Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.[F:18][C:19]1[CH:30]=[CH:29][C:22]2[NH:23][C:24]([CH:26]([NH2:28])[CH3:27])=[N:25][C:21]=2[CH:20]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CS(C)=O.C(OCC)(=O)C>[F:18][C:19]1[CH:30]=[CH:29][C:22]2[NH:23][C:24]([CH:26]([NH:28][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH3:27])=[N:25][C:21]=2[CH:20]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: CC(N)c1nc2cc(F)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(C(=O)NC(C)c2nc3cc(F)ccc3[nH]2)ccc1C(=O)N1CCCC1
Temperature: 25 °C

Procedure:
A solution of 0.10 g (0.43 mmol) of 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, 0.184 g (0.450 mmol) of 1-(5-fluoro-1H-benzimidazol-2-yl)ethylamine×2(CF3COOH) (prepared analogously to Methods 1a, 10b, 10c) and 0.35 mL (2.50 mmol) of triethylamine in 3 mL of dimethylsulfoxide is stirred at ambient temperature and combined with 0.193 g (0.600 mmol) of TBTU. The reaction mixture is stirred for 1 hour at ambient temperature, then diluted with ethyl acetate and washed successively with 10% aqueous citric acid, twice with 2 molar sodium hydroxide solution and with water. The organic phase is dried with sodium sulfate and concentrated. The crude product is taken up in ethyl acetate, precipitated with tert-butylmethylether, and dried. Yield: 83 mg (49% of theory); Rf value: 0.34 (silica gel; ethyl acetate/ethanol=9:1); C22H23FN4O2 (394.45); mass spectrum: (M+H)+=395
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][N:3]=1.Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([NH:1][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][N:3]=2)=[CH:19][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CCCNc1nc(N)ncc1C(=O)OCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)OCC
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 32.9 %

Procedure:
To a solution of tris(dibenzylideneacetone)dipalladium(0) (1.14 g) and 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene (1.45 g) in 1,4-dioxane (150 mL), ethyl 2-amino-4-(propylamino)pyrimidine-5-carboxylate (C3, 5.61 g), 4-bromobenzonitrile (6.83 g) and cesium carbonate (24.40 g) were added at room temperature, and the mixture was stirred at 100° C. for 11 hours and 30 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, then the insoluble matter was removed by filtration through Cerite, and then 1.0 mol/L aqueous hydrochloric acid and ethyl acetate were added. The organic layer was separated, washed successively with 1.0 mol/L aqueous hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue, ethyl acetate was added, and the solid matter was taken by filtration to obtain ethyl 2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylate (C4, 2.68 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:19])[C:8]3[NH:9][CH:10]=[N:11][C:12]=3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]2=[N:4][N:3]=1.[Br:20]N1C(=O)CCC1=O>C1COCC1>[Br:20][C:10]1[NH:9][C:8]2[C:7](=[O:19])[N:6]3[C:2]([CH3:1])=[N:3][N:4]=[C:5]3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]=2[N:11]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(C)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(C)nnc12
Temperature: 70 °C
Yield: 31 %

Procedure:
To a solution of 3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (1.0 g, 3.8 mmol) in THF (50 mL) was added N-bromosuccinimide (0.75 g, 4.2 mol). The mixture was heated at 70° C. for 1 h and concentrated in vacuum. The residue was taken up in water and EtOAc. The organic layer was separated and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuum. The residue was purified by preparative LCMS to provide the desired product as a white powder (0.4 g, 30% yield). 1HNMR (400 MHz, d6-DMSO): δ 4.18 (t, J=7.5 Hz, 2H), 2.71 (s, 3H), 1.79 (m, 2H), 1.29 (m, 4H), 0.84 (m, 3H). LCMS calculated for C12H16BrN6O (M+H): 339.1, 341.1. Found: 339.1, 341.1.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:8][C:7]1=[O:21])(=O)[CH2:2][CH2:3][CH3:4].[CH2:22]([O:24][NH2:25])[CH3:23]>C(O)C>[CH2:22]([O:24][NH:25][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:8][C:7]1=[O:21])[CH2:2][CH2:3][CH3:4])[CH3:23]
Reactant: CCCC(=O)C1C(=O)CC(C2CCCCCCC2)CC1=O
Reactant: CCON
Solvent: CCO
Product: CCCC(NOCC)=C1C(=O)CC(C2CCCCCCC2)CC1=O
Yield: 94 %

Procedure:
4.9 parts by weight of 2-butyryl-5-cyclooctylcyclohexane-1,3-dione, 1.1 parts by weight of ethoxyamine and 80 parts by volume of ethanol were stirred at room temperature for 12 hours, the solvent was distilled off under reduced pressure, the residue was taken up in 150 parts of dichloromethane, the solution was washed twice with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. 2-(1-ethoxyamino-butylidene)-5-cyclooctylcyclohexane-1,3-dione was obtained in 94% yield as an oil (compound no. 1); nD33 : 1.5234.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]=[C:6]1[C:10](=[O:11])O[C:8]([CH3:12])=[N:7]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[CH2:17]([N:24]1[C:10](=[O:11])[C:6](=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=2[O:2][CH3:1])[N:7]=[C:8]1[CH3:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccccc1C=C1N=C(C)OC1=O
Reactant: NCc1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccccc1C=C1N=C(C)N(Cc2ccccc2)C1=O
Temperature: 100 °C
Yield: 19.6 %

Procedure:
4-(2′-Methoxybenzylidene)-2-methyl-4H-oxazol-5-one (5 g) was dissolved in acetic acid (50 ml) and benzylamine (2.68 g) and sodium acetate (2 g) were added. The mixture was heated at 100° C. for 2 hr, poured into ice-water, neutralized with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.38 g) as yellow crystals.
Reaction SMILES: O1CCCC1.Cl.[C:7]12([C:17]3[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([CH3:24])[CH:18]=3)[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.C(N(CC)CC)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[S:42](Cl)(=[O:44])=[O:43]>O>[C:7]12([C:17]3[CH:23]=[CH:22][C:20]([NH:21][S:42]([C:34]4[CH:35]=[C:36]([N+:39]([O-:41])=[O:40])[CH:37]=[CH:38][C:33]=4[Cl:32])(=[O:44])=[O:43])=[C:19]([CH3:24])[CH:18]=3)[CH2:14][CH:13]3[CH2:15][CH:9]([CH2:10][CH:11]([CH2:12]3)[CH2:16]1)[CH2:8]2
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1N
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 40 °C
Reaction time: 7 h
Yield: 36.2 %

Procedure:
To 5 mL of a tetrahydrofuran solution comprising 250 mg of 4-(1-adamantyl)-2-methylaniline hydrochloride and 200 mg of triethylamine, 5 mL of a tetrahydrofuran solution comprising 230 mg of 2-chloro-5-nitrobenzenesulfonylchloride was dropwise added, followed by stirring at about 40° C. for about 7 hours. After the mixture was left to stand for cooling, water was added thereto, extraction with chloroform, drying over salt cake and concentration under reduced pressure were carried out to obtain crude crystals. The crude crystals were recrystalized from ether to obtain 150 mg of N-(4-(1-adamantyl)-2-methylphenyl)-2-chloro-5-nitrobenzenesulfonamide (Compound No. 48) having a melting point of 238° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=O)[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2].[C:16]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[N:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][C:16](=[O:18])[CH3:17])=[CH:26][CH:25]=2)[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(N)cc1
Reactant: CC(=O)N1c2ccccc2C(=O)CC1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc(N=C2CC(C)N(C(C)=O)c3ccccc32)cc1
Reaction time: 1 h
Yield: 30.2 %

Procedure:
[Step 1] 100 mg of 1-acetyl-4-oxo-2-methyl-1,2,3,4-tetrahydroquinoline and 227 mg of 4-acetoxyaniline were dissolved in 3 mL of toluene, and 250 μL of titanium tetrachloride (1.0 M dichloromethane solution) was added to the solution under ice cooling. The mixture was stirred for one hour under ice cooling, and then was stirred for another one hour at room temperature. After completion of the reaction, the reaction liquid was filtered through Celite and was concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (chloroform), and thus 50 mg (30%) of 1-acetyl-2-methyl-4-[(4-acetoxyphenyl)imino]-1,2,3,4-tetrahydroquinoline was obtained as a yellow soup-like substance.
Reaction SMILES: [CH3:1][Mg]Cl.CC1(C)C(C)(C)[O:8][B:7]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]=[O:19])=[N:16][CH:17]=2)[O:6]1>C1COCC1>[OH:19][CH:18]([C:15]1[N:16]=[CH:17][C:12]([B:7]([OH:6])[OH:8])=[CH:13][CH:14]=1)[CH3:1]
Reactant: C[Mg]Cl
Reactant: CC1(C)OB(c2ccc(C=O)nc2)OC1(C)C
Solvent: C1CCOC1
Product: CC(O)c1ccc(B(O)O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 M Methylmagnesium chloride in THF (0.4 mL, 0.4 mmol) was added dropwise to a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbaldehyde (50 mg, 0.2 mmol, Frontier Scientific, catalog #F2110) in THF (2 mL) at 0° C. After stirring for 1 h at room temperature, the reaction was quenched with 1 N NH4Cl and was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to give the crude [6-(1-hydroxyethyl)pyridin-3-yl]boronic acid. This was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]([CH2:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]([CH3:17])([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=O.Cl.C(N)C.C(OCC)(=O)C>O1CCCC1>[NH2:1][CH2:2][CH2:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]([CH3:16])([CH3:17])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CC(N)=O
Agent: CCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CCN
Temperature: 50 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-[2-(aminocarbonylmethyl)phenoxy]-2-methylpropionate (1.4 g, 4.87 mmol) was dissolved in tetrahydrofuran (5.0 mL). Subsequently, under nitrogen atmosphere, borane-THF complex in THF solution [1,0M BH3-THF in THF (14.6 mL, 14.6 mmol)] was added thereto, the mixture was stirred for three hours at 50° C. Thereafter, concentrated hydrochloric acid was gradually added thereto at 0° C. The resultant mixture was stirred for one hour at room temperature and made basic with an aqueous ethylamine solution. Ethyl acetate was added thereto. The mixture was sequentially washed with water and brine, followed by drying over sodium sulfate. The mixture was subjected to concentration under reduced pressure and purification by silica gel column chromatography (chloroform/methanol=30/1), whereby the target compound was obtained (830 mg, 2.97 mmol, 61%).
Reaction SMILES: [NH2:1][NH2:2].[C:3]([NH:7][C:8]([C:10]1[S:14][C:13]2[CH2:15][C:16]([CH3:19])([CH3:18])[CH2:17][C:12]=2[C:11]=1[CH:20]=O)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1>[C:3]([NH:7][C:8]([C:10]1[S:14][C:13]2[CH2:15][C:16]([CH3:19])([CH3:18])[CH2:17][C:12]=2[C:11]=1[CH:20]=[N:1][NH2:2])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC1(C)Cc2sc(C(=O)NC(C)(C)C)c(C=O)c2C1
Reactant: NN
Solvent: C1CCOC1
Product: CC1(C)Cc2sc(C(=O)NC(C)(C)C)c(C=NN)c2C1
Temperature: 20 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 85% aqueous hydrazine (10 mL) in THF (180 mL) was added 131f (5.6 g, 20.0 mmol) in anhydrous THF (20 mL) over a period of 5 minutes. See FIG. 15. It was stirred at 20° C. for 3 h. The reaction mixture was concentrated under reduced pressure to afford 131g as a black solid (6.0 g, yield: 95%, purity: 95%). MS-ESI: [M+H]+ 294.0
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:18][CH2:17][C:13]2=[N:14][O:15][CH2:16][C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22](I)[CH:21]=1.C([Li])CCC.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:18][CH2:17][C@:13]2([C:24]3[CH:25]=[C:20]([Br:19])[CH:21]=[CH:22][C:23]=3[F:26])[NH:14][O:15][CH2:16][C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1I
Reactant: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Fc1ccc(Br)cc1[C@]12CO[C@@H](COCc3ccccc3)C[C@H]1CON2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (3aR,5R)-5-[(benzyloxy)methyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (P1) (10.0 g, 40.4 mmol) in toluene (404 mL) was cooled down to −78° C. and then boron trifluoride-diethyl etherate (46.5%, 10.8 mL, 40.8 mmol) was added. The resulting solution was allowed to stir at the same temperature for 30 minutes, with fast stirring. After that time, 4-bromo-1-fluoro-2-iodobenzene (12.3 g, 40.8 mmol) was added to the reaction mixture, followed by the slow addition (temperature never varied more than 5° C.) of n-butyllithium (2.5 M in hexanes; 16.3 mL, 42.7 mmol). The resulting solution was allowed to stir at −78° C. for 90 minutes. At this time, a saturated aqueous solution of ammonium chloride (20 mL) was added to the reaction mixture at −78° C. The reaction mixture was warmed to room temperature and partitioned between ethyl acetate (400 mL) and water (800 mL). The organics were separated and the aqueous layer was extracted with additional ethyl acetate (3×200 mL). The combined organics were then washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a clear oily residue. Purification via silica gel chromatography (Gradient: 10% to 70% ethyl acetate in heptane) afforded the product as an orange solid. Yield: 11.5 g, 27.1 mmol, 67%. 1H NMR (400 MHz, CD3OD) δ 8.01 (dd, J=6.9, 2.6 Hz, 1H), 7.47 (ddd, J=8.8, 4.4, 2.7 Hz, 1H), 7.38-7.28 (m, 4H), 7.07 (dd, J=11.6, 8.7 Hz, 1H), 4.58 (s, 2H), 4.10 (dd, J=11.6, 2.4 Hz, 1H), 3.82-3.78 (m, 2H), 3.72 (d, J=7.2 Hz, 1H), 3.61-3.55 (m, 2H), 3.52 (dd, J=8.8, 4.7 Hz, 1H), 3.16-3.10 (m, 1H), 1.86 (ddd, J=14.1, 7.0, 2.2 Hz, 1H), 1.59 (dtd, J=13.7, 11.8, 1.7 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CN1CCNCC1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN(c2nc(Nc3ccc(P(C)(C)=O)cc3)ncc2C(F)(F)F)CC1
Yield: 79 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (25 mg, 0.072 mmol) in 1.5 mL of ethanol was added 10 L of triethylamine and 1-Methyl piperazine (7.2 mg, 0.072 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (24 mg, 79% yield.) MS/ES+: m/z=414.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl-].[NH2:23][C:24]([NH2:26])=[NH2+:25].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[NH2:25][C:24]([NH2:26])=[N:23][C:4](=[O:6])[C:3]1[CH:8]=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][C:2]=1[NH2:1]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(-c2cccnc2)cc1N
Reactant: NC(N)=[NH2+]
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1cc(C(=O)N=C(N)N)c(N)cc1-c1cccnc1
Reaction time: 0.25 h

Procedure:
1.0 g of methyl 2-amino-4-(3-pyridyl)-5-methylsulfonylbenzoate [obtainable by reacting methyl 2-amino-4-bromo-5-methylsulfonylbenzoate with pyridine-3-boronic acid] is dissolved in 15 ml of 1-methylpyrrolidone and the solution is stirred for 15 min. Subsequently 0.9 g of guanidinium chloride and 2.6 ml of diisopropylethylamine are added and the mixture is stirred at room temperature for one hour. Customary workup gives N-diaminomethylene-2-amino-4-(3-pyridyl)-5-methylsulfonylbenzamide.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:15][CH:14]2[C:16]([NH:18]/[N:19]=[CH:20]/[C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH:23]=[CH:24][N:25]=[CH:26]3)=[O:17])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:31]I>CN(C=O)C>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:15][CH:14]2[C:16]([N:18]([CH3:31])/[N:19]=[CH:20]/[C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH:23]=[CH:24][N:25]=[CH:26]3)=[O:17])=[CH:9][CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)c1ccc(C2CC2C(=O)N/N=C/c2cccc3cnccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(/N=C/c1cccc2cnccc12)C(=O)C1CC1c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
To a 0° C. suspension of NaH (16 mg, 0.6 mmol) in DMF (1 mL), (E)-2-(4-tert-butylphenyl)-N′-(isoquinolin-5-ylmethylene)cyclopropanecarbohydrazide (200 mg, 0.53 mmol) was added portionwise under nitrogen atmosphere. After being stirred for 1 h at 0° C., MeI (0.15 g, 1.0 mmol) was added and the reaction mixture stirred at RT for 1 h. The reaction mixture was then quenched with ice water and stirred for an additional 10 minutes. The precipitated solid was filtered and dried in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography using 20% ethyl acetate in hexanes to afford (E)-2-(4-tert-butylphenyl)-N′-(isoquinolin-5-ylmethylene)-N-methylcyclopropanecarbohydrazide (30 mg, 50%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 9.24 (bs, 1 H), 8.50-8.41 (m, 1 H), 8.26-8.20 (m, 1 H), 8.02-7.94 (m, 2 H), 7.66-7.58 (m, 2 H), 7.39 (d, J=7.2 Hz, 2 H), 7.14 (d, J=7.2 Hz, 2 H), 3.28 (s, 3 H), 3.39-3.12 (m, 1 H), 2.63-2.56 (m, 1 H), 1.84-1.78 (m, 1 H), 1.49-1.38 (m, 1 H), 1.37 (s, 9 H). MS: M+H: m/z=386.2 and HPLC: 91%, (Condition-G).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.O.[NH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:26]3[C:21](=[N:22][CH:23]=[N:24][C:25]=3[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)[NH:20][N:19]=2)=[CH:13][CH:12]=1>C1COCC1>[C:1]([CH2:2][CH2:3][C:4]([CH:10]([NH2:9])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:26]3[C:21](=[N:22][CH:23]=[N:24][C:25]=3[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)[NH:20][N:19]=2)=[CH:13][CH:12]=1)=[O:5])([OH:6])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC(C(=O)CCC(=O)O)c1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 25 °C

Procedure:
A solution of 57.4 mg (0.573 mmol) of succinic anhydride in 0.5 ml of THF is added dropwise, with stirring, to a suspension, cooled to 0° C., of 200 mg (0.521 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine hydrate (see Step 77.5) in 3 ml of THF. The reaction mixture is stirred at RT for 4 hours and then a further solution of 57.4 mg (0.573 mmol) of succinic anhydride in 0.5 ml of THF is added. The mixture is stirred for a further 3 hours at 40° C., then allowed to cool to RT and filtered, and the filter residue is washed with diethyl ether. 3-[4-({3-Carboxy-propionyl}-aminomethyl)-phenylamino]-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine having a water content of 2.45% is obtained; m.p. 205-207° C.; ESI-MS: (M−H)−=464.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=O)[CH3:9].Cl.[NH2:21][OH:22]>C(O)C>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:8](=[N:21][OH:22])[CH3:9])=[CH:12]1
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=NO)c1c[nH]c2ccccc12
Temperature: 90 °C
Yield: 96.9 %

Procedure:
Triethylamine (3.93 mL) was added to a solution of 3-acetylindole (500 mg) and hydroxylamine hydrochloride (981 mg) in ethanol (20 mL), and the reaction solution was heated to reflux at 90° C. for 14 hours. The reaction solution was allowed to be cooled to room temperature, the solvent was concentrated under reduced pressure, and ethyl acetate and water were added to the resulting residue and the organic layer was partitioned. The resulting organic layer was washed with brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate) to obtain 0.53 g of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:49]=[CH:48][C:31]([O:32][C:33]2[CH:34]=[CH:35][C:36]3[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]4[CH2:47][CH2:46]4)=[O:44])[N:41]=3)[N:38]=2)=[CH:30][CH:29]=1>CN(C)C(=O)C.O1CCCC1>[CH:45]1([C:43]([NH:42][C:40]2[N:41]=[C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]4[CH:30]=[CH:29][C:28]([NH:27][C:13]([C:4]5[CH:3]=[C:2]([CH3:1])[N:6]([C:7]6[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=6)[N:5]=5)=[O:15])=[CH:49][CH:48]=4)=[N:38][N:37]3[CH:39]=2)=[O:44])[CH2:46][CH2:47]1
Reactant: Cc1cc(C(=O)O)nn1-c1ccccc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)cc2)nn1-c1ccccc1
Yield: 69.5 %

Procedure:
Using 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (196 mg, 0.97 mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (85 μL, 0.97 mmol), N-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 255, the title compound (223 mg, 70%) was obtained as a white powder.