Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:9][C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]([O-:14])=[O:13])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>CN(C)C=O>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][O:13][C:12](=[O:14])[C:11]1[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:9][C:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8]
Reactant: ClCc1ccccn1
Reactant: Cc1cccc(Nc2ccccc2C(=O)[O-])c1C
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2ccccc2C(=O)OCc2ccccn2)c1C

Procedure:
A 2.36 g amount of sodium N-(2,3-xylyl)anthranilate was dissolved in 20 ml of dimethyl formamide and 1.25 g of 2-chloromethyl pyridine was then added thereto. The mixture was allowed to react at a temperature of 90° C. for 3 hours. After the reaction, the solvent was distilled off in vacuo and the residue was charged with water. The mixture was then extracted with ether. After dehydration, the ether was distilled off and the resultant residue was recrystallized from methanol. Thus, 3.00 g of the desired pale yellow 2-pyridylmethyl-N-(2,3-xylyl)anthranilate having the following physical properties was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28](Cl)[CH:27]=2)=[CH:4][C:5]([F:24])=[C:6]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])[CH:7]=1.[C:33]([NH2:36])(=[O:35])[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO>[C:33]([NH:36][C:28]1[CH:27]=[C:26]([O:25][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([NH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=4)=[O:15])[CH2:12][CH2:13]3)=[O:10])=[C:5]([F:24])[CH:4]=2)[CH:31]=[CH:30][N:29]=1)(=[O:35])[CH3:34]
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2cc(Cl)c(Oc3ccnc(Cl)c3)cc2F)CC1
Reactant: CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2Cl)ccn1
Temperature: 100 °C
Yield: 47.8 %

Procedure:
N-(5-cloro-4-(2-chloropyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.200 g, 0.418 mmol), acetamide (0.124 g, 2.091 mmol), cesium carbonate (0.136 g, 0.418 mmol), and xantphos (0.017 g, 0.029 mmol) were dissolved in dry dioxane (3 mL) in a 25 mL round bottom flask. Argon was bubbled through the reaction mixture for 5 minutes, and then palladium acetate (4.69 mg, 0.021 mmol) was added. The mixture was again degassed for five minutes, and then the reaction flask was fitted with a reflux condenser. The system was flushed with argon and then heated at 100° C. under a balloon of argon for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (30 mL) and a 4:1 mixture of ethyl acetate and THF (150 mL). The layers were separated, and the aqueous layer was washed with additional ethyl acetate/THF solution. The organic layers were combined and concentrated to yield a sticky orange oil. Upon addition of methanol (3 mL) a fine cream-colored precipitate formed, which was collected by suction filtration and washed with a small portion of dichloromethane to yield N-(4-(2-acetamidopyridin-4-yloxy)-5-chloro-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.100 g, 47.7% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.91 (s, 1H), 10.58 (s, 1H), 9.83 (s, 1H), 8.23 (d, 1H), 8.18 (d, 1H), 7.58 (m, 4H), 7.15 (m, 2H), 6.65 (dd, 1H), 2.02 (s, 3H), 1.61 (m, 2H), 1.56 (m, 2H); MS (ESI) m/z: 501.1 (M+H+).
Reaction SMILES: Cl.C(OC([N:9]1[C@H:14]([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C@@H:13]2[CH2:23][C@H:10]1[CH2:11][CH2:12]2)=O)(C)(C)C>O1CCOCC1>[C@H:10]12[CH2:23][C@H:13]([CH2:12][CH2:11]1)[C@@H:14]([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:20])([F:21])[F:19])[NH:9]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CNC(=O)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC[C@H]1N[C@@H]2CC[C@H]1C2)C(F)(F)F

Procedure:
A solution of HCl in dioxane (4 M, 40 mL) is added to a solution of (1R,3S,4S)-3-[(2,2,2-trifluoro-acetylamino)-methyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (12.0 mmol) in dioxane (15 mL). After 3 h the solvents are removed in vacuo to give the desired product as a brownish solid which is used without further purification in the next step. LC-MS (basic): tR=0.69 min; [M+H]+=223.2.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16](F)=[CH:15][C:14]=2[CH2:20][N:21]([C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])[CH2:22][CH3:23])[CH:9]=[C:10]([Cl:12])[CH:11]=1)C.[CH3:30][S-:31].[Na+].[F-].Cl>CN(C=O)C.O.CCOC(C)=O>[Cl:12][C:10]1[CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:29])[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([S:31][CH3:30])=[CH:15][C:14]=2[CH2:20][N:21]([C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])[CH2:22][CH3:23])[CH:9]=1
Reactant: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1
Reactant: C[S-]
Agent: Cl
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(Cc1cc(SC)ccc1-c1cc(Cl)cc(CC(=O)O)c1)C(=O)C1CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
{5-Chloro-2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-4′-fluoro-biphenyl-3-yl}-acetic acid ethyl ester (0.118 g, 0.28 mmol) and sodium thiomethoxide (0.043 g, 0.62 mmol) were combined in DMF (2 mL) and stirred at 100° C. overnight. Analytical LCMS indicated that the fluoride hadn't been displaced, but the ethyl ester had hydrolyzed. Additional sodium thiomethoxide (0.040 g, 0.57 mmol) was added, and the reaction was stirred overnight at 100° C. Analytical LCMS indicated that the reaction was complete, so the mixture was acidified with 1N aqueous HCl (4 mL) and worked-up with EtOAc and H2O. The combined organic layers were dried, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound. M+H is 418.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[S:14][C:13]2[CH:12]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:10][C:9]=2[CH:8]=1.CN([CH:23]=[O:24])C>>[Br:6][C:7]1[S:14][C:13]2[C:12]([CH:23]=[O:24])=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:10][C:9]=2[CH:8]=1
Reactant: CCOC(=O)c1cc2sc(Br)cc2[nH]1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1[nH]c2cc(Br)sc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To DMF (2.05 mL) cooled by ice/water was added POCl3 dropwise and the mixture was stirred for 30 min. A solution of carboxylate 61 (1.96 g, 7.15 mmol) in DMF (2.5 mL) was added at this temperature and the mixture was allowed to warm to room temperature then heated to 60° C. After 16 h, the reaction mixture was cooled to room temperature. and poured into ice/water. The mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with aqueous saturated NaHCO3 and brine, dried over Na2SO4. After removed the organic solvent, the residue was purified by column chromatography (EtOAc/Hexane: 1/4) to give the desired aldehyde 62 (1.62 g, 75%) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:30]([N:34]=[C:35]=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([NH:34][C:35]([NH:29][CH:17]1[CH2:18][CH:19]([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=2)[CH2:20][N:15]([C:13]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:14])[CH2:16]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Reactant: CC(C)(C)N=C=O
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)NC(C)(C)C)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
108 mg (0.22 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 7A) and 26 mg (0.26 mmol, 1.2 eq.) of tert-butyl isocyanate were reacted according to General Method 4. Yield: 69 mg (78% of theory)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][C:5]2([CH3:12])[CH3:11].[Br:13]Br>OS(O)(=O)=O.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[Br:13][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([CH3:12])([CH3:11])[CH2:6]1
Reactant: CC1(C)CNc2ccc(F)cc21
Reactant: BrBr
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: CC1(C)CN(Br)c2ccc(F)cc21
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
To a solution of 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole (1.6 g, 9.6 mmol) in 98% H2SO4 (20 mL), Ag2SO4 (1.6 g, 5.1 mmol) was added and the suspension was stirred under nitrogen for 30 minutes. The mixture was then cooled to −5° C., Br2 (508 μL, 9.9 mmol) was slowly added over 15 minutes and stirring maintained at the same temperature for 1 h. The reaction mixture was slowly poured over 200 mL of water/ice and subsequently filtered through Celite. 50% aqueous NaOH was added to the resulting solution (to pH ═9-10) and the product was extracted with EtOAc (3×). The organic phase was dried (MgSO4), filtered and concentrated to give the title compound (1.58 g) as a dark oil. 1H NMR (DMSO-d6): 7.03 (1H, d), 6.64 (1H, d), 5.59 (1H, s), 3.20 (2H, s), 1.25-1.15 (6H, m). MS: [M+H]+=244.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Oc1cccc(Cl)c1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3cccc(Cl)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-chloro-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-chloro-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 352(MH+).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:14]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:18]([O:17][C:15]([CH:13]1[CH2:12][N:11]2[C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=[C:10]2[CH:9]([OH:8])[CH2:14]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c2nc(C)c(C)n2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CC(O)c2nc(C)c(C)n2C1
Yield: 14.5 %

Procedure:
3 g of 8-benzyloxy-6-ethoxycarbonyl-2,3-dimethylimidazo[1,2-a]pyridine, suspended in 50 ml of ethanol, are treated with 0.5 g of 10% strength palladium/activated carbon and hydrogenated under a hydrogen pressure of 50 bar for 20 hours at an oil bath temperature of 75° C. After cooling, the catalyst is filtered off, the filtrate is concentrated to 1/5 of the volume in vacuo and the colourless precipitate formed here is filtered off. The filtrate of the precipitate is concentrated to dryness and chromatographed on silica gel (eluent: methylene chloride/methanol 100/3). 0.32 g of 6-ethoxycarbonyl-8-hydroxy-2,3-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine is obtained. For conversion into the title compound, it is dissolved in chloroform, treated with 1.6 g of manganese dioxide and stirred at room temperature for 20 h. The precipitate is then filtered off, the filtrate is concentrated to dryness in vacuo and the residue obtained is purified on silica gel (eluent: methylene chloride/methanol 13/1). 0.2 g of the title compound of melting point 138-40° C. (diethyl ether) is obtained.
Reaction SMILES: C([O:8][N:9]1[C@H:12]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[C@H:11]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]1=[O:26])C1C=CC=CC=1>CO.[Pd]>[C:22]([O:21][C:19]([NH:18][C@H:11]1[C@@H:12]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[N:9]([OH:8])[C:10]1=[O:26])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@@H]1COC(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(O)[C@@H]1COC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
In 10 ml of methanol is suspended 900 mg (2.46 mmole) of (3S,4S)-1-benzyloxy-3-(tert-butoxycarbonylamino)-4-carbamoyloxymethyl-2-azetidinone, and 100 mg of 10% palladium-charcoal is added to the solution, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour. The catalyst is filtered off, and the filtrate is concentrated to dryness under reduced presuure to give 680 mg of (3S,4S)-3-(tert-butoxycarbonyl- amino)-4-carbamoyloxymethyl-1-hydroxy-2-azetidinone as colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[SH:9].[CH:10](OCC)(OCC)OCC>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:10][S:9][C:3]=2[CH:4]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(Br)cc1S
Product: Brc1ccc2ncsc2c1

Procedure:
A 100 mL, one neck round bottom flask was charged with 2-amino-5-bromobenzenethiol (1.19 g, 5.83 mmol), triethyl orthoformate (9.70 ml, 58.3 mmol), 10 mL TFE, and a stirbar. A reflux condenser with a vacuum/nitrogen inlet was a fixed to the flask, and the system was degassed by evacuating to 5 mm Hg, and refilling with nitrogen. To the solution was added 200 mg dithiothreitol, and the reaction was heated using a 80° C. oil bath for 12 h. The reaction was cooled, and concentrated in vacuo. The crude was not characterized further.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[S:4][N:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:9](=[O:10])[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:4][N:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(N)sn1
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)Oc2ccccc2)sn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
3-Methylisothiazol-5-amine (156 mg, 1.04 mmol) in pyridine (1.2 mL) was mixed with phenyl chloroformate (260 μL, 2.07 mmol) under cooling with ice and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and after addition of water, extracted with chloroform twice, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a pale yellow solid (173 mg, yield 71%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]1([C:23]#[N:24])[CH2:22][CH2:21][CH2:20][CH2:19]1.[CH:25]1([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41]OS(C)(=O)=O)[CH:36]=2)[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C=O)C>[C:23]([C:18]1([CH2:17][C:11]2[CH:12]=[C:13]([O:16][CH2:41][C:37]3[CH:36]=[C:35]([CH:28]([CH:25]4[CH2:26][CH2:27]4)[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:40]=[CH:39][CH:38]=3)[CH:14]=[CH:15][C:10]=2[C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:19][CH2:20][CH2:21][CH2:22]1)#[N:24]
Reactant: CCOC(=O)CC(c1cccc(COS(C)(=O)=O)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC2(C#N)CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC3(C#N)CCCC3)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a solution of 1-((2′-fluoro-4-hydroxy-5′-methoxybiphenyl-2-yl)methyl)cyclopentanecarbonitrile (128 mg) and ethyl 3-cyclopropyl-3-(3-(((methylsulfonyl)oxy)methyl)phenyl)propanoate (197 mg) in DMF (5.0 mL) was added cesium carbonate (261 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (146 mg) as a colorless oil.
Reaction SMILES: C([O:5][C:6](=[O:44])[C@@H:7]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[N:25]=2)[CH2:20][CH2:19]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:38]1([S:35]([NH:34][C@@H:7]([CH2:8][N:9]2[CH:17]=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:33]=[CH:32][C:31]4[CH2:30][CH2:29][CH2:28][NH:27][C:26]=4[N:25]=3)[CH2:20][CH2:19]2)[C:6]([OH:44])=[O:5])(=[O:36])=[O:37])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21)NS(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@H](Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21)NS(=O)(=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
38 mg of the compound of step b) were dissolved in 1.5 ml of dichloromethane, and 1.5 ml of trifluoroacetic acid were added. After stirring for 5 hours at ambient temperature additional 0.1 ml of trifluoroacetic acid were added and stirring was continued for further 1.5 hours. The solvents were removed in vacuo, the residue was dissolved in acetic acid and again the solvent was removed in vacuo. The remaining resin was triturated with diethylether and the product isolated by filtration. Yield: 29 mg. MS (ES+): m/e=563.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]#[N:20])=[C:13]1[S-:21].[Na+].O>CC#N>[NH2:20][C:19]1[C:14]2[CH:15]=[CH:16][C:17](=[O:18])[N:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[Cl:5])[C:13]=2[S:21][C:2]=1[C:3]#[N:4]
Reactant: N#Cc1ccc(=O)n(-c2ccccc2Cl)c1[S-]
Reactant: N#CCCl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1sc2c(ccc(=O)n2-c2ccccc2Cl)c1N
Temperature: 40 °C
Yield: 33.5 %

Procedure:
Chloroacetonitrile (0.35 mL, 5.5 mmol) was added to a solution of Example 2 (1.42 g, 5.0 mmol) in MeCN (50 mL) and the mixture heated at 40° C. for 3 h. H2O (100 mL) was added and the mixture concentrated in vacuo to remove some of the MeCN (remaining volume ˜120 mL). The mixture was cooled to 0° C. and the solid filtered off, washed with H2O (15 mL) and Et2O (2×15 mL) and dried to give the title compound as a pale brown solid (505 mg, 32%). δH (DMSO-d6) 8.10 (1H, d, J 9.7 Hz), 7.75-7.73 (1H, m), 7.65-7.54 (3H, m), 7.14 (2H, br s, NH2), 6.54 (1H, d, J 9.7 Hz). LCMS (ES+) RT 2.97 minutes, 302 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[N:21]1([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][N:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CCO>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:1]=[C:31]2[C:30]2[CH:29]=[N:28][C:27]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:34][CH:33]=2)=[CH:8][CH:9]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: O=Cc1ccc(N2CCCCC2)nc1
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3ccc(N4CCCCC4)nc3)nc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
2-amino-N-(4-sec-butylphenyl)benzamide (0.350 g, 1.3 mmol) and 6-(piperidin-1-yl)nicotinaldehyde (1.3 mmol) were mixed in anyhydrous EtOH (40 mL) and anyhydrous CuCl2 (0.524 g, 3.9 mmol) was added. The reaction mixture was heated at reflux for 3 hours, cooled to room temperature, and stirred overnight. The reaction mixture was concentrated, diluted with ethyl acetate (150 mL), washed with water (2×100 mL), dried (MgSO4), filtered, and concentrated. Flash chromatograph on silica gel, eluting with 30% ethyl acetate/heptane to 80% ethyl acetate/heptane, afforded the title compound as a white solid (35%) as a white solid. 1H-NMR (300 MHz, DMSO-d6): δ 8.14-8.17 (m, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.85-7.90 (m, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.53-7.58 (m, 1H), 7.35 (d, J=6.5 Hz, 1H), 7.17-7.24 (m, 4H), 6.55 (d, J=9.1 Hz, 1H), 3.40-3.49 (m, 4H), 2.57-2.66 (m, 1H), 1.44-1.64 (m, 8H), 1.19 (d, J=6.9 Hz, 3H), 0.68 (t, J=7.3 Hz, 3H). MS (APCI) m/z: 439 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[C:12]1([CH3:23])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[CH:19][C:20](=[O:22])[CH3:21]>[O-]CC.[Na+]>[O:5]=[C:3]1[CH2:21][C:20](=[O:22])[CH2:19][CH:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH3:23])[CH:2]1[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1ccccc1C
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C1C(=O)CC(=O)CC1c1ccccc1C

Procedure:
To a solution of sodium ethoxide (from 1.9 g.sodium and dry ethanol, 30 ml.) was added dropwise diethyl malonate (13 g.). After the addition the mixture was heated under reflux for 1 minute, cooled and then treated with 4-o-tolyl-3-buten-2-one. (13 g.). After heating under reflux for 17 hrs. the mixture was cooled and the precipitated sodium enolate salt (formula III) was collected by filtration, washed with acetone and then dissolved in cold water. The solution was acidified with 2N-H2SO4 and extracted with dichloromethane. After washing the organic solution with water and drying over Na2SO4, removal of solvents under reduced pressure afforded the corresponding dione II, i.e. ethyl 2,4-dioxo-6-o-tolylcyclohexanecarboxylate.
Reaction SMILES: [K].[CH2:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:15](Br)[C:16]#[CH:17]>CN(C)C=O.O>[CH2:17]([N:13]1[C:14]2[CH2:2][CH2:3][CH2:4][CH2:5][C:6]=2[C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:16]#[CH:15]
Reactant: C#CCBr
Reactant: c1ccc2c3c([nH]c2c1)CCCC3
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCn1c2c(c3ccccc31)CCCC2
Reaction time: 0.75 h

Procedure:
Potassium tert.-buroxide, 3.6 g (33 mmol), was added to a solution of 5 g (30 mmol) of 1,2,3,4-tetrahydro-9H-carbazole in 50 ml of dimethylformamide. After stirring for 45 minutes under nitrogen, 3.9 g or 2.9 ml (33 mmol) of propargyl bromide was added and stirring was continued for 30 minutes at room temperature followed by 45 minutes on the steam bath. The cooled reaction mixture was diluted with water and the product was extracted with ether. The extracts were washed with water, dried over sodium sulfate and evaporated. The residue was passed over a plug of silica gel using methylene chloride/hexane 1:1. The fractions containing the least polar product were combined and evaporated. The residue was crystallized from hexane to give colorless crystals of 1,2,3,4-tetrahydro-9-(2-propynyl)-9H-carbazole with m.p. 74°-76°.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>CC(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[O:20])=[CH:17][CH:18]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: O=C(c1ccc(Nc2nc(Br)cn3ccnc23)cc1)N1CCOCC1
Yield: 69.1 %

Procedure:
A solution of 6,8-dibromoimidazo[1,2-a]pyrazine (500 mg, 1.8 mmol), (4-aminophenyl)(morpholino)-methanone (408 mg, 1.98 mmol) and CSA (356 mg, 1.53 mmol) in iPrOH (30 mL) was stirred at 90° C. overnight. The solvent was evaporated. The residue was dissolved in DCM (30 mL). A NaHCO3 solution (10 mL) was added to adjust to pH=8. The organic layer was separated and dried over Na2SO4. The drying agent was removed by filtration and the resultant solution was concentrated in vacuo. The residue was purified through a silica-gel column (ethyl acetate:petroleum ether=1:1) to give the desired product as a yellow solid (500 mg, 69% yield).