Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]1([NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CNCCN.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I.[Fe].C(O)(=O)C>[C:3]1([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:17]=[C:18]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: O=C(Nc1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Fe]
Agent: CNCCN
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 100 °C
Yield: 66.6 %

Procedure:
A reaction tube containing 1-iodo-2-nitrobenzene (124 mg, 0.5 mmol), N-phenylbenzamide (118 mg, 0.6 mmol), CuI (4.8 mg, 0.025 mmol), N-methylethylenediamine (4.4 μL, 0.05 mmol), potassium phosphate (212 mg, 1 mmol) in dry toluene (1.5 mL) was purged with dry argon for 3 min. After heating at 100° C. for 18 h, the iron powder (10 mol.-eq.) and glacial acetic acid (5 mL) are directly added. Then the reaction mixture is heated at reflux for 30 min. An additional 10 mol.-eq. of iron powder are added and the reaction mixture is heated at reflux for further 30 min. The solvents were removed under reduced pressure and the crude was extracted with ethyl acetate against saturated sodium bicarbonate solution. The organic phase was dried and the solvent was removed on a rotary evaporator. Then the residue was purified by preparative HPLC, affording the title compound as a solid (90 mg, 67% yield).
Reaction SMILES: [NH4+].[Cl-].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9]2)([O-])=O.COC(C)(C)C>C(O)C.O.C(O)C.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9]2
Reactant: O=C1NCc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: COC(C)(C)C
Solvent: O
Product: Nc1ccc2c(c1)CNC2=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
To a suspension of Fe (1.1 g, 19.6 mmole), NH4Cl (1.5 g, 28 mmole) in a mixture of ethanol/water (30 ml/7 ml) at 80° C. was added a mixture of 5-Nitro-2,3-dihydro-isoindol-1-one (1 g, 5.6 mmole) in 10 ml ethanol. The reaction mixture was stirred at 80° C. for 2 hours. Mixture was cooled down, filtered off, solid was washed with 50 ml ethanol. The filtrate was concentrated, taken into 50 ml ethylacetate, washed with 20 ml water. Organic layer was dried over Na2SO4, filtered and concentrated to give about 900 mg crude. Trituration with methyl t-butylether gave 400 mg pure product, 48% yield.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[N:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20].CON(C)[C:24]([C:26]1[CH:34]=[CH:33][C:29]2[O:30][CH2:31][O:32][C:28]=2[CH:27]=1)=[O:25]>C1COCC1>[O:30]1[C:29]2[CH:33]=[CH:34][C:26]([C:24](=[O:25])[CH2:20][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[N:13]=3)=[CH:27][C:28]=2[O:32][CH2:31]1
Reactant: Cc1cccc(C)n1
Reactant: CON(C)C(=O)c1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cccc(CC(=O)c2ccc3c(c2)OCO3)n1
Temperature: 0 °C
Reaction time: 0.1 h
Yield: 87.5 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 13.8 mL, 34.4 mmol) was added slowly to a solution of diisopropylamine (4.53 mL, 32.3 mmol) in anhydrous THF (50 mL) at −78° C. After being stirred for 0.1 hour, the mixture was allowed to warm up to 0° C. Stirring continued for 0.5 hour. The mixture was then cooled to −78° C. and 2,6-lutidine (3.76 mL, 32.3 mmol) was added slowly. The mixture was allowed to warm up to 0° C. and stirred for 0.5 hour. The mixture was then cooled to −78° C. before the slow addition of benzo[1,3]dioxole-5-carboxylic acid methoxy-methyl-amide (4.5 g, 21.5 mmol; see Example 2 above) in anhydrous THF (10 mL). The mixture was stirred at −78° C. for 0.5 hour, at 0° C. for 0.5 hour, and at room temperature for 2 hours. The mixture was then quenched with ammonium chloride aqueous solution and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. After purification using column chromatography on silica gel (eluent: ethyl acetate (2): hexanes (8)), 4.8 g (87%) of 1-Benzo[1,3]dioxol-5-yl-2-(6-methyl-pyridin-2-yl)-ethanone as a yellow solid was obtained. MS (ESP+) m/z 256.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.56 (t, 1H, J=7.5 Hz), 7.39 (dd, 1H, J=1.8 Hz, 8.3 Hz), 7.30 (dd, 1H, J=0.5 Hz, 1.8 Hz), 6.93 (m, 1H), 6.83 (m, 2H), 5.98 (s, 2H), 4.87 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([SH:16])=[N:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.I[C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[CH:19]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(Cl)Cl.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([S:16][C:18]4[CH:26]=[CH:25][C:24]5[C:20](=[CH:21][N:22]([CH3:27])[N:23]=5)[CH:19]=4)=[N:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc2cc(I)ccc2n1
Reactant: Cn1cc(-c2ccc3nnc(S)n3n2)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5nn(C)cc5c4)n3n2)cn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a solution of 6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (2.3 g, 10.0 mmol) in DMF (20 mL) is added 5-iodo-2-methyl-2H-indazole (2.6 g, 10.0 mmol), tris(dibenzylideneacetone) dipalladium(0) (460 mg; 502.7 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (580 mg, 1.0 mmol), diisopropylethylamine (4 mL, 22.9 mmol). The mixture is purged with N2 and stirred at 100° C. for 18 h. DMF is removed under vacuum, and the residue is purified by flash column chromatography (Combi-Flash, silica gel) eluting with DCM/methanol (20:1) to give a crude product. The crude product is suspended in 20 mL of DCM to give slurry, and the pure product is collected by filtration to afford the title compound (1.9 g, 52.5%) as a yellow solid. MS (m/z): 363.1 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:22]=[C:23]([NH:27]C(=O)OC(C)(C)C)[CH:24]=[CH:25][CH:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.CCCCCCC.CCOC(C)=O>C(Cl)Cl>[NH2:27][C:23]1[CH:22]=[C:21]([NH:20][C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:11][CH:10]=3)[N:4]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)OC(C)(C)C)c3)n2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
To a solution of tert-butyl (3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)carbamate (550 mg, 1.17 mmol) in DCM (20 mL) was added TFA (2 mL). Stirred for 30 min at rt for 4 h; removed solvent via rotary evaporation and partitioned oil with cold (0° C.) saturated sodium bicarbonate (10 mL) and EtOAc (10 mL), agitated and separated layers. Organic phase was dried over sodium sulfate and the solvent was removed via rotary evaporation to give a dark oil. Flash chromatography using 20%-100% Heptane/EtOAc gradient using combiflash system gave 309 mg of a light pink solid. LC/MS (RT=2.78/(M+1)) 370.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[C:5]([F:11])=[CH:4][N:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[C:5]([F:11])=[CH:4][N:3]=1
Reactant: CC(O)c1cc(Br)ncc1F
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Br)ncc1F
Temperature: 85 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
A mixture of 325b (7.5 g, 34.2 mmol) and 2-iodoxybenzoic acid (38.4 g, 137 mmol) in ethyl acetate (200 mL) was stirred at 85° C. for 20 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (20:1 to 10:1) to afford 325c (6.8 g, 92%) as a yellow oil. MS-ESI: [M+H]+ 217.9.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:19])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[C:14](I)=[CH:13][C:10]=3[C:11]=2[N:12]=1.[CH2:20]([N:23]([CH3:25])[CH3:24])[C:21]#[CH:22].O>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:19])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[C:14]([C:22]#[C:21][CH2:20][N:23]([CH3:25])[CH3:24])=[CH:13][C:10]=3[C:11]=2[N:12]=1
Reactant: Nc1ncc2c(n1)-c1cc(I)c(Cl)cc1NC(=O)C2
Reactant: C#CCN(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC#Cc1cc2c(cc1Cl)NC(=O)Cc1cnc(N)nc1-2
Temperature: 75 °C
Reaction time: 8 h
Yield: 109.8 %

Procedure:
A solution of 2-amino-9-chloro-10-iodo-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (1.66 g, 4.29 mmol) and propargyl(dimethylamine) (0.74 mL, 6.89 mmol) in triethylamine (7 mL) and DMF (7 mL) was degassed with argon. To this solution was added bis(triphenylphosphine)palladium(II)chloride (0.30 g, 0.43 mmol) and copper iodide (0.163 g, 0.86 mmol). The reaction mixture was allowed to stir at 75° C. overnight. After the reaction mixture was allowed to cool to rt, water was added. The precipitate that formed was filtered and dried to give 2-amino-9-chloro-10-[3-(dimethylamino)prop-1-yn-1-yl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (1.61 g, 98%) as a brown solid. LCMS (FA): m/z=342 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:12])[CH3:13])=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(C)(C)CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(C)(C)NC(=O)c1ccc(N)cc1
Yield: 76.1 %

Procedure:
4-Nitro-N-(tert-octyl)benzamide (30 g, 0.108 mol) dissolved in 200 ml of ethyl acetate is hydrogenated for 1 hour 15 minutes at a temperature of 70-75° C. in a 500 ml hydrogenator in the presence of 4.8 g of 10% palladium-on-charcoal comprising 50% water as catalyst (hydrogen pressure: 8-10 bar). After filtering, concentrating the solvent and drying under vacuum, 20.4 g (Yield: 76%) of 4-amino-N-(tert-octyl)benzamide are obtained in the form of a pale yellow powder which is used as is in the following stage.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([Li])CCC.CO[C:13](=O)[C@@H:14]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1.OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[CH3:1][C:2]1[CH:3]=[C:13]([C@H:14]2[NH:15][C:16](=[O:19])[CH2:17][CH2:18]2)[O:5][N:4]=1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: CC(C)=NO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc([C@@H]2CCC(=O)N2)on1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
Acetone oxime (2.924 kg, 40 mol) was dissolved in 17.5 L of THF stirred under N2, and the solution was cooled to -40° C. Addition of 8 L of n-butyllithium (10M in hexane, 6.19 kg) was carefully accomplished at a rate such that the temperature of the reaction did not rise above 5° C. To this solution was added 2.719 kg of the compound from step 4a above dissolved in 7 L of THF, also at a rate such that the temperature of the reaction did not rise above 5° C. After addition of the reactants, the mixture was stirred for 12 hr at room temperature. The mixture was cooled to 0° C., and 8.891 kg of H2SO4 and 4.8 L of water was added at a rate such that the temperature of the reaction did not rise above 35° C. The reaction was subsequently heated, and refluxing began at 60° C. The reaction was stirred for 1 hr, cooled to 20° C., and 9.32 kg of Na2CO3 was added slowly. The mixture, was filtered, then the filter cake was reintroduced into the reactor and stirred with 15 L of ethyl acetate for 1 hr. The solution was filtered, and the residue was washed with 2.5 L of ethyl acetate. The solutions were combined and evaporated to dryness. The residual dark oil was stripped with xylene to remove excess acetone oxime. The residue was dissolved in t-butylmethylether (TBME), and water was added. A tarry residue, which contained polar side-products, separated. The TBME solution was evaporated, and the residue was allowed to stand for 2 hr. A colorless oil containing apolar impurities rose to the top and was removed. The remaining residue was mixed with twice the volume of TBME and seeded, with subsequent crystallization occurring at room temperature. m.p=90°-91° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]>CN(C)C=O>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
For example, an amino resin such as Boc-Leu-Pam resin (0.5 g, approximately 0.3 mmole) is swollen in dimethylformamide (“DMF”), deprotected to yield H-Leu-Pam resin. The resin is then acylated with 4 mmole succinic anhydride (“SA”) by vortex mixing at room temperature for 10 to 30 minutes. SA is dissolved in 8 ml DMF (Burdick and Jackson High Purity grade) which is 0.5 M in HOBT and to which 400 μl DIEA is added. After draining and washing the resin with DMF, the Kaiser ninhydrin test is performed to establish that acylation is complete. If not, the acylation step is repeated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][C:7](OC)=[O:8].[OH-].[Li+]>O1CCCC1>[O:8]=[C:7]1[NH:1][CH2:2][CH2:3][CH2:4][N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1
Reactant: COC(=O)CN(CCCN)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCNC(=O)C1
Reaction time: 6 h

Procedure:
To a solution of methyl N-(3-aminopropyl)-N-(tert-butoxycarbonyl)glycinate (10.2 g) in tetrahydrofuran (THF)/methanol (2/1, 300 mL) was added 1M aqueous lithium hydroxide solution (60 mL). The resultant mixture was stirred at room temperature overnight. An additional 20 mL of 1M aqueous lithium hydroxide solution was added and the mixture was stirred for 6 h. Solvent was removed under reduced pressure, and the residue was dissolved in 50 mL of methanol and 200 mL of toluene and concentrated in vacuo. To the residue in dichloromethane (300 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 9.6 g) and 1-hydroxybenzotriazole (HOBT, 6.8 g). The mixture was stirred at room temperature for three days, then treated with saturated aqueous ammonium chloride solution and extracted with three portions of ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (silica gel, 4 to 5% methanol/aqueous ammonium hydroxide (10:1) in dichloromethane) to yield the title compound. LS/MS 215.0 (M+1).
Reaction SMILES: B(Br)(Br)Br.C(Cl)Cl.C[O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=[O:14].O>C(OCC)(=O)C>[F:18][C:17]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:9]
Reactant: COc1cc(C=O)ccc1F
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(F)c(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
Boron tribromide (1M methylene chloride solution, 100 mL) was gradually added dropwise to a methylene chloride (100 mL) solution of 3-methoxy-4-fluoro benzaldehyde (4.4 g) under ice-cooling. The reaction solution was agitated at room temperature for 2 hours after the dropping ended. The reaction solution was again cooled with ice, iced water was gradually added to the reaction solution to terminate the reaction, and further 5N hydrochloride solution was added until the pH reached 1. After condensing the reaction solution under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride solution, and the solvent was evaporated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 4:1), and 3.18 g (79%) of 4-fluoro-3-hydroxybenzaldehyde was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)(=[O:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1.[ClH:33].C(O)C.C(=O)([O-])[O-].[NH4+:41].[NH4+]>ClCCl.CO>[ClH:33].[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)(=[O:12])=[O:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:23][NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](=[NH:41])[NH2:32])=[CH:29][CH:30]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(S(=O)(=O)N3CCc4ccccc43)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(S(=O)(=O)N3CCc4ccccc43)ccc21
Yield: 15 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]-5-(2,3-dihydroindol-1-yl-sulfonyl)benzimidazole and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 15% of theory, C24H24N6O2S (460.6); Rf value: 0.36 (silica gel; dichloromethane/methanol=4:1); EKA mass spectrum: (M+H)+=461.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[OH:19]O.[OH-].[Na+].Cl>C(O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:12])=[O:19])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Temperature: 50 °C
Yield: 95 %

Procedure:
To a solution of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (2.6 g, 8.48 mmol) in 20 mL of ethanol was added 20 mL of commercial solution of hydrogen peroxide (30%) and 1.8 mL of aqueous solution of sodium hydroxide (6.0 N). The suspension was heated to 50° C. for 20 min. The reaction mixture was cooled down and neutralized with 6.0 N aqueous HCl. Further precipitation was observed upon addition of water (20 mL). The solid was collected by filtration, washed with small portions of water and dried in a vacuum oven at 40° C. (2.6 g, 95% yield) 1H NMR (CDCl3) δ 8.2 (s, 1H), 8.0 (d, 1H), 7.7 (br s, 1H), 7.6 (d, 1H), 6.4 (br s, 1H), 5.7 (dd, 1H), 4.0 (m, 1H), 3.75 (m, 1H), 2.5 (m, 1H), 2.0 (m, 2H), 1.7 (m, 3H); ES-MS (m/z) 276 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccccc1NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1ccccc1NCc1ccccc1
Temperature: 0 °C

Procedure:
[N-(2-Nitrophenyl)]-benzylamine (21.9 mmol, 5.0 g) in ethyl acetate (150 ml) is charged with SnCl22H2O (131 mmol, 29.55 g) and is refluxed for 3 hours. The mixture is poured into ice water (100 g), sodium bicarbonate is added to achieve pH 7, and the reaction mixture is extracted with ethyl acetate (3×50 ml). The organic layer is dried with MgSO4, is filtered and evaporated to yield a light sensitive oil, which is used as such in the next step.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]1[C:17](=O)[NH:18][C:19](=[O:22])[NH:20][CH:21]=1.C(=O)([O-])O.[Na+].C(=O)=O>COCCOCCOC.O>[F:15][C:16]1[C:17](=[S:2])[NH:18][C:19](=[O:22])[NH:20][CH:21]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: O=c1[nH]cc(F)c(=S)[nH]1
Temperature: 110 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
To a solution of phosphorus pentasulfide (102.6 g, 0.46 mol) in diglyme (1 L) was added 5-fluoropyrimidine-2,4(1H,3H)-dione (30 g, 0.23 mol). Solid sodium hydrogen carbonate (NaHCO3; 77.3 g, 1.04 mol) was added at a rate determined by the evolution of carbon dioxide. The reaction mixture was stirred overnight at 110° C. The yellow mixture was cooled and poured into 1 L of cold water. The precipitated solid product was isolated by filtration and purified by normal phase chromatography (gradient, 10 to 50% EtOAc/Petroleum ether) to give 5-fluoro-4-thioxo-3,4-dihydropyrimidin-2(1H)-one (13.4 g, 40%) as a yellow solid: mp 254-255° C.; 1H NMR (301 MHz, DMSO-d6) δ 7.81 (d, J=4.0 Hz, 1H); ESIMS m/z 145 ([M−H]−).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10]CC)=O.[NH2:13][C:14]([NH2:16])=[O:15].[OH-].[Na+]>CC(O)=O>[NH:13]1[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8](=[O:10])[NH:16][C:14]1=[O:15]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: NC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1[nH]c2c(c(=O)[nH]1)CCCC2
Temperature: 180 °C
Reaction time: 4.5 h
Yield: 38.6 %

Procedure:
A mixture of ethyl 2-oxocyclohexanecarboxylate (66 g, 0.39 mol) and urea (68 g, 1.1 mol) was heated at 175-185° C. and stirred for 4-5 h. After cooled to 70° C., adjusted pH=13-14 by NaOH (a.q.), and then the mixture was stirred at 70° C. for 2 h. After cooled to r.t, the mixture was adjusted pH=6-7 by AcOH, and then extracted with DCM for several times. The combined organic layer was dried and evaporated to give the title compound (25 g, 39% yield) as brown solid which was set to do next step without any purification. MS: m/z 167.3 [M+H]+.
Reaction SMILES: [OH-].[Na+].C([O-])(=O)C.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Br:30])[CH:28]=4)[N:23]([CH3:31])[CH:22]=3)[C:17]([O:19]C)=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1.CO>O1CCOCC1>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Br:30])[CH:28]=4)[N:23]([CH3:31])[CH:22]=3)[C:17]([OH:19])=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: COC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(Br)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cn1cc(C(C(=O)O)c2ccc3c(c2)OCO3)c2cc(Br)ccc21
Yield: 83.6 %

Procedure:
Aqueous sodium hydroxide (14.7 ml of 1M) was added to a solution of methyl 2-(1,3-benzodioxol-5-yl)-2-5-bromo-1-methyl-1H-3-indolyl) acetate from (b) (1.97 g, 4.9 mmol) in a 3:1 mixture of methanol and 1,4-dioxane at ambient temperature. The mixture was heated to reflux for 1 hour before recooling and removing the organic solvents in vacuo. The residue was redissolved in water and acidified with drops of concentrated hydrochloric acid. The resultant precipitate was extracted with diethylether, dried (magnesium sulphate) and the solvent removed in vacuo. The residue was crystallised from diisopropylether to give the subtitle compound (1.59 g).