Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]3([CH2:17][CH2:16][CH2:15][N:14]4[CH:18]=[N:19][CH2:20][CH:13]34)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]3([CH2:17][CH2:16][CH2:15][N:14]4[CH:18]=[N:19][CH:20]=[C:13]34)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)C21CCCN2C=NCC21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)NC(=O)C21CCCn2cncc21
Temperature: 25 °C

Procedure:
A mixture of 1.9 mmol of 6′-methoxy-1,6,7,8a-tetrahydro-5H-spiro[imidazo[1,5-a]pyridine-8,3′-indol]-2′(1′H)-one and 3 g of manganese-dioxide in 50 ml of toluene is heated to reflux for 1.5 hours. The reaction mixture is cooled to room temperature, the solid is removed by filtration over Hyflo and the filtrate is evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>CC#N.O>[C:1]([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)SCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)SCCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
Referring to FIG. 40, to a solution of 6-(acetylthio)hexanoic acid (3 g, 15.8 mmol) in CH3CN (80 mL) were added K2CO3 (4.3 g, 31.6 mmol) and benzyl bromide (2.68 g, 15.8 mmol). The reaction mixture was stirred at room temperature overnight and ethyl acetate (200 mL) and water (100 mL) were added. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.2 g, 50% yield) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH3:23])[CH:16]=3)[CH2:13][O:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@@:9]2([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH3:23])[CH:16]=3)[CH2:13][O:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(C2(c3ccc(F)c(Br)c3)COC(N)=N2)cc1C
Solvent: ClCCl
Product: COc1ccc([C@]2(c3ccc(F)c(Br)c3)COC(N)=N2)cc1C
Yield: 45.1 %

Procedure:
A solution of 0.90 g of (RS)-4-(3-bromo-4-fluoro-phenyl)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (Building Block E) in dichloromethane was divided in 200 mg aliquots which were separated on chiral HPLC (Chiralpak AD) using a 90:10-mixture of heptane and ethanol as the eluent. The fractions of the first eluting enantiomer were combined to give 406 mg of the (S)-(+)-4-(3-bromo-4-fluoro-phenyl)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine as a white solid. The later eluting enantiomer (R)-4-(3-bromo-4-fluoro-phenyl)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine was isolated to give 381 mg as a white solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:14]2([C:21]([OH:23])=O)[C:15]3[C:20]([CH:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=42)[CH2:6]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:3])[CH3:2].S(Cl)([Cl:26])=O>C1C=CC=CC=1>[C:1]([O:4][CH:5]1[C:14]2([C:21]([Cl:26])=[O:23])[C:15]3[C:20]([CH:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=42)[CH2:6]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OC1CC2c3ccccc3C1(C(=O)O)c1ccccc12
Solvent: c1ccccc1
Product: CC(=O)OC1CC2c3ccccc3C1(C(=O)Cl)c1ccccc12

Procedure:
A solution of 12-acetoxy-9,10-dihydro-9,10-ethanoanthracene-9-carboxylic acid (1.0 g) in benzene (10.0 ml) and thionyl chloride (4.0 ml) was refluxed for 4 hours. Evaporation of excess thionyl chloride and benzene gave 12-acetoxy-9,10-dihydro-9,10-ethanoanthracene-9-carboxylic acid chloride. The acid chloride was dissolved in dry acetone (25.0 ml), and a solution of sodium azide (0.63 g) in water (1.3 ml) was added thereto while ice cooling. The resulting mixture was stirred while ice cooling for 2 hours. The reaction mixture was diluted with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate, refluxed for 2 hours and evaporated to dryness to give 9-isocyanato-12-acetoxy-9,10-dihydro-9,10-ethanoanthracene.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][C:4]=1[F:12].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C1CCN2C(=NCCC2)CC1>>[F:12][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][NH:11][S:14]([CH3:13])(=[O:16])=[O:15])[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: NCCc1ccc(CN)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NCCc1ccc(CNS(C)(=O)=O)c(F)c1
Yield: 37 %

Procedure:
2-[4-(Aminomethyl)-3-fluorophenyl]ethylamine (0.3 g, 1.25 mmol) was combined with methanesulfonyl chloride (0.2 mL, 2.75 mmol), and DBU (1 mL, 3.12 mmol) in a manner analogous to the procedure described in example 2 to provide the final title compound, [(2-fluoro-4-{2-[(methylsulfonyl)amino]ethyl}phenyl)methyl](methylsulfonyl)amine, (0.15 g, 37%) as a white crystalline solid. Electron spray M.S. 323 (M*−H). Analysis for C11H17FN2O4S2:
Reaction SMILES: Br[CH2:2][C:3](=[O:14])[C:4]([CH3:13])([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:12][C:4]([CH3:13])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:14])[CH2:2][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: CC(C)(Cc1ccccc1)C(=O)CBr
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(Cc1ccccc1)C(=O)Cn1cncn1
Yield: 48.3 %

Procedure:
74 g (0.29 mol) of 1-bromo-3,3-dimethyl-4-phenylbutan-2-one, 40 g (0.58 mol) of 1,2,4-triazole and 80 g of potassium carbonate are dissolved in 700 ml of acetone, and the solution is heated under reflux for 3 hours. Thereafter, it is allowed to cool and is filtered off under suction from the inorganic residue, and the filtrate is concentrated. The residue is recrystallized from ether. 34.1 g (48.4% of theory) of 3,3-dimethyl-4-phenyl-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 79° C. are obtained. ##STR25##
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([C:2]1[N:27]=[CH:26][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1)[CH3:30]
Reactant: CNC
Reactant: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(Cl)cc23)cc1
Product: CN(C)c1cc2c(Nc3ccc(S(=O)(=O)c4ccccc4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure C from 6-chloro-4-(4-phenylsulphonylanilino)-pyrido[3,4-d]pyrimidine and dimethylamine (33% aqueous solution); δH (CDCl3) 9.00 (1H,s), 8.57 (1H,s), 7.78-8.00 (6H,m), 7.70 (1H,br s) 7.45-7.65 (3H,m), 6.50 (1H,s), 3.21 (6H,s); m/z (M+1)+254.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.Cl.[F:22][C:23]1[CH:24]=[N:25][C:26]([C@@H:29]([NH2:31])[CH3:30])=[N:27][CH:28]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[N:25][C:26]([C@@H:29]([NH:31][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=2)[CH3:30])=[N:27][CH:28]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 101.7 %

Procedure:
A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 7, 0.4 g) and [(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amine hydrochloride (Intermediate 15, 0.25 g) in n-BuOH (5 mL) with diisopropylethylamine (1.5 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.55 g of desired product. MS (electrospray): 403 (M+1) for C17H19FN8O3. 1H NMR (300 MHz, CD3OD) δ ppm 8.40 (s, 2H) 8.10 (d, 1H) 6.15 (d, 1H) 5.60 (s, 1H) 5.35 (m, 1H), 4.60 (m, 1H) 1.50 (d, 3H) 1.20 (d, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]C2SC3C=CC=CC=3N=2)[CH2:3][CH2:2]1.[S].[Na].[SH:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.[OH-].[Na+]>C(O)(C)C>[O:1]1[CH2:6][CH2:5][N:4]([S:7][S:19][C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:3][CH2:2]1
Reactant: Sc1nc2ccccc2s1
Reactant: c1ccc2sc(SN3CCOCC3)nc2c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CC(C)O
Product: c1ccc2sc(SSN3CCOCC3)nc2c1
Temperature: 82.5 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
There is charged to a glass or glass-lined reactor 25.2 grams (0.1 mole) of 2-(morpholinothio)benzothiazole, 3.2 grams (0.1 mole) of sulfur, and 150 ml. of essentially anhydrous isopropyl alcohol (0.4% by weight water). The catalyst, the sodium salt of mercaptobenzothiazole, is used in amount of 0.01 mole and is formed in situ by adding 0.01 mole of solid sodium hydroxide and then 0.01 mole of 2-mercaptobenzothiazole (MBT) to the reaction mixture. The reaction mixture is then stirred and heated at refluxing temperature (about 82-83°C) for 2 hours although it is found that the reaction is essentially complete in one hour. A clear solution usually forms in from 15 to 75 minutes. The reaction mixture is cooled to 30°C. during which cooling a precipitate usually begins to form in the range of 67-74°C. Stirring and cooling is continued to 0°C. and the mixture is held at 0-10°C. for about 30 minutes after which it is filtered and the solids air dried at 25-30°C. There is obtained a yield of 94.4-95% of 2-(morpholinodithio)benzothiazole, m.p. 132°-136°C.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:18][CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([O:30][CH3:31])=[CH:22][CH:21]=1>>[CH3:31][O:30][C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]([C:19]2[NH:18][C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)=[CH:21][CH:22]=1
Reactant: COc1ccc(CN)c2ccccc12
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Product: CCOC(=O)c1nc(-c2ccc(OC)c3ccccc23)[nH]c1-c1ccc(C)cc1
Yield: 84.5 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate (16.0 g) and 1-(aminomethyl)-4-methoxynaphthalene (15.3 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 2-(4-methoxy-1-naphthyl)-5-(4-methylphenyl)-imidazole-4-carboxylate (22.2 g), which was dissolved in ethyl alcohol (450 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(4-methoxy-1-naphthyl)-5-(4-methylphenyl)imidazole-4-carboxylic acid (12.1 g), melting point 226° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][O:15][CH3:16])[C:6]1[CH:11]=[C:10]([NH2:12])[N:9]=[CH:8][N:7]=1.[H-].[Na+].Cl[C:20]1[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=1>>[CH3:16][O:15][CH2:14][CH2:13][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]1[N:7]=[CH:8][N:9]=[C:10]([NH:12][C:20]2[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=2)[CH:11]=1
Reactant: COCCN(CCOC)c1cc(N)ncn1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Product: COCCN(CCOC)c1cc(Nc2ncc(C#N)s2)ncn1

Procedure:
N,N-bis(2-methoxyethyl)pyrimidine-4,6-diamine 6-2 (0.13 g, 0.58 mmol), sodium hydride (0.046 g, 1.16 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.083 g, 0.58 mmol) were treated as in Scheme 4 above. The product 6-3 was purified on a C18 preparative hplc column and isolated via lyophilization. Hi-Res MS: calc: 335.1285 found: 335.1282. 1H-NMR (DMSO): 8.39 ppm (s, 1H); 8.24 ppm (s, 1H); 6.22 ppm (s, 1H); 3.65 ppm (m, 4H); 3.51 ppm (m, 4H); 3.26 ppm (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[I-].[Na+]>[C:15]1([CH2:14][CH2:13][CH2:12][O:1][C:2]2[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(OCCCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
3′-Hydroxyacetophenone (6.81 g, 50 mmol) and 1-bromo-3-phenyl propane (11.95 g, 60 mmol) were dissolved in dimethylformamide (70 ml). Then, potassium carbonate (15 g) and sodium iodide (0.5 g) were added thereto and the mixture was allowed to react for 7 hours at 80° C. Ethyl acetate (300 ml) and purified water (200 ml) were further added to the reaction mixture prior to stirring for 30 min. The organic layer extracted with ethyl acetate was dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to obtain the title compound (12.0 g, yield 94.2%) as a gel.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:17]([O:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[C:18]#[CH:19].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.O.[Cu]I>[C:11]1([C:10]2[C:3]3[C:2]([C:19]#[C:18][CH2:17][O:20][CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#CCOCCN1CCCC1
Reactant: Clc1ncnc2scc(-c3ccccc3)c12
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: C(#Cc1ncnc2scc(-c3ccccc3)c12)COCCN1CCCC1
Temperature: 100 °C

Procedure:
Nitrogen gas was bubbled through a mixture of 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine (1 g, 4.06 mmol), 1-(2-prop-2-ynoxyethyl)pyrrolidine (1.53 g, 10 mmol), bistriphenylphosphine palladium (II) dichloride (180 mg, 0.25 mmol), triethylamine (3.5 mL, 25 mmol), copper (I) iodide (75 mg, 0.4 mmol) in THF (20 mL) for 5 minutes. The reaction was then heated at 100° C. for 60 minutes in a microwave. The reaction was then diluted with ethyl acetate (50 ml) and water (50 ml) and shaken. The ethyl acetate layer was then separated, dried over sodium sulphate and concentrated in vacuum to a gum. The gum was chromatographed on silica in a gradient of 2-15% methanol in dichloromethane. A peak eluted in about 8-12% methanol in dichloromethane to give 5-phenyl-4-[3-(2-pyrrolidine-1-ylethoxy)prop-1-ynyl]thieno[2,3-d]pyrimidine as a gum. (55 mg, 0.15 mmol, 3.7%). LCMS [M+H]+=364; RT=3.04 min.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[C:16](=[O:22])[N:15]([CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:14]1[C:32]3[CH:33]=[C:34]4[O:42][CH2:41][O:40][C:35]4=[CH:36][C:37]=3[C:38](=[O:39])[C:13]2=1>CS(C)=O.C(Cl)(Cl)Cl>[N:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[C:16](=[O:22])[N:15]([CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:14]1[C:32]3[CH:33]=[C:34]4[O:42][CH2:41][O:40][C:35]4=[CH:36][C:37]=3[C:38](=[O:39])[C:13]2=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCBr)C(=O)c1cc2c(cc1-3)OCO2
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCN=[N+]=[N-])C(=O)c1cc2c(cc1-3)OCO2
Temperature: 100 °C
Yield: 29.9 %

Procedure:
Sodium azide (0.021 g, 0.22 mmol) and compound 19 (0.128 g, 0.22 mmol) were diluted with DMSO (4 mL), and the mixture was heated at 100° C. for 2 h. The mixture was diluted to a volume of 200 mL with CHCl3, washed with H2O (2×60 mL) and saturated aq NaCl (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by flash column chromatography (SiO2, ˜40 g), eluting with a gradient of 0.5% MeOH in CHCl2, to yield the product 21 as a solid (0.036 g, 60%). The solid was used for next step without further purification. ESIMS m/z 548 (MH+); HRESIMS m/z 548.2141 (MH+), calcd for C28H30N5O7 548.2145.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:15][CH2:14][CH2:13][O:6]1
Reactant: OCCO
Reactant: O=C(CCCCl)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: ClCCCC1(c2ccccc2)OCCO1
Reaction time: 20 h

Procedure:
A mixture of γ-chlorobutyrophenone (33.2 g; 0.182 mol), ethylene glycol (20.3 ml; 0.363 mol), p-toluenesulfonic acid (a pinch) and toluene (300 ml) is heated at reflux for 40 hours, and the water formed in the reaction is azeotroped off. After 20 hours, more ethylene glycol (20.3 ml; 0.363 mol) is added. On completion of the reaction the mixture is extracted with saturated aqueous sodium bicarbonate solution (300 ml), the organic layer is washed with 1 N sodium hydroxide solution and then with water, and is evaporated to afford 37.0 g of a cream colored solid, m.p. 54°-55.5° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=4)=[CH:23][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)#[N:7]>>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[N:28]=4)=[CH:23][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)#[N:7]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: C1CCNC1
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(N5CCCC5)n4)cc3)cc12

Procedure:
Using pyrrolidine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 437 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[C:8](O)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:5].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][C:3]=1[C:4]1[O:5][C:8]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=[CH:16][C:7]=2[N:6]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccncc3)cc2F)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2nc(-c3ccc(-c4ccncc4)cc3F)oc12
Temperature: 118 °C
Reaction time: 48 h
Yield: 21 %

Procedure:
Methyl 3-(2-fluoro-4-(pyridin-4-yl)benzamido)-2-hydroxybenzoate (2.50 g, 6.83 mmol) and 4-methylbenzenesulfonic acid (3.25 g, 17 mmol) were added to toluene (50 mL) and the mixture was stirred at 118° C. for 2 days. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1 to 10:1) to obtain methyl 2-(2-fluoro-4-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxylate as white solid (500 mg, yield 21%). LC-MS (ESI) m/z: 349 (M+1)+.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[Cl:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([F:20])[C:10]2=1.CO.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:17](=[C:18]([N+:1]([O-:4])=[O:2])[CH:19]=1)[NH:16][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([F:20])[C:10]2=1
Reactant: Fc1cncc2[nH]c3ccc(Cl)cc3c12
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cc(Cl)cc2c1[nH]c1cncc(F)c12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 102.2 %

Procedure:
Sodium nitrate (1.5 eq, 53 mmol, 4.5 g) was added portionwise to a solution of Intermediate 65 (1.0 eq, 35 mmol, 7.8 g) in trifluoroacetic acid (200 mL) and the resulting mixture heated at 70° C. for 3 h. After cooling to RT the trifluoroacetic acid was removed on a rotary evaporator to afford a crude solid which was suspended in a small volume of methanol and added dropwise to a vigorously stirred mixture of saturated sodium bicarbonate solution (500 mL). The resulting slurry was stirred for 15 min then the precipitated solids were collected by suction filtration, washed with water (300 mL) and then dried in vacuo to afford 6-chloro-4-fluoro-8-nitro-9H-β-carboline (about 9.5 g) which was used in the subsequent step without further purification. Retention Time (LC, method: ammonium acetate standard): 1.79 min. MS (M+H+): 266
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:42]=[C:41]([CH3:43])[C:19]3[N:20]=[C:21]([C:23]4[C:24](=[O:40])[NH:25][CH:26]=[CH:27][C:28]=4[NH:29][CH2:30][CH:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=4)[OH:32])[NH:22][C:18]=3[CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.Cl>CO>[Cl:39][C:35]1[CH:34]=[C:33]([CH:31]([OH:32])[CH2:30][NH:29][C:28]2[CH:27]=[CH:26][NH:25][C:24](=[O:40])[C:23]=2[C:21]2[NH:22][C:18]3[CH:17]=[C:16]([C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[O:15])[CH:42]=[C:41]([CH3:43])[C:19]=3[N:20]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(C(=O)N2CCNCC2)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.6 %

Procedure:
To a solution of (±)-4-[1-(2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-7-methyl-3H-benzimidazol-5-yl)-methanoyl]-piperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.06 mmol) in methanol (5 mL) was added 4.0 M HCl dioxane solution (0.1 mL, excess). The reaction mixture was stirred at room temperature for 14 h. After concentration, the residue was purified by prep. HPLC to give the title compound (16 mg, 63%) as a white foam. 1H NMR (300 MHz, CD3OD) δ 7.56 (1H, s), 7.53 (1H, s), 7.23–7.41 (4H, m), 7.17 (1H, m), 6.26 (1H, d, J=7.6 Hz), 4.99 (1H, dd, J=4.7, 6.4 Hz), 3.91 (4H, broad s), 3.74 (1H, dd, J=4.7, 13.5 Hz), 3.65 (1H, dd, J=6.4, 13.5 Hz), 3.31 (4H, broad s), 2.63 (3H, s). LCMS (M+H)+ m/z 507 (t=1.38 min.).
Reaction SMILES: [CH2:1]([N:3]1[CH2:12][CH2:11][C@:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[C@H:5]([CH2:6][C:7]3[C:23]([CH3:24])=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:21][C:8]=3[CH2:9]2)[CH2:4]1)[CH3:2].B(Br)(Br)Br>>[CH2:1]([N:3]1[CH2:12][CH2:11][C@:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[C@H:5]([CH2:6][C:7]3[C:23]([CH3:24])=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:21][C:8]=3[CH2:9]2)[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)c1[nH]c2c(c1C)C[C@@H]1CN(CC)CC[C@@]1(c1cccc(OC)c1)C2
Agent: BrB(Br)Br
Product: CCOC(=O)c1[nH]c2c(c1C)C[C@@H]1CN(CC)CC[C@@]1(c1cccc(O)c1)C2
Yield: 20.9 %

Procedure:
0.6 g (1.5 mmol) of (±)-trans-6-ethyl-2-ethoxycarbonyl-3-methyl-8a-(3-methoxyphenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline were treated with 0.84 ml (9.0 mmol) of boron tribromide as described in example 2. The crude solid was purified by flash chromatography (AcOEt/MeOH/conc. NH4OH 80:20:2), yielding 0.12 g of the title compound. M.p.=195°-197° C.