Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC([C:12]1([I:38])[C:17]([C:18]([NH2:20])=[O:19])=[C:16]([I:21])[C:15]([N:22]2[C:27](=[O:28])[CH2:26][O:25][CH2:24][CH:23]2[CH2:29][O:30]C(=O)C)=[C:14]([I:34])[CH:13]1[C:35]([NH2:37])=[O:36])COC(=O)C)(=O)C.[CH3:39][O-:40].[Na+].[Na]>CO>[OH:40][CH2:39][CH:17]([NH:37][C:35]([C:13]1[C:14]([I:34])=[C:15]([N:22]2[C:27](=[O:28])[CH2:26][O:25][CH2:24][CH:23]2[CH2:29][OH:30])[C:16]([I:21])=[C:17]([C:18]([NH:20][CH:23]([CH2:29][OH:30])[CH2:24][OH:25])=[O:19])[C:12]=1[I:38])=[O:36])[CH2:18][OH:19]
Reactant: C[O-]
Reactant: CC(=O)OCC1COCC(=O)N1C1=C(I)C(C(N)=O)C(I)(C(COC(C)=O)COC(C)=O)C(C(N)=O)=C1I
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=C(NC(CO)CO)c1c(I)c(C(=O)NC(CO)CO)c(I)c(N2C(=O)COCC2CO)c1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N,N'-Bis[2-(acetyloxy-1-[(acetyloxy)methyl]ethyl]-5-[3-[(acetyloxy)methyl]-5-oxo-4-morpholinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide of example 7c (1.03 g, 1 mmol) was added to a solution of sodium methoxide in methanol, prepared from sodium (23 mg, 1 mmol) and anhydrous methanol (20 ml). The solution was stirred for 4 hours at room temperature. The pH of the solution was then adjusted to 7 by the addition of Dowex-50 (H+) resin. The resin was filtered off and the solvent removed from the filtrate to obtain a white solid (0.8 g) which, upon purification by low pressure reverse phase column chromatography over the CHP-20P resin yielded pure N,N'-Bis[2-Hydroxy-1-(hydroxymethyl)ethyl]-5-[3-(hydroxymethyl)-5-oxo-morpholinyl]-2,3,6-triiodo-1,3-benzenedicarboxamide as a snow-white glassy solid (0.65 g, 79% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:18][C:11]=3[C:12]=2[C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:18][C:11]=3[C:12]=2[C:13]2[NH:17][CH:16]=[CH:15][N:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)Oc1cc2c(C3=NCCN3)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1cc2c(-c3ncc[nH]3)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(2-(4-fluorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-yl)-4,5-dihydro-1H-imidazole (1.0 g, 2.61 mmol) in DMSO (40 mL) at room temperature was added Dess-Martin periodinane (2.213 g, 5.22 mmol), and the stirring was continued at rt overnight. The reaction mixture was diluted with water. The product was extracted into EtOAc (100 mL×3), and the combined EtOAc extracts were washed with 10% NaHCO3 (100 mL×2) and brine, dried over Na2SO4 and then concentrated. The crude product was recrystallized from EtOAc and petroleum ethers to obtain 2-(2-(4-fluorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-yl)-1H-imidazole as a yellow solid. Yield: 800 mg (80%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 12.46 (br. s., 1H) 8.33 (s, 1H) 7.85-8.08 (m, 2H) 7.16-7.60 (m, 5H) 4.79 (d, J=5.95 Hz, 1H) 1.15-1.47 (m, 6H). LCMS: (ES+) m/z=382.24 (M+H)+; Column—ACQUITY UPLC BEH C8 (50×2.1 mm; 1.7 μm); M phase A: 5 mM Ammonium Acetate:MeCN (95:5); M phase B: 5 mM Ammonium Acetate:MeCN (5:95)
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([OH:29])[CH:28]=1.N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:24]1/[C:23]([NH2:22])=[CH:28][C:27](=[O:29])[C:26]([O:30][CH3:31])=[CH:25]/1
Reactant: Nc1c(N)n2n(c1=O)CCC2
Reactant: COc1ccc(N)cc1O
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: CCO
Solvent: O
Product: COC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)C(N)=CC1=O

Procedure:
0.05 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.05 mmol of 5-amino-2-methoxyphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:10]([Br:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1cccc2c1cnn2Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2c1c(Br)nn2Cc1ccccc1
Temperature: 80 °C
Yield: 99.3 %

Procedure:
To a solution of 1-benzyl-4-nitro-1H-indazole (350 mg, 1.38 mmol) in acetic acid (5 mL), in a reaction vial was added bromine (265 mg, 1.66 mmol). The reaction vial was sealed and heated to 80° C., with magnetic stirring, for 2 hours. The mixture was allowed to cool. Saturated aqueous sodium bicarbonate solution was added (sufficient for the mixture to reach pH 8). The resulting solids were collected by filtration and washed with water. The material was dried under vacuum to give 1-benzyl-3-bromo-4-nitro-1H-indazole (455 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]Br)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=1)[CH2:39][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:30])[CH:10]2[CH2:19][CH2:20][CH:21]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[OH:22])=[CH:17][CH:16]=1
Reactant: BrCc1cccc(CBr)c1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3cccc(CBr)c3)cc2)N1c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one (11) was reacted with 1,3-bisbromomethylbenzene and potassium carbonate analogously to Example IV, giving a colorless solid (18) of molecular weight 592.49 (C32H28BrF2NO3); MS (ESI): 592.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[N:13]=1.C(Cl)(=O)C(Cl)=O.[NH3:31]>O1CCCC1.CN(C)C=O>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:31])=[O:20])=[CH:16][CH:15]=2)[N:13]=1
Reactant: O=C(O)c1ccc(-c2csc(-c3cnccc3C(F)(F)F)n2)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2csc(-c3cnccc3C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound (162) (0.45 g, 1.29 mmol) in tetrahydrofuran (12 ml) were added oxalyl chloride (0.17 ml, 2.59 mmol) and dimethylformamide (3 drops) under ice-cooling, and the mixture was stirred at room temperature for one hr. To this reaction mixture was added 28% aqueous ammonia (1.00 ml, 16.44 mmol) and the mixture was stirred at room temperature for one hr. and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate. The extracts were combined, washed with brine and dried (MgSO4). The solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethanol-ethyl acetate to give white crystals (0.45 g, quant.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.O.NN>>[NH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][C:9](=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:10][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: NN
Solvent: O
Product: NCCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 97 %

Procedure:
The title compound was prepared in a yield of 97% in a similar manner to that described in Preparation 15 by reacting 4-[bis(4-fluorophenyl)methylene]-1-(2-phthalimidoethyl)piperidine and hydrazine hydrate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:17][CH2:18][CH2:19]OS(C1C=CC(C)=CC=1)(=O)=O>CC(=O)CC>[Cl:17][CH2:18][CH2:19][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cccc(OCCCl)c1
Temperature: 25 °C

Procedure:
A mixture of 6.96 g. of m-nitrophenol, 100 ml. of 2-butanone, 6.9 g. of potassium carbonate, and 11.74 g. of 2 chloroethyl-tosylate was stirred and heated under reflux for 24 hours. After cooling to room temperature, the salts were filtered off and the filtrate concentrated under vacuum. The residue crystallized on seeding and was recrystallized from carbon tetrachloride to give 8.3 g. of product, m.p. 54.5°-57° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)[N:3]=1.[CH2:26]([O:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH3:27]>CS(C)=O>[CH2:26]([O:28][CH2:29][CH2:30][CH2:31][NH:32][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)[N:3]=1)[CH3:27]
Reactant: CCOCCCN
Reactant: Cc1cc(Cl)nc(-c2nn(Cc3ccccc3F)c3ncccc23)n1
Solvent: CS(C)=O
Product: CCOCCCNc1cc(C)nc(-c2nn(Cc3ccccc3F)c3ncccc23)n1
Temperature: 60 °C

Procedure:
35 mg (0.10 mmol) of 3-(4-chloro-6-methyl-2-pyrimidinyl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (example I, step 7) and 52 mg (0.50 mmol) of 3-(ethyloxy)-propylamine are dissolved in 0.40 ml of DMSO and heated at 60° C. for 48 hours. The reaction mixture is diluted with 0.20 ml of DMSO and then purified by preparative
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][NH2:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]=1[N:28]=[C:29]=[O:30])([CH3:18])[CH3:17]>C(OCC)(=O)C>[CH3:18][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:26])[CH3:27])[C:20]=1[NH:28][C:29]([NH:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:30])[CH3:17]
Reactant: NCC1c2ccccc2-c2ccccc21
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1c2ccccc2-c2ccccc21

Procedure:
To 3.88 g (0.02 mol of 9-fluorenemethyl amine in 100 ml of ethyl acetate was added, in one portion, 4.06 g (0.02 mol) of 2,6-diisopropylphenyl isocyanate in 100 ml of ethyl acetate.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[N:17]2[C:26]=1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH3:13])=O)C1C=CC=CC=1.CSC>C(O)(C(F)(F)F)=O>[NH2:11][C@H:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[N:17]2[C:26]=1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH3:13]
Reactant: COC(=O)c1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)c(-c3cccnc3)n12
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc2nc([C@H](C)N)c(-c3cccnc3)n12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of (S)-methyl 2-(1-(((benzyloxy)carbonyl)amino)ethyl)-3-(pyridin-3-yl)imidazo[1,2-a]pyridine-5-carboxylate (450 mg, 1.04 mmol) and dimethylsulfide (0.4 mL) in TFA (1.2 mL)) was stirred at rt overnight. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc. The organic layer was washed with satd. sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide (S)-methyl 2-(1-aminoethyl)-3-(pyridin-3-yl)imidazo[1,2-a]pyridine-5-carboxylate: LC-MS (ESI) m/z 297.2 [M+H]+. The crude product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[CH:6]=[CH:7]/[C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=2[N:9]=1.[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:30])[C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=2[N:9]=1
Reactant: O=C([O-])[O-]
Reactant: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3)nc2n(CCC)c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(OC)c3)n2C)n(CCC)c1=O
Yield: 97.9 %

Procedure:
Compound B (1.20 g, 3.02 mmol) was dissolved in 20 ml of dimethylformamide. To the solution were added 1.04 g (7.55 mmol) of potassium carbonate and subsequently 0.38 ml (6.04 mmol) of methyl iodide, and the resultant mixture was stirred at 50° C. for 30 minutes. After cooling, insoluble matters were filtered off, and 400 ml of water was added to the filtrate. The mixture was extracted three times with 100 ml of chloroform. The extract was washed twice with water and once with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 1% methanol/chloroform), followed by recrystallization from propanol/water to give 1.22 g (yield 98%) of Compound 1 as white needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH2:8].[O:13]1[CH2:15][CH:14]1[CH2:16][O:17][C:18]1[C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.O.Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH2:15][CH:14]([OH:13])[CH2:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]=12
Reactant: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Reactant: COc1ccccc1OCCN
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
2-(2-Methoxyphenoxy)ethylamine (III) (4.89 g) was heated to about 100° C., after which 4-(oxiran-2-ylmethoxy)-9H-carbazole (II) (3.31 g) was added portionwise. After approximately 20 minutes, the reaction mixture was cooled to about 70° C., after which water (25 ml) and ethyl acetate (15 ml) were added. The pH of the two-phase mixture was then adjusted to 5 with 2 N hydrochloric acid. The solid that formed, Carvedilol hydrochloride hydrate, is filtered, washed with water (20 ml) followed with ethylacetate (15 ml). The resulting material is reslurried in ethylacetate (50 ml) and water (20 ml) containing 5% Sodium carbonate until the pH reached 7.5. The organic phase was separated and dried over sodium sulfate. The dried solution was concentrated to a turbid solution and cooled overnight to about 4° C. Precipitated carvedilol was isolated by filteration and crystallized from isopropanol.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([CH2:23][CH2:24][C:25]#[N:26])[CH2:19][CH2:20][C:21]#[N:22])[CH:12]=1)[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H][H]>O1CCOCC1>[NH2:22][CH2:21][CH2:20][CH2:19][N:18]([CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:5]([CH2:4][CH2:3][CH2:1][NH2:2])[CH2:6][CH2:7][CH2:8][NH2:9])[CH:12]=1)[CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: N#CCCN(CCC#N)Cc1cccc(CN(CCC#N)CCC#N)c1
Reactant: [H][H]
Solvent: C1COCCO1
Product: NCCCN(CCCN)Cc1cccc(CN(CCCN)CCCN)c1
Yield: 94.3 %

Procedure:
6.97 g of 1,3-bis(N,N-bis(2-cyanoethyl)aminomethyl)benzene, 0.70 g of Raney Co and 100 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 9.0 MPa at 180° C. for 2 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 6.88 g of the title compound.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH:22]([CH3:24])[CH3:23])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)C.[Cl-].[Ca+2].[Cl-]>O.[Fe]>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[NH2:19])[CH:22]([CH3:24])[CH3:23])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1)C2(c1cccc([N+](=O)[O-])c1)C(C)C
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCCCCCN1CC2C(C1)C2(c1cccc(N)c1)C(C)C
Yield: 104.8 %

Procedure:
To a stirred suspension of 3-hexyl-6-isopropyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane (Preparation 60, 0.18 g, 0.54 mmol), ethanol (15 ml) and iron powder (0.27 g, 4.88 mmol) was added calcium chloride (0.06 gm 0.54 mmol) in water (3 ml). The reaction mixture was heated under reflux for 3 h and then filtered through a pad of Celite®, the mother liquors were concentrated in vacuo. The residue was dissolved in dichloromethane and filtered again through a Sep-Pak® Plus cartridge containing silica (1.5 g), (Water Division Millipore), to remove any residual iron salts and then concentrated to give the crude title compound as a yellow solid (0.17 g, 100%).
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([F:20])[C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1.[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([NH2:42])([CH3:41])[CH3:40])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([NH:42][C:2]1[C:3](=[O:21])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([F:20])[C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1)([CH3:40])[CH3:41])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(Br)c2=O)c1
Reactant: CC(C)(N)c1ccccc1CCCOCc1ccccc1
Product: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3CCCOCc3ccccc3)c2=O)c1

Procedure:
The subtitle compound was prepared using a similar method to Example 252h from methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-5-fluoro-4-methylbenzoate (Example 252g) and 2-(2-(3-(benzyloxy)propyl)phenyl)propan-2-amine (Example 323e).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=[C:7]2[CH:21]=O)([O-:3])=[O:2].[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29].[S]>CN(C)C=O>[NH:29]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:30]=[C:21]1[C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=1
Reactant: Nc1ccccc1N
Reactant: C[Si](C)(C)CCOCn1nc(C=O)c2cc([N+](=O)[O-])ccc21
Agent: [S]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3[nH]2)c2cc([N+](=O)[O-])ccc21
Yield: 19.6 %

Procedure:
3-(1H-Benzimidazol-2-yl)-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole can be obtained in the following way: a suspension of 720 mg of 5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole-3-carboxaldehyde, of 216 mg of 1,2-phenylenediamine and of 77 mg of sulfur (0) in 70 ml of anhydrous dimethylformamide is heated at 95° C. for 16 hours. After returning to a temperature in the region of 20° C., the reaction medium is concentrated to dryness under reduced pressure and the evaporation residue is taken up with 20 ml of distilled water and 20 ml of ethyl acetate. The insoluble material floating at the surface is isolated by filtration, washed and dried and makes it possible to obtain a first crop of 160 mg of 3-(1H-benzimidazol-2-yl)-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in the form of a yellow solid (Rf=0.22, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (75/25 by volume)). The filtrate is concentrated to dryness under reduced pressure and the solid residue is resuspended in a cyclohexane/ethyl acetate (80/20 by volume) mixture, isolated by filtration, washed and dried. A second crop of 200 mg of 3-(1H-benzimidazol-2-yl)-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole is thus obtained in the form of an orangey solid with the same Rf as the first crop (mass analysis: Cl: m/z 410 (M+H)+)+ (base peak)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13][N:14]=[C:15]=[S:16])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9].[N-:17]=[N+:18]=[N-:19].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13][N:14]2[C:15]([SH:16])=[N:19][N:18]=[N:17]2)[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(F)cc(CCCN=C=S)cc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1c(F)cc(CCCn2nnnc2S)cc1F
Yield: 38.8 %

Procedure:
3-(3,5-Difluoro-4-methoxyphenyl)propylisothiocyanate (0.036 mol) and sodium azide (0.054 mol) were reacted substantially as described in Example 7H above to give 4 g (39%) white crystals: mp 64°-65°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[NH:13][C:12](=O)[C:11]3=[CH:15][CH:16]=[CH:17][N:10]3[N:9]=2)[CH:7]=1.P(Cl)(Cl)([Cl:21])=O.CN(C)C1C=CC=CC=1>>[Cl:21][C:12]1[C:11]2=[CH:15][CH:16]=[CH:17][N:10]2[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:18])[N:13]=1
Reactant: O=c1[nH]c(-c2cc(Cl)ccc2F)nn2cccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Fc1ccc(Cl)cc1-c1nc(Cl)c2cccn2n1
Temperature: 110 °C
Yield: 56 %

Procedure:
2-(5-Chloro-2-fluoro-phenyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (60 mg, 0.228 mmole) was added to phosphorous oxychloride (1 ml). Added 57 microliters N,N-dimethylaniline (catalyst) and heated to 110° C. overnight. Removed excess phosphorous oxychloride under vacuum, residue treated with ice, and product extracted with chloroform. Dried chloroform extract over sodium sulfate (anh.) and removed solvent to give crude product. Product was purified by silica gel chromatography eluted with chloroform to give 36 mg product (yield: 56%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(CO)C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OCC1=CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To an ice-cooled solution of 4.13 g (20.7 mmol) 3-hydroxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert.-butylester and 244 mg (2 mmol) DMAP in 50 ml pyridine was added 3.06 g (30 mmol) acetic anhydride. The mixture was stirred for 30 min at 0° C., then for additional 60 min at room temperature. The mixture was poured on ice and extracted twice with ether. The combined organic layers were evaporated in vacuo, dissolved in ether, washed with sat. CuSO4, water and brine and dried over MgSO4. Evaporation and bulb-to-bulb distillation gave 4.82 g (97%) 3-acetoxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert.-butylester as a colorless oil, b.p. 105° C. (0.2 mbar).