Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12](=O)[CH2:13][Cl:14])[C:3]=1[C:4]([OH:6])=O.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].C(N(CC)CC)C.P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:6])[N:20]([CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[Cl:16])[C:12]([CH2:13][Cl:14])=[N:11]2
Reactant: O=C(CCl)Nc1cccc(Br)c1C(=O)O
Reactant: NCc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=c1c2c(Br)cccc2nc(CCl)n1Cc1ccccc1Cl
Temperature: 110 °C
Yield: 58.8 %

Procedure:
To a stirred mixture of compound (7a) (7.50 g, 27.4 mmol), 2-chlorobenzylamine (5.00 mL, 41.05 mmol) and triethylamine (5.70 mL, 41.1 mmol) in toluene (250 mL) was added a solution of phosphorus trichloride (2.60 mL, 30.1 mmol) in toluene (250 mL) dropwise over 1 hr. The reaction mixture was heated to 110° C. for 24 hr, whereupon the hot solution was decanted and concentrated in vacuo. The residue was triturated with propan-2-ol (50 mL) to afford the title compound (8) (6.41 g, 59%) as a yellow solid: m/z 397/399 (M+H)+ (ES+).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH2:5][S:6][C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2>N1C=CC=CC=1>[CH:2]([CH:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[S:6][CH2:5][CH2:4]1)=[O:1]
Reactant: OCC#CCSc1cc2ccccc2[nH]1
Solvent: c1ccncc1
Product: O=CC1CCSc2[nH]c3ccccc3c21
Yield: 67.8 %

Procedure:
A solution of the product of the above (1) (12.0 g) in pyridine (120 ml) is heated at 100° C. for 2 hours and evaporated to remove the pyridine. The residue is dissolved in ether (300 ml), washed with water, 2 N hydrochloric acid and a saturated saline solution, dried and evaporated to remove the solvent. The residue (11.0 g) is chromatographed on silica gel (50 g) and eluted with benzene. The eluate is evaporated to give the title compound as an oil (8.14 g). The oil is gradually solidified in a refrigerator.
Reaction SMILES: [I-].CN1C2C(=CC=CC=2)C([C@H]([C@H:14]2[NH:19][C:18](=[O:20])[C@@H:17]([CH2:21][CH2+:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]3[CH3:28])[NH:16][C:15]2=[O:29])C)=C1.CO.[BH4-].[Na+]>O>[CH3:28][N:23]1[CH:22]([CH2:21][CH:17]2[NH:16][C:15](=[O:29])[CH2:14][NH:19][C:18]2=[O:20])[CH:27]=[CH:26][CH2:25][CH2:24]1
Reactant: C[C@H](c1cn(C)c2ccccc12)[C@H]1NC(=O)[C@@H](C[CH2+]2C=CC=CN2C)NC1=O
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCC=CC1CC1NC(=O)CNC1=O
Reaction time: 1 h
Yield: 56.7 %

Procedure:
To a mixture of (3R,6R)-3-[(R)-1-(1-methylindol-3-yl)ethyl]-6-(1-methyl-2-pyridiniomethyl)piperazine-2,5-dione iodide (0.12 g), methanol (1.2 ml), and water (1.2 ml) was added sodium borohydride (0.12 g). The mixture was stirred on an ice bath for 1 hour, diluted with water (10 ml), and set aside in a refrigerator overnight. A precipitated solid was filtered, washed with water, and dried in vacuo to afford (3R,6R)-3-[(R)-1-methylindol-3-yl)ethyl]-6-[(RS)-1-methyl-1,2,3,6-tetrahydropyridin-6-yl-methyl]piperazine-2,5-dione (0.03 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:11]1([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][C:24]([OH:26])=[O:25])[CH:18]=[CH:17]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)Cn1ccc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1ccc2cc(N3CCNCC3)ccc21
Yield: 205 %

Procedure:
4-(1-tert-butoxycarbonylmethyl-1H-indol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (8.80 g) was treated with a mixture of 60 mL of TFA in 120 mL of methylene chloride overnight at room temperature. At this time, the solvent was removed in vacuo. This resulted in 11.26 g of a light yellow residue. This residue was used without further purification in the next step.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:22]=[C:21]([Cl:23])[C:20]([F:24])=[CH:19][C:5]=1[C:6]([C:8](=[CH:14][NH:15][CH:16]1[CH2:18][CH2:17]1)[C:9]([O:11]CC)=[O:10])=[O:7]>O1CCOCC1.O>[Cl:23][C:21]1[CH:22]=[C:4]2[C:5]([C:6](=[O:7])[C:8]([C:9]([OH:11])=[O:10])=[CH:14][N:15]2[CH:16]2[CH2:18][CH2:17]2)=[CH:19][C:20]=1[F:24]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.7 %

Procedure:
3.44 g of 80 percent strength sodium hydride are added in portions to a stirred ice-cooled solution of 31.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (6) in 100 ml of anhydrous dioxane. Thereafter, the mixture is stirred for 30 minutes at room temperature and for 2 hours under reflux, and the dioxane is stripped off in vacuo. The residue (40.3 g) is suspended in 150 ml of water, 6.65 g of caustic alkali are added and the mixture is refluxed for 1.5 hours. The warm solution is filtered, and the residue is rinsed with H2O. The ice-cooled filtrate is then acidified to pH=1-2 with semi-concentrated hydrochloric acid, and the precipitate is filtered off under suction, washed with water and dried in vacuo at 100° C. In this manner, 27.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid Via of melting point 234°-237° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:51][C:52]1[CH:61]=[CH:60][CH:59]=[C:58]2[C:53]=1[CH:54]=[CH:55][N:56]([C@@H:63]([CH3:67])[C:64]([NH2:66])=[O:65])[C:57]2=[O:62]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:51][C:52]2[CH:61]=[CH:60][CH:59]=[C:58]3[C:53]=2[CH:54]=[CH:55][N:56]([C@@H:63]([CH3:67])[C:64]([NH2:66])=[O:65])[C:57]3=[O:62])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](C(N)=O)n1ccc2c(NC(=O)Cc3ccc(Cl)c(Cl)c3)cccc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3,4-dichlorophenyl acetic acid (0.12 g, 0.00056 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.3 g, 0.0009 mol) and N,N-diisopropylethylamine (0.2 mL, 0.0009 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) was added (S)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)propanamide (0.10 g, 0.00043 mol). The reaction was stirred for 16 h at room temperature. The reaction was quenched with water, extracted with dichloromethane, washed with 2N HCl, saturated sodium bicarbonate solution, brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (12 g, 0-10% MeOH/DCM) to yield the product as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]([CH3:9])[CH2:7][OH:8])=[O:4].[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].[N+:18]([C:21]1[CH:22]=[N:23][NH:24][CH:25]=1)([O-:20])=[O:19]>C(#N)C.O>[OH:8][CH2:7][C@@H:6]([NH:5][C:3](=[O:4])[CH2:2][N:23]1[CH:22]=[C:21]([N+:18]([O-:20])=[O:19])[CH:25]=[N:24]1)[CH3:9]
Reactant: C[C@@H](CO)NC(=O)CCl
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: C[C@@H](CO)NC(=O)Cn1cc([N+](=O)[O-])cn1
Temperature: 160 °C
Yield: 896.8 %

Procedure:
2-Chloro-N—((S)-1-hydroxypropan-2-yl)acetamide (700 mg, 4.64 mmol), potassium iodide (960 mg, 5.8 mmol) and cesium carbonate (1.9 g, 5.8 mmol) were added to a solution of 4-nitropyrazole (436 mg, 3.86 mmol) in acetonitrile (10 mL) then the mixture was heated to 160° C. for 30 min in a microwave reactor. The reaction mixture was combined with those from 13 other identical reactions, diluted with water then extracted four times with ethyl acetate. The combined organic layers were dried, concentrated in vacuo and purified by column chromatography (3% v/v MeOH/DCM) to afford (S)—N-(1-hydroxypropan-2-yl)-2-(4-nitro-1H-pyrazol-1-yl)acetamide (7.9 g, 64%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[Cl-].[NH+]1C=CC=CC=1.O>C(OCC)(=O)C>[CH:4]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:13][C:14]=2[CH:15]=[CH:16][C:3]=1[OH:2]
Reactant: COc1ccc2c(c1)Nc1ccccc1S2
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc2c(c1)Nc1ccccc1S2
Temperature: 170 °C
Yield: 53 %

Procedure:
A mixture of 25 g (109 mmol) of 2-methoxyphenothiazine and 60 g (4.8 eq.) of pyridinium chloride is heated at 170° C. for 15 hours. After cooling down to a temperature of approximately 80° C., the brown solution obtained is diluted with 200 ml of ethyl acetate. Stirring is maintained for 30 minutes before pouring the reaction mixture into 200 ml of water. After stirring and decantation, the organic phase is dried over sodium sulphate and concentrated to dryness, under vacuum. The greenish solid obtained is recrystallized from 700 ml of boiling toluene. An insoluble solid is eliminated by filtration, the filtrate crystallizes spontaneously overnight. The crystals are collected by filtration and rinsed using isopentane. After drying, 12.43 g of a grey solid is obtained with a yield of 53%. Melting point: 207-208° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[NH:13][C:12]3[CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][CH2:19][C:11]=3[C:10]=2[CH:9]=1.[Li+].[OH-].Cl>O1CCOCC1>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:33])([F:34])[F:1])[CH:28]=1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[NH:13][C:12]3[CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19][C:11]=3[C:10]=2[CH:9]=1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
Ethyl 2-(7-(3,5-bis(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (28.6 mg, 0.059 mmol) was dissolved in dioxane (1.0 mL) and 1.0 M aqueous LiOH (0.166 mL, 0.166 mmol) was added. The solution was stirred at room temperature for 3 h before it was acidified to pH 3 with 1.0 M HCl and extracted twice with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (23 mg). LCMS m/z=458.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.12-2.24 (m, 1H), 2.61 (dd, J=17.0, 10.7 Hz, 1H), 2.73-2.89 (m, 4H), 3.53-3.63 (m, 1H), 5.19 (s, 2H), 6.86 (dd, J=8.6, 2.5 Hz, 1H), 7.0 (d, J=2.5 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 7.82 (s, 1H), 7.94 (s, 2H), 8.33 (s, 1H).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([OH:26])=O)[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:50][NH:51][CH2:52][C:53]1[CH:66]=[CH:65][C:56]([CH2:57][N:58]2[CH2:62][CH:61]([OH:63])[CH:60]([OH:64])[CH2:59]2)=[CH:55][CH:54]=1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:51]([CH2:52][C:53]3[CH:54]=[CH:55][C:56]([CH2:57][N:58]4[CH2:62][CH:61]([OH:63])[CH:60]([OH:64])[CH2:59]4)=[CH:65][CH:66]=3)[CH3:50])=[O:26])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CNCc1ccc(CN2CC(O)C(O)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)Cc3ccc(CN4CC(O)C(O)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (35 mg, 0.09 mmol), EDCI (25 mg, 0.13 mmol), HOBt (19 mg, 0.19 mmol) DIPEA (0.03 mL, 0.21 mmol), 1-{4-[(methylamino)methyl]benzyl}pyrrolidine-3,4-diol dihydrochloride (30 mg, 0.11 mmol) and DCM (10 mL).
Reaction SMILES: [C:1]1([S:7][C:8]2([O:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=3[N+:23]([O-])=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O.C(O)(=O)C.[Fe]>[C:1]1([S:7][C:8]2([O:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:20])([F:21])[F:22])=[CH:14][C:13]=3[NH2:23])[CH2:9][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1OC1(Sc2ccccc2)CC1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(OC(F)(F)F)ccc1OC1(Sc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
Iron powder (13.5 g, 241 mmol) was added to a suspension of 2-(1-phenylthiocycloprop-1-yl)oxy-5-(trifluoromethoxy)nitrobenzene (Description 4, 11.27 g, 30.1 mmol) in water (300 mL) and acetic acid (75 mL) and the mixture was stirred at 80° C. overnight. The mixture was cooled and filtered through celite, washing with ether. The filtrate was extracted with ether, the combined organic fractions were washed with aqueous sodium hydroxide (1M), dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2O (90:10 increasing to 80:20), to give the title compound as a yellow solid (8 g, 78%). 1H NMR (360 MHz, CDCl3) δ7.48 (2H, m), 7.34-7.23 (3H, m), 7.15 (1H, d, J 8.74 Hz), 6.60-6.56 (2H, m), 3.78 (2H, br s), 1.49-1.46 (2H, m), and 1.39-1.35 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.CC(=O)OCC.O.[CH3:20][N:21](C)C=O>[C-]#N.[C-]#N.[Zn+2].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>[C:20]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])#[N:21]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 140 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 4-hydroxy-3-iodobenzoate (2.78 g) and Zn(CN)2 (1.409 g) in N,N-dimethylformamide (DMF) (30 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (1.155 g). The reaction mixture was stirred at 140° C. for 12 h. After cooling the reaction, EA (100 mL) and water (40 mL) were added to the solution. After filtration, the filtrate was washed with water and brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography to afford methyl 3-cyano-4-hydroxybenzoate (D21) (1.3 g) as a white solid. MS (ES): C9H7NO3 requires 177. found 178.0 (M+H+).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=1[CH3:25])C1C=CC=CC=1>[Pd].CN(C)C=O>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:21])[CH3:23])[C:10]=1[CH3:25]
Reactant: Cc1c(OCc2ccccc2)c(=O)ccn1CCOC(=O)C(C)(C)C
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1c(O)c(=O)ccn1CCOC(=O)C(C)(C)C
Reaction time: 24 h
Yield: 77.46 %

Procedure:
3-Benzyloxy-2-methyl-1-(2-pivaloyloxyethyl)pyridin-4-one (1.08 g, 0.003 mol) was hydrogenated over Pd/C catalyst in dimethylformamide (30 ml) with stirring for 24 hours. The solution was filtered and rotary evaporated to dryness to provide a crude product (1.08 g) which was flash chromatographed (silica gel, Kieselgel 60,7734, 20 mm×300 mm column, eluting with ethyl acetate:ethanol, 1:1 v/v). Rotary evaporation in vacuo at 60° C. provided the title compound in 77.46% yield as orange crystals, m.p. 147°-149° C.; νmax 1580, 1625, 1725, 2850 cm-1 ; δ(d6 dimethylsulphoxide) 1.1 (9H,s), 2.35 (3H,s), 4.30 (4H,s), 4.4 (1H,s), 6.15 (1H,d), 7.55 (1H,d).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH3:26][N:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33]>>[CH3:26][N:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CN(C)CCCCCN
Product: CN(C)CCCCCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Example 26, starting from (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (Intermediate 67) and 5-dimethylaminopentylamine.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[CH:13]2.[F:17][C:18]1[CH:23]=[C:22](F)[CH:21]=[C:20]([F:25])[N:19]=1>CS(C)=O.C(Cl)Cl>[F:17][C:18]1[CH:23]=[C:22]([N:15]2[C:16]3[C:12](=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:7])[CH:13]=[CH:14]2)[CH:21]=[C:20]([F:25])[N:19]=1
Reactant: Cc1cccc2cc[nH]c12
Reactant: Fc1cc(F)nc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cccc2ccn(-c3cc(F)nc(F)c3)c12
Temperature: 25 °C

Procedure:
Potassium tert-butoxide (410 mg, 3.6 mmol) is added to a mixture of 7-methyl-1H-indole (470 mg, 3.6 mmol) in DMSO (20 ml) with ice cooling. Stirring is continued for 10 minutes before 2,4,6-trifluoropyridine E (350 μl, 3.6 mmol) is added dropwise. The mixture is warmed to RT and stirred for 2 h. The mixture is diluted with DCM and extracted with water. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 350 mg (40%). HPLC-MS: M+H=245; tR=1.03 min (Method—2).
Reaction SMILES: [O:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1)=[O:19].C([O-])(O)=O.[Na+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C1COCC1>[O:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(OC2CCNCC2)cc1
Reactant: O=C(NCCCl)Nc1ccnc2ccccc12
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCN1CCC(Oc2ccccc2)CC1)Nc1ccnc2ccccc12
Temperature: 70 °C
Reaction time: 144 h

Procedure:
To a solution of 4-phenoxy-piperidine (0.03 mmol) in dry THF (1 mL) is added 1-(2-chloro-ethyl)-3-quinolin-4-yl-urea (0.03 mmol), solid NaHCO3 (2.5 mg), and Nal (1 mg). The flask is tightly sealed, and shaken at 70° C. for 6 days. The reaction mixture is evaporated, taken up in aqueous formic acid, and purified by preparative HPLC to provide the title compound.
Reaction SMILES: [C:1](O)(=O)C.O.C1(C)C=CC=CC=1.[CH3:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[N+:24]([O-])=O>CN(C=O)C.[Fe].C1CCCCC1>[NH:24]1[C:15]2[C:14](=[CH:23][CH:22]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH:13]=[CH:1]1
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: [Fe]
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc2cc[nH]c2c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 62.4 %

Procedure:
Into a reaction flask were introduced 176.4 g of iron powder, 43.5 g of acetic acid, 71.2 g of water and 273.3 g of toluene. The content of the flask was heated to 80° C. Then, a solution of 131.8 g of methyl 4-methyl-3-nitrobenzoate in 110.4 g of DMF was dropwise added into the above-mentioned mixed solution over a period of about one hour, after which the resulting mixture was stirred for an additional 4 hours at 80° C. After cooling the reaction mixture, the solid material was removed by filtration. The filtrate was washed with 5% aqueous solution of NaOH, and washed with 5% aqueous solution of hydrochloric acid and water, and then the toluene was distilled off to obtain a brown-colored solid product. Then, 164.3 g of cyclohexane was added to dissolve the solid product at about 80° C. The resulting solution was cooled to room temperature, and the deposited crystalline material was collected by filtration and dried to obtain 73.8 g (yield 80.0%) of methyl indole-6-carboxylate monomer.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a suspension of 3-(4-bromophenyl)-propionic acid (3.0 g, [CAS Reg. No. 1643-30-7]) in diethyl ether (50 mL) was added lithium aluminium hydride (746 mg) in three portions. The mixture was then heated to reflux for 16 hours. The mixture was cooled to room temperature and saturated sodium sulfate solution (3 mL) was added dropwise over a period of 5 minutes. Stirring was continued for 30 minutes at RT. A white precipitation was obtained. The solid was filtered off, washed with diethyl ether and the filtrate was concentrated in vacuo to afford the title compound as a colorless liquid (2.62 g, 93%) that was used without further purification. MS (EI): 215.0 [MH+].
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[O:23]=[S:24]1(=[O:29])[CH2:28][CH2:27][CH2:26][NH:25]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:1]([C:5]1[N:6]=[C:7]([N:25]2[CH2:26][CH2:27][CH2:28][S:24]2(=[O:29])=[O:23])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCCN1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(N2CCCS2(=O)=O)c2nnn(Cc3ccccc3Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
A mixture of 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (15.9 mg, 47.2 μmol), 1,1-dioxo-isothiazolidine (11.4 mg, 94.4 μmol) and DBU (14.2 μL, 94.4 μmol) in DMF (250 μL) was stirred at the room temperature overnight. The reaction mixture was directly purified by preparative HPLC (column: Gemini Sum C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 75:25% to 5:95%. WL: 230 nm Flow: 30 mL/min.) to afford the title compound as white solid (3.10 mg, 16%). MS (m/e): 387.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH:5]=[CH:4][N:3]=1.[Cl-].[NH4+].CN(C)C=O.C(O)C>[Fe].O>[NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([O:15][C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)/C=C/c1c(Oc2ccc([N+](=O)[O-])cc2)ccnc1N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)/C=C/c1c(Oc2ccc(N)cc2)ccnc1N

Procedure:
Ethyl (E)-3-[2-amino-4-(4-nitrophenoxy)-3-pyridyl]-2-propenoate (350 mg), iron powder (700 mg), ammonium chloride (1.4 g), dimethylformamide (7 ml), ethanol (2 ml) and water (2 ml) were stirred at 100° C. for 20 minutes. The mixture was filtered with celite, and then water and ethyl acetate were added for extraction. The organic layer was washed 5 times with aqueous ammonium chloride solution and then dried over magnesium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 230 mg of the target substance as a light yellow solid.