Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=O)#[N:2].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:24]=1[NH2:25].Cl.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5]([NH:25][C:24]1[C:26]([O:32][CH3:33])=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:23]=1[O:22][CH3:21])=[O:7])#[N:2]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: N#CC(CC(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(NC(=O)CC(C#N)c2ccccc2)c(OC)c1
Temperature: 25 °C

Procedure:
To a dichloromethane (150 mL) solution of 3-cyano-3-phenylpropionic acid (5 g, 0.0286 mol) at 0° C. under a nitrogen atmosphere was added triethylamine (4 mL, 0.0286 mol) and 2,4,6-trimethoxyaniline.HCl (6.3 g, 0.0286 mol). To this solution was added DCC (6.2 g, 0.29 mol). The resulting mixture was allowed to warm to room temperature over 3 hours. This was then filtered and the filtrate partitioned between 1N HCl and dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid (5.1 g) was recrystallized from dichloromethane/hexanes, mpt 157°-160° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][O:8][S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccco1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccco2)cc1
Temperature: 60 °C
Yield: 53.6 %

Procedure:
To a stirred solution of 2-furan-2-yl-ethanol (1.6 g, 14.0 mmol) in a mixture of pyridine (5 mL) and chloroform (15 mL) was added para-toluenesulfonyl chloride (5.5 g, 28.0 mmol) and heated at 60° C. for 3 hrs. The reaction was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, sat. sodium bicarbonate solution and dried over anhydrous sodium sulfate. The filtrate was concentrated, and the crude compound purified by column chromatography over silica gel (60-120 mesh) using 10% ethyl acetate/petroleum ether as eluent to afford toluene-4-sulfonic acid 2-furan-2-yl-ethyl ester (2.0 g, 32%) as an oil.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>C1COCC1>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:20](=[O:21])[CH2:19][CH2:18][Cl:17])[C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: O=C(Cl)CCCl
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2N(C(=O)CCCl)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
The synthesis was performed according to the below synthetic scheme. To a solution of 11-Oxo-10,11-dihydro-5H-dibenzo[b,e][1,4] diazepin (0.376 gr., 1.79 mmol) in dry THF, (10 ml) NaNH2 (0.132 gr., 3.39 mmol) was added. The mixture was cooled to 0° C., and 0.2 ml 3-chloropropionyl chloride (2.09 mmol) was added dropwise. The mixture was stirred for 30 min at 0° C., allowed warming to room temperature, washed with 5% aq. potassium bicarbonate and extracted with CH2Cl2 (20 ml). The resulting organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was crystallized from ether, resulting in 0.467 gr. (87% yield) of 11-Oxo-10,11-dihydro-5-[(3-chloro)1-oxopropyl] 5-H-dibenzo[b,e] [1,4] diazepin in the form of a yellow solid, mp 241-242° C. 1H NMR (CDCl3): 8.78 (s, 1H), 7.98 (s, 1H), 7.59 (s, 1H), 7.4-7.26 (m, 6H), 3.77 (m, 4H). FAB/MS: 301(M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[SH:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11]>CC(O)C>[SH:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccc1S
Reactant: Clc1ccccn1
Solvent: CC(C)O
Product: Sc1ccccc1Nc1ccccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
340.5 g (3 moles) 2-chloropyridine are added dropwise to a boiling solution of 375 g (3 moles) 2-mercaptoaniline in 1.8 liters 2-propanol with agitation and under an atmosphere of protective gas within 15 min. After termination of the addition, the mixture is agitated for 5 hours at boiling temperature. The mixture is then allowed to cool to room temperature, and the precipitated yellowish product is filtered off and washed twice with 50 ml 2-propanol per wash. After drying in a vacuum, 592 g (86% of theory), 2-(2-mercapto-phenylamino) pyridine is obtained as colorless to yellowish crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:18]1[C:19]([OH:29])=[CH:20][C:21]3[O:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]=3[CH:28]=1)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:18]1[C:19]([OH:29])=[CH:20][C:21]3[O:25][C:24]([CH3:26])([CH3:27])[CH2:23][C:22]=3[CH:28]=1)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OC(C)(C)C3)c2c(Br)cccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OC(C)(C)C3)c2c(Br)cccc21
Temperature: 35 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
A mixture of ethyl [4-bromo-3-hydroxy-3-(6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate (1.32 g, 2.80 mmol), triethylsilane (2.00 mL, 12.2 mmol) and trifluoroacetic acid (0.94 mL, 12.2 mmol) in dichloromethane (50.0 mL) was stirred at 35° C. for 3 hours. The mixture was diluted with dichloromethane (100 mL), washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/3) to give the title compound (1.04 g, 81%): 1H NMR (300 MHz, CDCl3) δ 7.32-7.15 (m, 2H), 6.74 (d, 1H), 6.50-6.36 (br, 2H), 5.04 (s, 1H), 4.51-4.34 (m, 2H), 4.25-4.14 (m, 2H), 2.92-2.69 (m, 2H), 1.43 (s, 3H), 1.37 (s, 3H), 1.23 (t, 3H); MS (ES+) m/z 460.5 (M+1), 462.5 (M+1).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]=[O:10].C1(=[O:18])CCCCC1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:11])[C:2]=1[C:9]([OH:18])=[O:10]
Reactant: O=C1CCCCC1
Reactant: Cc1cc(C)c(C=O)c(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: Cc1cc(C)c(C(=O)O)c(C)c1
Reaction time: 5 h
Yield: 87.7 %

Procedure:
To a flask equipped with a stirrer, oxygen inlet and condenser were added mesitaldehyde (10.0 g, 67.6 mmol), 25 mL (0.242 mol) of cyclohexanone and 100 mg of benzoyl peroxide. Oxygen was bubbled in at fast rate while the stirred solution was maintained at 85°. After 24 hour an additional 50 mg of benzoyl peroxide was added and the reaction was continued at 90° for an additional 5 hr. After 29 hr total time the solution was mixed with 150 mL of water and 150 mL of methylene chloride; 20% aqueous potassium hydroxide was added dropwise until a pH of 8 was reached. The aqueous layer was separated and acidified with concentrated hydrochloric acid, after which the precipitated product was collected, washed with water and air dried to give 9.74 g (88% yield) of white mesitoic acid: mp 153°-155°.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)[CH:2]([CH3:4])[CH3:3].C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)=[O:13])[CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3n2C)cc(CC(C)C)cc1NS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(NC(=O)c2cc3cccc(CN4CCNCC4)c3n2C)cc(CC(C)C)cc1NS(C)(=O)=O

Procedure:
Tert-butyl 4-[2-(5-isobutyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperazine-1-carboxylate is used instead of tert-butyl [5-tert-butyl-2-methoxy-3-({1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carbonyl}-amino)-phenyl]-carbamate. The crude product is divided between dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried on magnesium sulphate and the solvents are eliminated in vacuo. The product thus obtained is further reacted directly.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Br:27]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:27])[N:6]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrBr
Reactant: Nc1nc(NCCc2ccccc2)nc2c1ncn2Cc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(NCCc2ccccc2)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
6-Amino-9-benzyl-2-(N-benzylmethylamino)purine (77 mg, 0.22 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (91 mg, yield 96%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][CH:16]=1)(C(C)(C)C)(C)C.[Br:20]Br.C([O-])(O)=O.[Na+]>O1CCCC1>[Br:20][CH2:18][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][CH2:9][OH:8])[CH:12]=1)=[O:19]
Reactant: CC(=O)c1cccc(CCO[Si](C)(C)C(C)(C)C)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CBr)c1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]ethanone (755 mg) in tetrahydrofuran (4 ml) was added bromine (168 ml) drop wise at 0° C. The mixture was stirred at 25° C. for 1 h. To the reaction mixture was added aq. saturated NaHCO3, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give crude of 2-bromo-1-[3-(2-hydroxyethyl)phenyl]ethanone as colorless oil. This compound was used for the next reaction without further purification.
Reaction SMILES: C1(Cl)C(Cl)=C(Cl)C(=O)C(=O)C=1Cl.[Br:13][C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][CH2:23]3)=[N:18][N:17]2[C:33]=1[CH:34]1[CH:39]=[CH:38][N:37](C(OCC)=O)[N:36]=[CH:35]1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.ClCCl>[Br:13][C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][CH2:23]3)=[N:18][N:17]2[C:33]=1[C:34]1[CH:39]=[CH:38][N:37]=[N:36][CH:35]=1
Reactant: CCOC(=O)N1C=CC(c2c(Br)nc3ccc(N4CCC(N5CCCC5)CC4)nn23)C=N1
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Brc1nc2ccc(N3CCC(N4CCCC4)CC3)nn2c1-c1ccnnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
0.101 g of ortho-chloranil (0.41 mmol) in solution in 1 ml of toluene is added to a mixture of 0.16 g (0.32 mmol) of ethyl 4-[2-bromo-6-(4-pyrrolidin-1-ylpiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl]-4H-pyridazine-1-carboxylate in 4 ml of chloroform. The mixture is stirred at ambient temperature for 1 hour and then diluted with 40 ml of dichloromethane. The solution is washed with 2 ml of a 2N aqueous solution of sodium hydroxide and then with a saturated solution of sodium chloride. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure after the addition of silica gel. The evaporation residue is loaded onto a silica gel column and the product is purified by chromatography on a silica gel column, elution being carried out with a mixture of 0 to 10% of methanol in dichloromethane. 0.080 g of product is thus isolated.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([N:11]3[CH2:16][CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[ClH:27]>O>[ClH:27].[CH3:1][C:2]1[C:3]2[N:4]([C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Cc1nccn2c(N3CCN(C(=O)OCc4ccccc4)CC3)ncc12
Agent: Cl
Solvent: O
Product: Cc1nccn2c(N3CCNCC3)ncc12
Yield: 91.8 %

Procedure:
Benzyl 4-(8-methylimidazo[1,5-a]pyrazin-3-yl)piperazine-1-carboxylate (486 mg) in 37% hydrochloric acid (97 mmol, 8 ml) was stirred at room temperature for two hours. Then water (16 ml) was added and the mixture washed twice with diethyl ether. The aqueous layer was concentrated in vacuo and co-evaporated with toluene and ethanol to give 8-methyl-3-(piperazin-1-yl)imidazo[1,5-a]pyrazine hydrochloride (322 mg).
Reaction SMILES: [C:1]1([N:7]2C(C([O-])=O)=CN=C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(OC(=O)CBr)(=O)C.Br[CH2:31][C:32]([NH:34][C:35]1[N:36]=[C:37]([N:53]([CH3:55])[CH3:54])[N:38]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:39]=1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:33].NC1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[CH3:54][N:53]([CH3:55])[C:37]1[N:38]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[C:35]([NH:34][C:32](=[O:33])[CH2:31][NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:36]=1
Reactant: O=C([O-])c1cncn1-c1ccccc1
Reactant: CN(C)c1nc(NC(=O)CBr)c(C(=O)OC(C)(C)C)n1-c1ccccc1
Agent: CC(=O)OC(=O)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)c1nc(NC(=O)CNc2ccccc2)c(C(=O)OC(C)(C)C)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.5 %

Procedure:
The 1-phenyl-1H-imidazole-5-carboxylate (1 equivalent (eq), 0.33 mmol) and triethylamine (2 eq, 0.66 mmol) were dissolved in DCM (5 mL) and bromoacetyl acetate (1.5 eq, 0.49 mmol) was added dropwise. The solution was stirred for 3 hours at room temperature. Then, the reaction was quenched with K2CO3 (aqueous (aq)) (1 M, 25 mL) and extracted with iPr2O. The organic layers were pooled, dried over Mg2SO4, filtered and evaporated. The residue was used directly without any further purification in the next step. The tert-butyl 4-[(bromoacetyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate (1 eq) and aniline (2.5 eq) were dissolved in DMF (5 mL) and heated to 100° C. for 1 hour. The solution was evaporated and K2CO3(aq) (1 M, 25 mL) was added. The reaction mixture was subsequently extracted several times with i-Pr2O. The organic phases were pooled, dried over MgSO4, filtered and evaporated. Eventually the residue was purified by preparatory HPLC, which afforded the desired product.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:9](O)=[O:10])(=[O:5])=[O:4])[CH3:2].ClC1C=C(Cl)C=CC=1C[NH:26]CCNCC>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:9]([NH2:26])=[O:10])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(OC)c(C(=O)O)c1
Reactant: CCNCCNCc1ccc(Cl)cc1Cl
Product: CCS(=O)(=O)c1ccc(OC)c(C(N)=O)c1

Procedure:
By following general method B using 0.9 g. of 3-ethylsulfonyl-6-methoxybenzoic acid and 0.9 g. of N-(2',4'-dichlorophenylmethyl)-N'-ethylethylenediamine, 1.5 g. of N-[2-(N'-2',4'-dichlorophenylmethyl)-N'-ethylamino)ethyl]-3-ethylsulfonyl-6-methoxybenzamide was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:17][CH:18]([CH3:20])[CH3:19])=[C:4]([C:14](O)=[O:15])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]=1[Br:7].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1.Cl>C1COCC1>[Br:1][C:2]1[C:3]([O:17][CH:18]([CH3:20])[CH3:19])=[C:4]([C:14]([NH:33][C:34]2[NH:38][N:37]=[N:36][N:35]=2)=[O:15])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]=1[Br:7]
Reactant: Nc1nnn[nH]1
Reactant: CC(C)Oc1c(Br)c(Br)n(-c2ccccc2)c1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Oc1c(Br)c(Br)n(-c2ccccc2)c1C(=O)Nc1nnn[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A solution of 4,5-dibromo-3-(1-methylethoxy)-1-phenyl-1H-pyrrole-2-carboxylic acid (2.0 g, 0.005 moles) and 1,1'-carbonyldiimidazole (0.8 g, 0.005 moles) in THF (25 mL) is heated under argon to reflux. After 1 hour, 5-aminotetrazole (0.4 g, 0.005 moles) is added. After 2.5 hours, the mixture is stirred into ice water (250 mL) and acidified with dilute HCl. The precipitate is filtered off, rinsed with water and dried. Recrystallization from methyl t-butyl ether gave the pure product (0.8 g); mp 184° C. (dec).
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:33][CH:32]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:33][CH:32]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2c(-c3ccnc(-c4ccc(Oc5ccccc5)cc4)c3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: Cc1cc(O)cc(-c2c(-c3ccnc(-c4ccc(Oc5ccccc5)cc4)c3)cnn2CC#N)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (56.7 mg, 0.12 mmol) prepared in Example 42 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL) and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (34 mg, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][CH:25]1[CH2:30][NH:29][CH2:28][CH2:27][N:26]1[C:31]1[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH2:22][N:29]3[CH2:28][CH2:27][N:26]([C:31]4[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=4)[CH:25]([CH3:24])[CH2:30]3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4cccc(C)c4)C(C)C3)nn2-c2ccccc2)cc1

Procedure:
120 mg (89%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.261 mmol), 2-methyl-1-m-tolylpiperazine (50 mg, 0.261 mmol), DIPEA (0.068 mL, 0.392 mmol) and NaBH(OAc)3 (166 mg, 0.783 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:17]([NH:19][CH:20]([C:22]1[N:23]=[CH:24][C:25]2[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:29]=[CH:28][C:26]=2[N:27]=1)[CH3:21])[CH3:18].CCN(C(C)C)C(C)C.CCCCO>CCOC(C)=O>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([N:19]([CH2:17][CH3:18])[CH:20]([C:22]4[N:23]=[CH:24][C:25]5[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:29]=[CH:28][C:26]=5[N:27]=4)[CH3:21])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: CCNC(C)c1ncc2c(ccn2COCC[Si](C)(C)C)n1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCN(c1nccc(Nc2cc(C3CC3)[nH]n2)n1)C(C)c1ncc2c(ccn2COCC[Si](C)(C)C)n1
Temperature: 115 °C
Yield: 80 %

Procedure:
A vial was charged with 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-pyrimidin-4-amine (60 mg, 0.25 mmol), N-ethyl-1-(5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)ethanamine (367.0 mg, 1.14 mmol), DIPEA (1.3 mL) and n-BuOH (3.5 mL), sealed and heated at 115° C. for 96 h. The reaction mixture was poured into EtOAc, and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2chromatography to afford 103.9 mg (52.35%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-ethyl-N2-(1-(5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)ethyl)pyrimidine-2,4-diamine as a racemic mixture. MS (ESI) m/z: 520.3 [M+1]+.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]O.C1OC2C=CC(C[Cl:21])=CC=2O1>CCOCC>[CH3:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][Cl:21]
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: COc1ccccc1CO
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COc1ccccc1CCl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
16.8 ml of thionyl chloride are added dropwise, over the space of approximately 30 min, to 10 ml of 2-methoxybenzyl alcohol (Fluka, Buchs, Switzerland) and 53.76 g of diisopropylaminomethylpolystyrene (polyhunig base, see Ex. 44a)) in 200 ml of abs. ether. After the mixture has been stirred at 0° C. for a further 1.5 h, it is filtered with suction and the filtrate is concentrated on a RE and under HV. The residue is purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 6:1). TLC Rf (hexane:ethyl acetate=4:1)=0.5. 1H-NMR (200 MHz, CDCl3): 7.42-7.24 (m, 2H); 7.0-6.84 (m, 2H); 4.68 (s, 2H); 3.9 (s, 3H).