Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:7]2[N:8]3[CH:16]([CH3:17])[CH2:15][N:14]([CH2:18][CH3:19])[C:13](=[O:20])[C:9]3=[C:10]([O:11][CH3:12])[C:6]=2[C:5](=[O:21])[N:4]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[N:3]=1.N([O-])=O.[Na+].N1C=CC=CC=1.[FH:41]>>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[F:29])[CH2:22][N:4]1[C:5](=[O:21])[C:6]2[C:10]([O:11][CH3:12])=[C:9]3[C:13](=[O:20])[N:14]([CH2:18][CH3:19])[CH2:15][CH:16]([CH3:17])[N:8]3[C:7]=2[C:2]([F:41])=[N:3]1
Reactant: F
Reactant: CCN1CC(C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(N)c32)C1=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCN1CC(C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(F)c32)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred, cold (0° C.) solution of 4-amino-2-(3-chloro-4-fluorobenzyl)-10-methoxy-8-ethyl-6-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.55 g, 1.26 mmol) in hydrogen fluoride-pyridine (9.5 mL) in a polyethylene tube, solid sodium nitrite (96 mg, 1.38 mmol) was added in small portions over a period of 10 minutes. The reaction mixture was stirred at room temperature for 1 hour. The product mixture was added dropwise into an ice-cold saturated aqueous sodium bicarbonate solution. The resultant mixture was extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford the title material.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:20][C:21](OCC)=[O:22].O>CN(C=O)C>[C:3]1([N:9]2[CH2:20][C:21](=[O:22])[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]2=[O:18])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cc1ccccc1)Nc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CN(c2ccccc2)C(=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred slurry of 500 mg (12 mmol) of a 60% oil dispersion of sodium hydride (which had been washed with hexane) in 12 ml dry DMF under argon atmosphere was added 1.06 g (5.0 mmol) of N-phenyl-2-phenyl acetamide (IVa) in 5 mL dry DMF. Gas evolution had ceased after 30 minutes and 0.560 mL (5.0 mmol) of ethyl bromoacetate was added via syringe. The solution was stirred at 25° C. for 30 minutes, then warmed to 80° C. for 4 hours. The cooled solution was carefully poured into 200 mL H2O, washed with ether, filtered over celite and acidified to pH=2. The white precipitate was filtered, washed well with H2O and dried under high vacuum to give 1.04 g (4.0 mmol, 80% yield) of 1,3-diphenyl-2,4-pyrrolidinedione Ia, mp 285°-287° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[I-].[C:13]([CH2:15][P+](C)(C)C)#[N:14].C(#N)CC.C(N(C(C)C)CC)(C)C>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][CH2:15][C:13]#[N:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#CCCc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
To a mixture of 4-nitrobenzyl alcohol (37) (1 g, 6.53 mmol) and (cyanomethyl)trimethylphosphonium iodide (36) (4 g, 16.32 mmol) were added propionitrile (32 mL) and diisopropylethylamine (2.5 g, 19.58 mmol) at room temperature. The mixture was heated at ˜100° C. for 24 hours. The reaction was quenched with water (1 mL), followed by addition of concentrated HCl (5 mL). The resulting reaction mixture was extracted with ethyl acetate (3×100 mL), washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a dark brown solid. The crude solid product was purified by flash column chromatography (silica gel, ethyl acetate: hexanes 1:1) to give 740 mg of 3-(4-nitrophenyl)propionitrile (38) as a light orange solid. 1H NMR (DMSO-d6): δ 8.20-8.17 (dd, J=8.7 Hz, 2H), 7.59-7.56 (d, J=9.0 Hz, 2H), and 3.06-3.01 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.F[C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[C:16]#[N:17].Cl>CS(C)=O>[OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=3[C:16]#[N:17])[CH2:11][CH:6]2[CH2:5][CH2:4]1
Reactant: N#Cc1cc(F)ccc1F
Reactant: OCC1CCC2CNCCN2C1
Agent: Cl
Solvent: CS(C)=O
Product: N#Cc1cc(F)ccc1N1CCN2CC(CO)CCC2C1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
A mixture of 1.05 g (6.17 mmol) of (7RS,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (U.S. Pat. No. 5,326,874) and 1.29 g (9.25 mmol) of 2,5-difluorobenzonitrile in 20 mL of DMSO was heated at 100° C. for 16 h. The mixture was cooled to room temperature, acidified with 1M HCl, washed with ether (3×), made basic with conc. ammonium hydroxide, and extracted with ethyl acetate (3×). The combined organic layers were washed with water (3×), dried (magnesium sulfate), filtered and evaporated. Purification by silica gel MPLC with 90:10 chloroform:methanol gave 0.51 g of (7RS,9aSR)-7-hydroxymethyl-2-(2-cyano-4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([CH:17]=[O:18])=[CH:10][C:9]=1[O:19][CH3:20].[Mn]([O-])(=O)(=O)=[O:23].[K+]>CC(C)=O>[CH3:20][O:19][C:9]1[C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:21])=[CH:13][C:12]([N+:14]([O-:16])=[O:15])=[C:11]([CH:10]=1)[C:17]([OH:23])=[O:18]
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(C=O)cc1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(C(=O)O)cc1OC
Yield: 50 %

Procedure:
The slightly wet nitroaldehyde 12 (80 g, wet) was dissolved in acetone (500 mL) in a 2 L flask fitted with a condenser and a mechanical stirrer. A hot solution of 10% potassium permanganate (50 g in 500 mL of water) was quickly added via a dropping funnel (in 5 to 10 minutes). Halfway through the addition the solution began to reflux violently and until the end of the addition. The solution was allowed to stir and cool down for an hour and was then filtered through celite and the brown residue was washed with 1 L of hot water. The filtrate was transferred in a large flask and a solution of sodium bisulfite (80 g in 500 mL 1N HCl) was added. The final volume was adjusted to 3 L by addition of water, and the pH was adjusted to 1 with conc. HCl. The product 42 precipitated and it was filtered and dried. 31 g (50% yield over 2 steps). The product was pure as proved by TLC (85/15/0.5 EtOAc/MeOH/Acetic acid). 1H NMR (CDCl3) δ 7.33 (1H, s), 7.19 (1H, s), 4.09 (2H, t, J=5.72 Hz), 3.91 (3H, s), 3.64 (3H, s), 2.50 (2H, t, J=6.98 Hz), 2.14 (2H, p, J=6.33 Hz); 13C NMR (DMSO-d6) δ 172.8, 166.0, 151.8, 149.1, 141.3, 121.2, 111.3, 107.8, 68.1, 56.4, 51.3, 29.7, 23.8; IR (golden gate) vmax 1736, 1701, 1602, 1535, 1415, 1275, 1220, 1054, 936, 879, 820, 655 cm−1; MS (ES−) m/z (relative intensity) 312.01 ([M−H]−, 100).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[N:11][CH2:12][C:13]3[N:14]([C:15]([CH2:18]Cl)=[N:16][N:17]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[I-].[K+].[CH2:29]([CH:32]=[CH:33][CH2:34][NH2:35])[CH2:30][CH3:31]>O1CCCC1>[CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[N:11][CH2:12][C:13]3[N:14]([C:15]([CH2:18][NH:35][CH2:34][CH2:33][CH2:32][CH2:29][CH:30]=[CH2:31])=[N:16][N:17]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCCC=CCN
Reactant: CCSc1cccc2c1C(c1cccc(Cl)c1)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCCCNCc1nnc2n1-c1cccc(SCC)c1C(c1cccc(Cl)c1)=NC2

Procedure:
In the manner given in Example 32, 7-(ethylthio)-1-(chloromethyl)-6-(m-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, potassium iodide and propylallylamine in tetrahydrofuran are reacted to give 7-(ethylthio)-1-[(allylpropylamino)methyl]-6-(m-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+]>O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:16]/[N+:13]([O-:15])=[O:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(/C=C/[N+](=O)[O-])cc(OC)c1
Temperature: 0 °C

Procedure:
A solution of 3,5-dimethoxybenzaldehyde (34.5 g., 0.208 mole) and nitromethane (12.69 g., 0.208 mole) in 40 ml. of MeOH was cooled to 0° under N2 . A solution was prepared by dissolving NaOH (8.43 g., 0.211 mole) in 10 ml. of H2O then diluting to 20 ml. with ice-water. This solution was then added dropwise to the methanol mixture. After 15 minutes the reaction was diluted with ice-H2O and added slowly to a solution of 40 ml. concentrated HC1in 60 ml. H2O. The resulting precipitate (44 g.) was filtered and recrystallized from methanol to give 28.6 g. of product, m.p. 132°; reported, J. Org. Chem. 27, p. 376 (1962), m.p. 133.5-134.5.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:27])[C:9]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([OH:26])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH2:28][CH2:29][CH2:30][C:31]#[N:32].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:27])[C:9]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([NH:32][CH2:31][CH2:30][C:29]#[N:28])=[O:26])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#CCCN
Reactant: CC1(C)c2cc(OCC(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1(C)c2cc(OCC(=O)NCCC#N)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetic acid (Compound A8-7, 30 mg, 0.083 mmol), 3-aminopropionitrile (12 mg, 2 eq.) and HOBt (30 mg, 3 eq.) were dissolved in 0.5 ml DMF, added with EDC (48 mg, 3 eq.), and stirred at room temperature overnight. Thereafter, the solvent was removed under reduced pressure and the resulting residues were purified by preparative TLC to obtain the title compound (23 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:20]([CH3:23])=[N:21][N:22]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.O1CCCC1.[H][H]>[C].[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:20]([CH3:23])=[N:21][N:22]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2COc3ccc(-c4nnc(C)o4)cc32)cc1
Yield: 74.4 %

Procedure:
A mixture of 2-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-5-methyl-1,3,4-oxadiazole (447 mg, 1.46 mmol), 10% palladium carbon (50% containing water, 450 mg), tetrahydrofuran (5 mL) and methanol (15 mL) was stirred at room temperature for 48 hr under 1 atm hydrogen atmosphere. Palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), and crystallized from hexane/ethyl acetate to give the title compound (335 mg, yield 74%) as colorless crystals.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Cl[C:6]1[CH:11]=[C:10]([SH:12])[N:9]2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=1>CO>[SH:12][C:10]1[N:9]2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=[C:6]([O:2][CH3:1])[CH:11]=1
Reactant: Sc1cc(Cl)nc2ncnn12
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc(S)n2ncnc2n1

Procedure:
To a sodium methoxide solution, prepared from 1.4 g of sodium and 50 ml of methanol, was added all at once the product obtained in Step 1 of Example 43 (4.6 g) under ice cooling. The mixture was refluxed for one hour, the solution was concentrated under reduced pressure, and the remaining yellow oil was dissolved in 50 ml water. The pH was adjusted to 1.0 with 1N hydrochloric acid, and the formed crystals were collected by filtration and washed with 30 ml ethanol, giving 1.7 g of the objective compound as faint yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[CH2:16][NH:17]C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26]>CO.O1CCOCC1>[Cl:26][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[CH2:16][NH2:17])[CH2:10][CH2:9]2)=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)NC1CCN(Cc2ccccc2)CC1
Reactant: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCC(=O)NC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 1-benzyl-4-{N-(tert-butoxycarbonyl)glycyl}aminopiperidine (6.59 g) in methanol (80 mL) was added 4 N HCl in dioxane (19 mL). The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated and 2 N aqueous NaOH solution (20 mL) was added. The mixture was extracted with dichloromethane (40 mL×3), and the combined extracts were dried over anhydrous sodium sulfate and concentrated. Column chromatography (SiO2, AcOEt/MeOH/Et3N=85/12/3) gave 1-(4-chlorobenzyl)-4-(glycylamino)piperidine (3.91 g, 83%): 1H NMR (CDCl3, 400 MHz) d 1.47-1.59 (m, 2 H), 1.59 (br, 2 H), 1.76-1.96 (m, 2 H), 2.10-2.19 (m, 2 H), 2.75-2.87 (m, 2 H), 3.29 (s, 2 H), 3.50 (s, 2 H), 3.65-3.89 (m, 1 H), 7.15-7.23 (m, 1 H), 7.23-7.33 (m, 5 H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][OH:17].[N+]([O-])(O)=O>O>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:16]=[O:17]
Reactant: Cc1[nH]c(-c2ccc([N+](=O)[O-])cc2)nc1CO
Solvent: O=[N+]([O-])O
Solvent: O
Product: Cc1[nH]c(-c2ccc([N+](=O)[O-])cc2)nc1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
A mixture of 5-methyl-2-(p-nitrophenyl)-4-imidazole methanol (2.9 g, 0.012 mole) and 70% nitric acid (20 ml) is stirred at 50° C. for 3 hours, followed by dilution with water and neutralization with base. The precipitated yellow solid is collected by filtration to yield 2.4 g. (0.011 mole) of title product, dec >270° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([O-])([OH:10])=[O:9]>O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])([O-:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: Clc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1Cl

Procedure:
According to the equation of the process according to the invention, chlorobenzene is reacted with nitric acid to give nitrochlorobenzene and water. Thus, chlorobenzene and nitric acid are introduced into the process, and nitrochlorobenzene and water are discharged; the sulphuric acid/phosphoric acid/water mixture described being the reaction medium. Since, in the case of industrial implementation, it is advantageous to use water-containing nitric acids, the water of the water-containing nitric acid used has to be discharged in addition to the water of the reaction.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1F)[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:8]=1)[CH:16]=[O:17]
Reactant: Oc1cccc(C(F)(F)F)n1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Temperature: 150 °C
Yield: 44.3 %

Procedure:
To a solution of 6-(trifluoromethyl)pyridin-2-ol (1.205 g, 7.39 mmol) in DMF (7 mL), was added 3,4-difluorobenzaldehyde (0.776 mL, 7.04 mmol) and K2CO3 (1.167 g, 8.44 mmol). The mixture was heated with a microwave condition at 150° C. for 1 h. After cooling, the mixture was diluted with EA, washed with water, brine, and concentrated. The residue was purified via flash chromatography to afford the title compound (890 mg, 44.3% yield) as a white solid. LCMS: rt=2.62 min, [M+H+]=286
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[C:6](NN)[C:5]=1Cl.O>C(O)(C)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:11])=[C:8]([Cl:10])[N:9]=1
Reactant: NNc1c(Cl)c(Cl)nc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Clc1ccc(Cl)c(Cl)n1
Reaction time: 2 h

Procedure:
To a 10 milliliter solution of 5 Normal sodium hydroxide was added a mixture of 5 grams of tetrachloro-4-hydrazinopyridine in 25 milliliters of isopropanol. The mixture was heated at its boiling point with rapid stirring for 2 hours. The mixture was mixed with 100 milliliters of water and the organic material extracted with methylene chloride. The organic phase was water washed and subjected to sublimation. The 2,5,6-trichloropyridine product was recovered in a yield of 1.85 grams (~ 51 percent of theoretical).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:14]=2[N:15]=[CH:16][N:17]=1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][CH2:4][C:3]4[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=4[F:1])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Reactant: O=Cc1cc(F)ccc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ncnc2c1c(C(=O)c1cccc(NCc3cc(F)ccc3F)c1)cn2C1CCCC1
Yield: 57.7 %

Procedure:
2,5-difluorobenzaldehyde (88.1 mg, 0.62 mmol) was added to a solution of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone (100 mg, 0.31 mmol) and AcOH (18.6 mg, 0.31 mmol) in MeOH (10 mL). After 5 min NaCNBH3 was added. After 3 h the reaction was quenched with 1N NaOH. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with water, dried over MgSO4, and concentrated. Purification by flash column chromatography (CH2Cl2/MeOH 98:2) afforded the title compound as a white solid (80 mg, 58%). MS: 448.1 (MH+); HPLC Rf: 6.59 min. (HPLC method 4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:4]([O:20][CH3:21])[CH:3]=1.[CH3:22][N:23]([CH3:40])[S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])(=[O:26])=[O:25]>C(Cl)Cl.CCOC(C)=O>[CH3:22][N:23]([CH3:40])[S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:38])([F:37])[F:39])[CH:35]=1)[C:30]([N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:20][CH3:21])[CH2:15][C:16]([F:18])([F:17])[F:19])=[O:31])(=[O:25])=[O:26]
Reactant: COc1cc(F)ccc1-c1ccncc1NCC(F)(F)F
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(F)ccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)C)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine and 3-dimethylsulfamoyl-5-trifluoromethyl-benzoic acid (Buttpark Ltd.) and using a gradient of CH2Cl2: EtOAc (100:0 to 90:10) for the chromatographic purification. Light yellow foam (42%). MS (ESI): m/z=580.112 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][C:15]3=[N:18][NH:19][C:20]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])=[C:14]3[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[C:35](Cl)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[F:8][C:6]1[CH:5]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][C:15]3[N:18]([C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[N:19]=[C:20]([NH:21][C:22](=[O:27])[C:23]([F:24])([F:25])[F:26])[C:14]=3[CH2:13]2)(=[O:11])=[O:10])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1[nH]nc2c1CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c1CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl]-2,2,2-trifluoro-acetamide (43.76 g, 106.65 mmol) and triethylamine (44.6 mL, 319.95 mmol) in dichloromethane (1 L), at room temperature, trityl chloride (31.22 g, 111.98 mmol) was added. The reaction was stirred at room temperature for 1 hour. The organic phase was washed with NaHCO3 saturated solution, water and brine, dried over sodium sulfate filtered and evaporated to dryness affording the crude title compound as white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>CCOC(C)=O>[F:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=1[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: OB(O)c1cccc(F)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccccc3F)nc12

Procedure:
1-[2-(2-Fluoro-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-fluorobenzeneboronic acid following general procedures as described in these Examples. Silica gel chromatography using 20-100% EtOAc in hexanes as eluant gave a brown solid which was washed with 1:1 Et2O/Hexanes to provide 10 mg (12%) of a pale yellow solid. M+H=298.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][C:18]=4[O:25][CH3:26])[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.[OH:28]O>C(O)(=O)C.O.N>[CH3:1][C:2]1([CH3:27])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:28])=[CH:19][C:18]=4[O:25][CH3:26])[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1
Reactant: COc1cc(SC)ccc1C1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Reactant: OO
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(S(C)=O)ccc1C1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Reaction time: 50 h

Procedure:
5.1 gm of 7,7-dimethyl-2-(2-methoxy-4-methylmercapto-phenyl)-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione were reacted in 100 ml of 70% acetic acid with 1.7 gm of 30% hydrogen peroxide, and the mixture was allowed to stand for 50 hours at room temperature (the first 3 hours while stirring). After 18 and again after 26 hours 1.3 gm of 30% hydrogen peroxide were added. The reaction mixture was then diluted with water, and ammonia was added until alkaline reaction. The precipitate was suction-filtered off and the filtrate was extracted twice with chloroform. The combined chloroform phases were evaporated, and the evaporation residue was combined with the precipitate. The thus obtained product was purified on a silicagel column (eluant: chloroform/acetone 19:1).