Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([N:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22])=[O:8]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reactant: OCCNCCO
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)N(CCO)CCO)c1I

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride was reacted with diethanolamine according to the general procedure in Example 24g. Yield of isolated crude product was 98%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1I.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)OC)c(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)OC)c(Oc2ccccc2)c1
Yield: 103.7 %

Procedure:
2-Iodo-terephthalic acid dimethyl ester (10 g, 31 mmol), phenol (3.23 g, 34 mmol), tetrakis-acetonitrilecopper hexafluorophosphate (2.9 g, 7.8 mmol), and cesium carbonate (10.2 g, 31 mmol) were added to a 1 L 3-neck round bottom flask equipped with a mechanical stirrer, a reflux condenser and containing toluene (350 mL). The reaction was refluxed 5 h under nitrogen with stirring. After cooling, EtOAc (200 mL) was added and the mixture was filtered. The filtrate was concentrated to afford the crude title compound (9.2 g) that was used without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)C(=O)[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:12]([NH:11][C:7](=[N:8][OH:9])[C:3]1[C:2]([NH:1][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:6][O:5][N:4]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nonc1-c1noc(=O)n1Cc1ccccc1
Product: O=C(Nc1nonc1C(=NO)NCc1ccccc1)c1ccccc1

Procedure:
This compound was prepared according to the procedure of Example 35 using 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-benzyl-1,2,4-oxadiazol-5(4H)-one and benzoyl chloride as the starting materials. LCMS for C17H16N5O3 (M+H)+: m/z=338.2.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([CH3:36])[CH:27]=1)#[N:25]>C(Cl)Cl>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:6]2[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]2)(=[O:34])=[O:33])=[C:28]([CH3:36])[CH:27]=1)#[N:25]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reaction time: 8 h
Yield: 104.2 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (2.79 g, 13.91 mmol, supplier Antlantic Scitech) in DCM (80 mL), DIPEA (3.64 mL, 20.87 mmol) was added under argon atmosphere at room temperature then 4-cyano-2-methylbenzenesulfonyl chloride (3 g, 13.91 mmol) was added at 0° C. The ice bath was removed and the reaction mixture was stirred overnight. The reaction mixture was partitioned between DCM (30 ml) and aqueous sodium bicarbonate (2×20 ml). The organic phase was washed with HCl (2×20 ml) and water (2×20 ml) then it was dried (phase separator) and concentrated under vacuum to give the title compound (5.5 g) as a yellow viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:22]([N:24]([CH2:27]CCl)[CH2:25]C)[CH3:23].CN(CCCl)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:23][CH2:22][N:24]([CH3:27])[CH3:25])[CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc(CN2CCNCC2c2ccccc2)cc1Cl
Reactant: CCN(CC)CCCl
Agent: CN(C)CCCl
Product: CN(C)CCN1CCN(Cc2ccc(Cl)c(Cl)c2)C(c2ccccc2)C1

Procedure:
1-(3',4'-Dichloro benzyl)-2-phenyl piperazine prepared according to Example 3 (b), is alkylated by following the procedure described in Example 3 (c), whereby, in place of the diethylamino ethylchloride, the equimolecular amount of dimethylamino ethylchloride is used. The resulting reaction product is obtained in the form of a light yellow oil boiling at 190° C./0.01 mm. Hg.
Reaction SMILES: [Br:1]Br.[C:3]1(=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:8]1[CH2:7][CH2:6][CH2:5][C:4](=[O:9])[C:3]1=[O:10]
Reactant: O=C1CCCCC1=O
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CCCC(Br)C1=O
Temperature: 25 °C

Procedure:
Step AAE (1): Followed the method of B. Miller and H.-S. Wong Tetrahedron 1972, 28, 2369. Bromine (0.651 mL, 12.6 mmol) in was added dropwise to a solution of cyclohexane-1,2-dione (1.35 g, 12.0 mmol) in CCl4 (30 mL) at 0° C. The reaction mixture was allowed to warm to rt. The resulting solution was concentrated in vacuo to afford 3-bromocyclohexane-1,2-dione. The crude product, which is prone to decomposition, was used for subsequent chemistry without purification or characterization.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1)([O-])=O.C(O)(=O)C.CCOC(C)=O.CCCCCC.C([O-])(O)=O.[Na+]>O.[Fe].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)c1ccc([N+](=O)[O-])cn1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(N)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
3-Nitro-6-(methylsulfonyl)pyridine (10 g, 49.5 mmol) was suspended in water (200 mL). Iron powder (5.0 g, 89.3 mmol) and acetic acid (0.5 mL) were added to the above mixture. The mixture, which resulted, was heated to reflux for 2 h. The reaction was monitored by TLC (EtOAc/hexane, 1/1). The reaction mixture was then cooled to rt and a saturated solution of NaHCO3 (100 mL) was added to the mixture. Ethyl acetate (200 mL) was added to the above mixture and the mixture which resulted was stirred at rt for 30 min. The mixture was filtered through celite and the organic layer was collectd. The aqueous layer was extracted with ethyl acetate (200 mL×3). The organic extractions were combined and dried (NaSO4). The solvent was removed under reduced pressure to provide the 3-amino-6-(methylsulfonyl)pyridine (6 g, 70.5%).
Reaction SMILES: C1O[C:4]2([C:9]3[N:10]([CH3:17])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:8]=3[S:7](=[O:19])(=[O:18])[N:6]([CH3:20])[CH2:5]2)[O:3]C1>Cl.CO>[CH3:20][N:6]1[CH2:5][C:4](=[O:3])[C:9]2[N:10]([CH3:17])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7]1(=[O:19])=[O:18]
Reactant: CN1CC2(OCCO2)c2c(c3ccccc3n2C)S1(=O)=O
Agent: Cl
Solvent: CO
Product: CN1CC(=O)c2c(c3ccccc3n2C)S1(=O)=O
Yield: 81.8 %

Procedure:
2.2 gm (7.4 millimols) of 2,5-dihydro-2,5-dimethyl-1,2-thiazino[5,6-b]-indole-4(3H)-one-1,1-dioxide-ethylene ketal were refluxed for one hour in a mixture of 60 ml of 9% hydrochloric acid and 60 ml of methanol. Subsequently, the mixture was evaporated to dryness in vacuo. After taking up the residue in methylene chloride, washing the solution with water, drying and evaporating it, and recrystallizing the raw product from ethanol, 1.6 gm (82% of theory) of 2,5-dihydro-2,5-dimethyl-1,2-thiazino-[5,6-b]indole-4(3H)-one-1,1-dioxide were obtained; M.p.: 180° C.; 1H-NMR (CDCl3): δ = 8.0 (m, 1) and 7.4 (m, 3; arom. H) 4.15 (s, 2, CH2); 4.06 (s, 3, 5-CH3); 3.00 (s, 3, 2-CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.Cl[C:12]1[S:13][C:14]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:15]=2[N:16]=1.C([O-])([O-])=O.[K+].[K+].Cl>CS(C)=O.O>[Cl:8][C:6]1[CH:7]=[C:2]([NH2:1])[CH:3]=[C:4]([Cl:10])[C:5]=1[O:9][C:12]1[S:13][C:14]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Yield: 49.3 %

Procedure:
To the solution of 4-amino-2,6-dichloro phenol (6 g, 26.5 mmol) and 2,6-dichloro-benzothiazole (363) (6 g, 29.4 mmol, 1.1 eq) in DMSO (25 ml), was added K2CO3 (11 g, 80 mmol, 3.0eq). The mixture was stirred and heated to 160 degree. After 5.5-hr water (20 ml) was added to the reaction mixture, which was neutralized with 2N HCl., and was extracted with AcOEt three times. And the organic layer was washed with Brine and was dried over anhydrous MgSO4, and then concentrated. Crude residue was purified by column chromatography (CHCl3/Acetone=9/1, 180 g of silica gel) to afford 3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (364) as a black solid (4.52 g, 49%).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([OH:13])=[O:12].[OH-].[K+]>CCO>[O:10]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[CH:18][C:17]1[CH:20]=[CH:21][C:14]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C1CCc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C=C2Cc3ccccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a suspension of indanone (2.00 g, 15.1 mmol) and 4-carboxybenzaldehyde (1.89 g, 12.6 mmol) in EtOH (10 ml) was added KOH (1.77 g, 31.5 mmol) at 0° C. The reaction mixture was stirred 30 min at 0° C. then at room temperature for 16 h. The solvent was evaporated and the residue was dissolved in water, acidified to pH 5 with HCl 1 M. The precipitate was filtered and rinsed with water to afford the title compound 273 (2.27 g, 57%) as a yellow solid. LRMS: 264.1 (Calc.); 265.0 (found).
Reaction SMILES: O[C@@H:2]([C:8]([CH3:16])=[CH:9][C:10]1[N:11]=[C:12]([CH3:15])[S:13][CH:14]=1)[CH2:3][CH:4]=[C:5]([I:7])[CH3:6].C1(P([N:31]=[N+:32]=[N-:33])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:31]([C@H:2]([C:8]([CH3:16])=[CH:9][C:10]1[N:11]=[C:12]([CH3:15])[S:13][CH:14]=1)[CH2:3][CH:4]=[C:5]([I:7])[CH3:6])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(I)=CC[C@@H](O)C(C)=Cc1csc(C)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(I)=CC[C@H](N=[N+]=[N-])C(C)=Cc1csc(C)n1
Temperature: 25 °C

Procedure:
A solution of (5R)-5-hydroxy-2-iodo-6-methyl-7-(2-methylthiazol-4-yl)-2,6-heptadiene (1.74 g) in 30 mL of toluene is cooled to 0° C. and treated with diphenylphosphoryl azide (1.65 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.91 g) for 2 hours. The mix is warmed to ambient temperature and diluted with ethyl acetate. The solution is washed sequentially with water, sat. NaHCO3, and brine, then dried over MgSO4, filtered, and evaporated. The product is purified by SiO2 chromatography (7.5% ethyl acetate/hexanes).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C:13](OCC)=[O:14])=[CH:5][CH:4]=1.C([Al]CC(C)C)C(C)C>>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH2:13][OH:14])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C/C=C/c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al]CC(C)C
Product: OC/C=C/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
Ethyl (2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienoate was treated with diisobutyl aluminum hybride in the same manner as in Reference example 21 to obtain the title compound in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]3[S:15][CH:16]=[CH:17][C:18]=3[Cl:19])[CH2:9]2)=[CH:4][CH:3]=1.CNN>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]3[S:15][CH:16]=[CH:17][C:18]=3[Cl:19])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN1N=C(c2sccc2Cl)CC1c1ccc(Cl)cc1
Agent: CNN
Product: Cn1nc(-c2sccc2Cl)cc1-c1ccc(Cl)cc1

Procedure:
5-(4-Chloro-phenyl)-3-(3-chloro-thiophen-2-yl)-1-methyl-4,5-dihydro-1H-pyrazole: The title compound was prepared from 3-(4-chloro-phenyl)-1-(3-chloro-thiophen-2-yl)-propenone (50 mg, 0.176 mmol) and methylhydrazine (9 μL, 0.17 mmol) by a procedure similar to Example 105a as a yellowish oil (20.9 mg, 38%). 1H NMR (CDCl3): 7.24 (m, 4H), 7.09 (d, J=6.6 Hz, 1H), 6.75 (d, J=6.60 Hz, 1H), 4.08 (m, 1H), 3.83 (m, 1H), 2.98 (t, 1H), 2.67 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH:20]=[CH2:21]>C(#N)C>[CH2:21]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:20][CH:19]=[CH2:18]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCCOc1ccc([N+](=O)[O-])cc1

Procedure:
To an acetonitrile (20 mL) solution of 4-nitrophenol (0.423 g; 3.04 mmol) and potassium carbonate (1.11 g; 8.02 mmol), 4-bromo-1-butene (0.827 g; 6.13 mmol) was added, and the mixture was refluxed and then reacted for 17 hours. After completion of the reaction, the solution was filtrated by Celite, and then the filtrate was concentrated under a reduced pressure. The residue was purified by flash column chromatography using methylene chloride, and then the effluent was concentrated to obtain 4-(3-butenyloxy)nitrobenzene (1) (0.571 g, 97% of yield, a light yellow oil) represented by the following formula.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[F:10].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: N#CCc1ccc(F)c(F)c1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(CCOC1CCCCO1)c1ccc(F)c(F)c1
Reaction time: 3 h
Yield: 54 %

Procedure:
14.4 g of sodium hydride as a 60% dispersion in oil are suspended in 250 ml of THF and cooled in a water bath. A solution of 50 g of 3,4-difluorophenylacetonitrile in 50 ml of THF is added dropwise, the mixture is then left to stand for 3 hours at RT and a solution of 68.16 g of 2-(2-bromoethoxy)tetrahydropyran in 100 ml of THF is added dropwise. After one night at RT, the mixture is acidified with a buffer of pH 2, the THF is evaporated off and the residue is taken up with water and extracted with ether. The extract is washed twice with a buffer solution of pH 4 and then with water and with saturated sodium chloride solution. It is decanted and the organic phase is dried over MgSO4 and concentrated under vacuum. The residue is chromatographed on silica using pure toluene and then toluene containing up to 3% of AcOEt as the eluent to give 49.5 g of the expected product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.N[C:35]1[CH:40]=[CH:39][C:38]([NH:41]C(=O)CN(C)C)=[CH:37][CH:36]=1>>[CH2:2]1[C:36]2[C:35](=[CH:40][CH:39]=[C:38]([NH:41][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:37]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CN(C)CC(=O)Nc1ccc(N)cc1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and N-(4-aminophenyl)-N2,N2-dimethylglycinamide by a procedure similar to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 6H), 3.09 (s, 2H), 6.46 (d, 1H, J=5.3 Hz), 7.10 (t, 1H, J=6.7 Hz), 7.22 (d, 2H, J=8.0 Hz), 7.34 (d, 1H, J=7.7 Hz), 7.42-7.51 (m, 4H), 7.56 (t, 1H, J=8.2 Hz), 7.61 (d, 2H, J=8.9 Hz), 7.80 (d, 1H, J=8.0 Hz), 7.96 (s, 1H), 8.22 (d, 1H, J=5.3 Hz), 8.46 (bd, 1H, J=8.8 Hz), 8.82 (d, 1H, J=6.8 Hz), 9.47 (s, 1H), 9.60 (s, 1H), 10.91 (s, 1H); ESIMS (M+H)+=619.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:35])[C:11]2[O:17][C:16]3[C:18]([Cl:31])=[CH:19][C:20]([NH:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:21][C:15]=3[CH2:14][S:13](=[O:33])(=[O:32])[C:12]=2[CH:34]=1)=[O:7].FC(F)(F)C(O)=O.C([BH3-])#N.[Na+]>CO>[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:35])[C:11]2[O:17][C:16]3[C:18]([Cl:31])=[CH:19][C:20]([N:22]([CH2:1][CH3:2])[CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:21][C:15]=3[CH2:14][S:13](=[O:33])(=[O:32])[C:12]=2[CH:34]=1)=[O:7]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCOCC3)cc(Cl)c1O2
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCN(CCN1CCOCC1)c1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Acetaldehyde (0.21 mL, 3.80 mmole) was added to a solution of Example 66k (0.370 gm, 0.76 mmol) in dry methanol (15 mL) followed by the addition of trifluoro-acetic acid (0.06 mL, 0.76 mmol). The reaction mixture was stirred at 0° C. for 2 h, allowed to come to room temperature, treated with sodium cyanoborohydride (0.119 g, 1.9 mmol), and stirred overnight. It was concentrated, treated with 10% aqueous sodium bicarbonate solution, water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.3 g, (76.72%); 1H NMR (CDCl3): δ 2.15 (t, 3H, CH3), 2.45-2.55 (m, 6H, 3CH2), 2.70 (s, 3H, CH3), 3.40 (q, 2H, CH2), 3.50 (t, 2H, CH2), 3.70-3.80 (m, 4H, CH2), 3.95 (s, 3H, OCH3), 4.70 (s, 2H, CH2), 6.55 (s, 1H, Ar), 6.70 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.45 (s, 1H, Ar); MS: m/e (CI+) 511 (M—CH3).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[N:12][N:13]2[C:18]3[N:19]([CH2:22][CH3:23])[CH:20]=[CH:21][C:17]=3[C:16]([CH3:24])=[N:15][C:14]=12>C(Cl)(Cl)Cl>[Br:9][C:10]1[CH:11]=[N:12][N:13]2[C:18]3[N:19]([CH2:22][CH3:23])[C:20]([Br:1])=[CH:21][C:17]=3[C:16]([CH3:24])=[N:15][C:14]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1ccc2c(C)nc3c(Br)cnn3c21
Solvent: ClC(Cl)Cl
Product: CCn1c(Br)cc2c(C)nc3c(Br)cnn3c21
Reaction time: 2 h
Yield: 80 %

Procedure:
N-bromosuccinimide was added at room temperature to a solution of 1.675 g (6 mmoles) of 3-bromo-8-ethyl-5-methyl-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (prepared as described in Example 13) dissolved in 12 ml of chloroform, and the mixture was stirred for 2 hours. At the end of this time, the reaction mixture was washed with a 2N aqueous solution of potassium hydroxide and then with water, after which it was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with chloroform) and recrystallized from ethyl acetate to afford 1.72 g (yield 80%) of the title compound as colorless needles, melting at 135°-137° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C[Si]([N:14]=[C:15]=[O:16])(C)C>C(O)(C)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:15]([NH2:14])=[O:16])[CH2:6][CH2:5]1
Reactant: OCCN1CCNCC1
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: NC(=O)N1CCN(CCO)CC1
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a stirred solution of 1-(2-hydroxy-ethyl)-piperazine (1.95 g, 15 mmol) in isopropanol (30 mL) at rt was added trimethylsilylisocyanate (2.8 mL, 21 mmol) and the resulting solution stirred overnight before the volatiles were removed in vacuo. The residue was partitioned between CH2Cl2 and water. The aqueous phase was concentrated in vacuo to give 4-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid amide (2.3 g, 88%); 1H-NMR (300 MHz, d6-DMSO) 5.92 (2H, s), 4.40 (1H, t), 3.46-3.52 (2H, m), 3.22-3.34 (4H, m), 2.30-2.39 (6H, m); m/z (ES+) 173 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([NH:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH3:18])[C:13]([NH2:26])=[CH:12][CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[N:27]([O-])=O.[Na+]>C(O)(=O)C>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]4[N:16]([C@H:17]([C:19]5[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=5)[CH3:18])[N:27]=[N:26][C:13]4=[CH:12][CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)ccc1N)c1ccc(F)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@H](c1ccc(F)cc1)n1nnc2ccc(Nc3cc(C4CC4)[nH]n3)nc21
Reaction time: 0.08 h
Yield: 50.9 %

Procedure:
To a solution of (S)—N6-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,3,6-triamine (Method 9; 0.08 g, 0.2 mmol), in aqueous acetic acid (5%, 3 ml) was slowly added the aqueous NaNO2 (0.01 g, 0.2 mmol, 1 ml H2O) solution at 25° C. The reaction was allowed to stir for an additional 5 minutes, then quenched with water (10 ml), and extracted with DCM (3×25 ml). The combined organic was washed with saturated NaHCO3 (50 ml), dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM:MeOH=40:1) to give the title compound (0.037 g, 50%). NMR (400 MHz, CD3OD) 8.02 (d, J=8.9 Hz, 1H), 7.46-7.42 (m, 2H), 7.08-7.04 (m, 2H), 6.91 (d, J=8.9 Hz, 1H), 6.23-6.19 (m, 2H), 2.12 (d, J=7.0 Hz, 3H), 1.95-1.91 (m, 1H), 1.02-1.00 (m, 2H), 0.75-0.72 (m, 2H). MS: Calcd.: 363. Found: [M+H]+ 364.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C:10]1([CH3:20])[C:11]([C:16]([NH:18][NH2:19])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=1>C(O)C>[N:7]1[CH:8]=[CH:9][C:4]([C:1](=[N:19][NH:18][C:16](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:20])[CH3:2])=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(=O)NN
Reactant: CC(=O)c1ccncc1
Solvent: CCO
Product: CC(=NNC(=O)c1ccccc1C)c1ccncc1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
A mixture of 3.63 gm (0.03 mole) of 4-acetylpyridine, 4.51 gm (0.03 mole) of o-toluic acid hydrazide and 100 ml of 95% ethanol is refluxed 8 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point and cooled to room temperature. The mixture is chilled in the refrigerator and the product collected, washed with water, and dried to yield 4.78 gm (63%) of the title compound having a melting point of 187.4° C.
Reaction SMILES: O.[F:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[C:6](=[O:11])[NH:5][CH:4]=1.OO.S(=O)(=O)(O)[OH:15]>[OH-].[Na+]>[F:2][C:3]1[N:8]=[C:7]([C:9]([NH2:10])=[O:15])[C:6]([OH:11])=[N:5][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1nc(F)c[nH]c1=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1nc(F)cnc1O
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
At a water-cooled temperature, 2.2 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was dissolved in an aqueous solution of sodium hydroxide prepared from 1.27 g of sodium hydroxide and 24.2 ml of water. After adding 2.75 ml of 30% hydrogen peroxide at the same temperature as above, the mixture thus formed was stirred at 40° C. for 1.5 hours. After dropwise adding 2.77 mL of concentrated sulfuric acid to the reaction mixture obtained above while cooling it with ice, the mixture thus formed was cooled to 10° C. The deposited crystalline product was collected by filtration and washed with 2 mL of cold water to obtain 2.2 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a light yellow-colored solid product.