, 1H), 7.40 (td, J=7.9, 6.1 Hz, 1H), 7.59 (dd, J=8.3, 1.6 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 8.22 (d, J=5.0 Hz, 1H), 8.54 (s, 1H), 11.81 (bs, 1H) MS (ESI+) m/z 424.2 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]([CH2:11]C(O)=O)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][Li].C([O:19][CH2:20][CH3:21])C>>[C:1]1([C@H:7]([CH2:11][C:20](=[O:19])[CH3:21])[C:8](=[O:10])[CH3:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C[C@H](C(=O)O)c1ccccc1
Reactant: [Li]C
Reactant: CCOCC
Product: CC(=O)C[C@H](C(C)=O)c1ccccc1

Procedure:
(S)-3-Phenylhexane-2,5-dione was synthesized from (S)-2-phenylsuccinic acid with methyllithium in diethyl ether. The analytical data apart from the optical rotation and CD corresponds to the product formed by means of PigD catalysis (FIGS. 10 and 16).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][C@H:20]([C:22]2[N:26]([CH3:27])[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[N:24][N:23]=2)[CH3:21])=[C:7]([C:9]2[O:13][C:12]([C:14]([O:16]CC)=O)=[N:11][N:10]=2)[CH:8]=1.O>C(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][C@H:20]([C:22]2[N:26]([CH3:27])[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:36])([F:35])[F:37])=[N:24][N:23]=2)[CH3:21])=[C:7]([C:9]2[O:13][C:12]([C:14]([NH2:1])=[O:16])=[N:11][N:10]=2)[CH:8]=1
Reactant: CCOC(=O)c1nnc(-c2cc(Cl)ccc2O[C@@H](C)c2nnc(-c3ccccc3C(F)(F)F)n2C)o1
Reactant: N
Solvent: CCO
Solvent: O
Product: C[C@H](Oc1ccc(Cl)cc1-c1nnc(C(N)=O)o1)c1nnc(-c2ccccc2C(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 29% aqueous ammonia solution (0.3 ml) was added to a solution of ethyl 5-{5-chloro-2-[(1S)-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy]phenyl}-1,3,4-oxadiazole-2-carboxylate (120 mg) in ethanol (1 ml), followed by stirring at room temperature for one hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was powdered with diisopropylether to obtain, as a light yellow solid, 5-{5-chloro-2-[(1S)-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy]phenyl}-1,3,4-oxadiazole-2-carboxamide (86 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:7]=1[CH3:8].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35][CH2:2][C:3]2[N:4]=[CH:5][NH:6][C:7]=2[CH3:8])=[CH:31][CH:30]=1
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Sc1ccc(Cl)cc1
Product: Cc1[nH]cnc1CSc1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to example 42 using 4-chloromethyl-5-methyl-1-trityl-1H-imidazole (CAS106147-85-7) for the alkylation of 4-chlorobenzenethiol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38].[Cl-].[NH4+]>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([N:17]1[C:18](=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]1=[O:26])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: COC(=O)C(CNCCNC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N(CCNC(=O)OC(C)(C)C)CC(C(=O)OC)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 90.8 %

Procedure:
To a solution of 18.80 g (47.54 mmol) of 3-(2-tert-butoxycarbonylamino-ethylamino)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester dissolved in 156 mL of anhydrous dichloromethane was added 8.02 mL (57.05 mmol) of triethylamine. The resulting mixture was cooled at 0° C. and 5.00 mL (52.29 mmol) of ethyl chloroformate dissolved in 30 mL of anhydrous dichloromethane was added. The resulting mixture was stirred at room temperature for 12 h. Saturated aqueous solution of ammonium chloride was added and the mixture extracted with dichloromethane. The extracts were washed with a saturated aqueous solution of sodium chloride, sodium carbonate, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 99/1 led to afford 20.00 g (90%) of the desired compound as an oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:19]#[N:20])[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:9]=2[NH:8][C:7]1=[O:21])[CH3:2].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Cl.[C:33](=[O:36])([O-])[O-:34].[K+].[K+]>CN(C)C=O>[F:16][C:15]([F:18])([F:17])[C:33]([OH:34])=[O:36].[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:19]([NH2:20])=[O:34])[CH:13]=[C:14]([C:15]([F:16])([F:17])[F:18])[C:9]=2[N:8]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[F:24])[C:7]1=[O:21])[CH3:23]
Reactant: Fc1ccccc1CCl
Reactant: CCN(CC)CCn1c(=O)[nH]c2c(C(F)(F)F)cc(C#N)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCn1c(=O)n(Cc2ccccc2F)c2c(C(F)(F)F)cc(C(N)=O)cc21
Product: O=C(O)C(F)(F)F
Temperature: 80 °C
Yield: 51 %

Procedure:
A solution of 3-[2-(diethylamino)ethyl]-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-5-carbonitrile (10.3 mg), 2-fluorobenzyl chloride (0.05 ml) and potassium carbonate (23.8 mg) in N,N-dimethylformamide (1.5 ml) was stirred with heating at 80° C. for 1.5 hours. The reaction mixture was concentrated in vacuo. To the resultant residue was added t-butanol (1.5 ml), and the mixture was stirred with heating at 60° C. To the solution was added powdered potassium hydroxide crashed in mortar (46.7 mg), and the mixture was stirred with heating at 60° C. for 1 hour. To the reaction mixture was added 1N hydrochloric acid, and the mixture was concentrated in vacuo. The resultant residue was purified by HPLC using condition 2 to give the title compound (9.1 mg, 51%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C1C(=O)N([Br:19])C(=O)C1>OS(O)(=O)=O>[Br:19][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc2cnccc2c1
Agent: O=S(=O)(O)O
Product: Fc1ccc2cnccc2c1Br

Procedure:
To a stirring mixture of 6-fluoroisoquinoline in H2SO4 (5 mL) at 0° C. was added solid NBS (1.5 EQ) slowly over 5 min. The reaction mixture was reacted at 0° C. for 1 h. To this reaction mixture was added NBS (0.5 EQ). The cold bath was then removed. The reaction mixture was reacted until all the starting material was consumed. To this reaction mixture was neutralized with a cold solution of NaOH (5N) until the pH of this mixture >10. The white solid was filtered off and dissolved in DCM and washed with a solution of NaOH (1N). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified via a column to give 5-bromo-6-fluoroisoquinoline. Retention time (min)=2.810, method [3], MS(ESI) 226.0 (M+H).
Reaction SMILES: C[C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.C(Cl)Cl.N1C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27](C)[C:28](Cl)=O)=[CH:23][CH:22]=1.Cl.C(O)C>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:28])[C:4](=[O:9])[CH2:5][C:6]([O:7][CH2:2][CH3:10])=[O:8])=[CH:23][CH:22]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C(=O)Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)C(C)c1ccc(Cl)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
In a round bottomed flask, to a suspension of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid, 2.91 g, 20.2 mmol) in methylene chloride (11.3 mL, 177 mmol) at −10° C. (internal temp) was added pyridine (4.00 mL, 49.5 mmol) over 10 minutes. To the resulting clear solution at −10° C., was added dropwise a solution of 2-(4-chlorophenyl)propanoyl chloride (4.10 g, 20.2 mmol) in methylene chloride (7.93 mL, 124 mmol) over 1 h. The reaction mixture was then stirred for 1 h at −10° C., and then for 1 hour at room temperature. The mixture was poured into hydrochloric acid (2.00M in water, 45.3 mL, 90.6 mmol) and ice, the layers were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with 1N HCl and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. To the crude residue was added ethanol (39.6 mL, 679 mmol) and the mixture was heated at reflux (89 degree bath temp) for 3 hours. After cooling to room temp, the volatiles were removed in vacuo. Residue was adsorbed onto silica using DCM and purified via column chromatography (gradient elution: 0 to 20% EtOAc/hexanes to afford ethyl 4-(4-chlorophenyl)-3-oxopentanoate (2.94 g, 92%) as a yellow oil. LCMS: (FA) ES+ 255; 1H NMR (400 MHz, DMSO)S 7.34-7.30 (m, 2H), 7.17-7.13 (m, 2H), 4.16-4.09 (m, 2H), 3.90 (q, J=7.2, 1H), 3.40 (d, J=15.6, 1H), 3.30 (d, J=15.6, 1H), 1.40 (d, J=6.8, 3H), 1.23 (t, J=7.2, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C@H:12]([C:14]2[N:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16](=[O:28])[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])[CH3:13])[CH:5]=[CH:4][N:3]=1.[SH-:35].[Na+]>CO>[SH:35][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C@H:12]([C:14]2[N:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16](=[O:28])[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])[CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: [SH-]
Reactant: C[C@H](Nc1ccnc(Cl)c1[N+](=O)[O-])c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Agent: [Na+]
Solvent: CO
Product: C[C@H](Nc1ccnc(S)c1[N+](=O)[O-])c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of (S)-3-(1-(2-chloro-3-nitropyridin-4-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl) isoquinolin-1 (2H)-one III-33 (500 mg, 1.0 mmol, 1 eq) in MeOH (10 mL), sodium hydrosulphide (69 g, 1.29 mmol, 1.2 eq) was added and the resulting mixture was stirred at reflux for 2 h. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2-3% MeOH-DCM) to afford the product, (S)-3-(1-(2-mercapto-3-nitropyridin-4-ylamino) ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-one III-34.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[CH:14]=[C:15]([NH:23][C:24](OC2C=CC=CC=2)=[O:25])[C:16](=[CH:21][CH:22]=1)[C:17](OC)=[O:18]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:17](=[O:18])[C:16]2[C:15](=[CH:14][C:13]([Cl:12])=[CH:22][CH:21]=2)[NH:23][C:24]1=[O:25])(=[O:9])=[O:10]
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: Nc1ccccc1S(N)(=O)=O
Product: Nc1ccccc1S(=O)(=O)n1c(=O)[nH]c2cc(Cl)ccc2c1=O
Yield: 58 %

Procedure:
From 2.7 g (15.7 mmol) of 2-aminobenzenesulfonamide and 4.8 g (15.7 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate in a manner similar to Preparation Example 1, 3.2 g (yield 58%: 3 steps) of the title compound was obtained. Property: colorless crystals, melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6): 6.46 (2H, s), 6.65 (1H, t), 6.81 (1H, d), 7.12 (1H, s), 7.23 (1H, d), 7.34 (1H, t), 7.76 (1H, d), 7,86 (1H, d).
Reaction SMILES: [CH2:1]([CH:3]([CH2:28][CH2:29][CH2:30][CH3:31])[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=2[O:26][CH3:27])=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[Cl-].[C:40]1([N+:46]2([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)C=CC=C[CH:47]2C(=O)N)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C[OH:62]>>[C:40]1([N:46]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:47]([O:22][C:21](=[O:23])[C:20]2[CH:24]=[CH:25][C:17]([CH2:16][N:13]3[C:14]4[C:10](=[CH:9][CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH:3]([CH2:1][CH3:2])[CH2:28][CH2:29][CH2:30][CH3:31])[CH:15]=4)[CH:11]=[CH:12]3)=[C:18]([O:26][CH3:27])[CH:19]=2)=[O:62])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCCCC(CC)C(=O)Nc1ccc2ccn(Cc3ccc(C(=O)O)cc3OC)c2c1
Reactant: NC(=O)C1C=CC=C[N+]1(c1ccccc1)c1ccccc1
Reactant: CO
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CCCCC(CC)C(=O)Nc1ccc2ccn(Cc3ccc(C(=O)OC(=O)N(c4ccccc4)c4ccccc4)cc3OC)c2c1
Yield: 79 %

Procedure:
A solution of the acid (D) (3.1 g) and triethylamine (1.0 ml) in methanol (30 ml) was treated with a solution of N,N-diphenylcarbamoylpyridinium chloride (2.5 g) in methanol (30 ml). The resultant precipitate was collected by filtration, washed with methanol, and dried under vacuum to give 4-[6-(2-ethylhexanamido)indol-1-ylmethyl]-3-methoxybenzoic N,N-diphenylcarbamic anhydride (A) as a white solid (3.54 g, 79%); mp 159°-162° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH3:4].[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:18]2[CH2:19][CH2:20][CH2:21][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:16][CH2:17]2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCN(c2cccnc2)CC1
Product: N
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 3-bromopyridine (3.95 g, 25.0 mmol), 1-tert-butoxycarbonyl-homopiperazine (5.0 g, 25.0 mmol), tetrakis(triphenylphosphine)palladium(0) (145 mg, 0.125 mmol), potassium tert-butoxide (6.1 g, 50.0 mmol) and anhydrous toluene (75 ml) was stirred at 80° C. for 4 hours. Water (100 ml) was added and the mixture was extracted three times with ethyl acetate (50 ml). Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound as an oil. Yield 0.92 g, 13%.
Reaction SMILES: [CH2:1]([C:5]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]([CH:8](C(OCC)=O)[C:9]([O:11]CC)=O)=[O:7])[CH2:2][CH2:3][CH3:4].FC1C=CC(C(CCC)(CCC)C(C(C(OCC)=O)C(OCC)=O)=O)=CC=1>>[CH2:19]([C:5]1([CH2:1][CH2:2][CH2:3][CH3:4])[C:23]2[C:28](=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9]([OH:11])=[CH:8][C:6]1=[O:7])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(CCCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccc(F)cc1
Agent: CCCC(CCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccc(F)cc1
Product: CCCCC1(CCCC)C(=O)C=C(O)c2cc(F)ccc21

Procedure:
The title compound was prepared according to the procedure of Example 14G, substituting the compound of Example 18E for the compound of Example 14F. 1H NMR (300 MHz, CDCl3): δ 0.52 (m, 2 H) 0.68 (t, J=7.35 Hz, 6 H) 0.88 (m, 2 H) 1.09 (m, 4 H) 1.82 (m, 2 H) 2.23 (m, 2 H) 6.17 (s, 1 H) 7.27 (m, 1 H) 7.42 (m, 1 H) 7.80 (dd, J=9.38, 2.76 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:25][C:12]3([CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:11](=[O:26])[C:10]=2[CH:27]=1.C(Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>>[CH2:18]([N:15]1[CH2:16][CH2:17][C:12]2([C:11](=[O:26])[C:10]3[CH:27]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:2])=[O:28])[CH:7]=[CH:8][C:9]=3[O:25]2)[CH2:13][CH2:14]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)C1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)C1(CCN(Cc3ccccc3)CC1)O2
Yield: 93 %

Procedure:
(E)-3-{1′-Benzyl-3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-acrylic acid methyl ester was obtained starting from (E)-3-{3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-acrylic acid methyl ester (247 mg, 0.76 mmol, Intermediate 4) and benzyl bromide, according to the procedure described in Example 2, Step A (280 mg, 98%). The methyl ester was hydrolyzed with NaOH following the procedure described in Example 1, Step A, giving (E)-3-{1′-benzyl-3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-acrylic acid as a white solid (249 mg, 93%). The resulting acid was treated with NH2OTHP according to the procedure described in Example 1, Step B, giving (E)-3-{1′-benzyl-3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow solid (62 mg, 20%). Finally, removal of the THP protecting group following the procedure described in Example 1, Step C gave (E)-3-{1′-benzyl-3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-N-hydroxy-acrylamide as its hydrochloride salt (30 mg, 50%).