Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].[O:31]1[C:36]2[CH:37]=[CH:38][C:39]([CH:41]=O)=[CH:40][C:35]=2[O:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.ClCCl>[O:31]1[C:36]2[CH:37]=[CH:38][C:39]([CH2:41][N:21]3[CH2:20][CH2:19][C:18]([CH2:17][N:15]([CH3:16])[C:8]4[N:7]=[C:6]([NH2:30])[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:23][CH2:22]3)=[CH:40][C:35]=2[O:34][CH2:33][CH2:32]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc2nc(N(C)CC3(c4ccccc4)CCN(Cc4ccc5c(c4)OCCO5)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 (250 mg) and 1,4-benzodioxan-6-carboxaldehyde (105 mg) in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (140 mg) in one portion. The mixture was stirred at room temperature for two days. Aqueous NaOH (1N, 5 ml) was added and stirring was continued for one hour. The product was isolated by extraction with dichloromethane and purified by flash chromatograpy, to yield N2-[1-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-phenyl-piperidin-4-ylmethyl]-6,7-dimethoxy-N2-methyl-quinazoline-2,4-diamine 16, MS: 556 ([M+H]+). Treatment of the product with HCl in methanol/ethyl acetate gave 320 mg of the dihydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([CH3:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([C:17]([O:19][CH3:20])=[O:18])[C:4]=2[CH:3]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl.O>O1CCCC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([CH3:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:17]([O:19][CH3:20])=[O:18])([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[C:4]=2[CH:3]=1
Reactant: CN(C)CCCl
Reactant: COC(=O)C1c2ccccc2N(C)c2ccc(Cl)cc21
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(CCN(C)C)c2ccccc2N(C)c2ccc(Cl)cc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
3.9 gm of 2-chloro-9-methoxycarbonyl-10-methyl-acridane were dissolved in 10 cc of tetrahydrofuran and 5 cc of hexamethyl phosphortriamide and the solution was heated to 45°C and 3.4 gm of potassium tert.-butylate were added thereto. After stirring the mixture for 1 hour at 45°-47°C, 4.5 gm of β-dimethylaminoethyl chloride were added thereto and the mixture was stirred for 16 hours at 46°-48°C. After cooling the mixture, 150 cc of water were added and the mixture was extracted with ether. The organic phases were washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to dryness to obtain 4.2 gm of raw 2-chloro-9-methoxycarbonyl-9-(β-dimethylaminoethyl)-10-methyl-acridane.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.Br[CH2:31][CH2:32][OH:33].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][N:25]([CH2:31][CH2:32][OH:33])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCNC2)c2cnccc12
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCN(CCO)C2)c2cnccc12
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 1-({5-chloro-1-[(3R)-(pyrrolidin-3-yl)]-1H-benzo[d]imidazol-2-yl}methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (300 mg, 0.70 mmol) in 5 mL of DMF was added 2-bromoethanol (173 mg, 2.1 mmol) and Cs2CO3 (682 mg, 2.1 mmol). The mixture was heated to 70° C. and stirred overnight. The mixture was filtered and then purified by preparative-HPLC to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc(N)cc1
Yield: 63.1 %

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 1-(4-nitrophenyl)ethanone (6 g, 36.36 mmol, 1.00 equiv) in ethanol (100 mL), water (15 mL). This was followed by the addition of NH4Cl (3.85 g, 72.64 mmol, 2.00 equiv) in several batches. To this was added Fe (10.18 g, 181.79 mmol, 5.00 equiv) in several batches, while the temperature was maintained at reflux. The resulting mixture was heated to reflux for 2 h. The solids were filtered out and the resulting filtrate was concentrated under vacuum. The residue was diluted with 50 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.1 g (60%) of 1-(4-aminophenyl)ethanone as a yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[NH:6])[NH2:5].[C:7](OC)(=[O:13])[CH2:8][C:9](OC)=[O:10].C[O-].[Na+]>CO>[CH3:2][O:3][C:4]1[N:5]=[C:9]([OH:10])[CH:8]=[C:7]([OH:13])[N:6]=1
Reactant: COC(=N)N
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(O)cc(O)n1
Temperature: 25 °C
Yield: 109.5 %

Procedure:
In a sealed tube O-methylisourea hydrochloride (3.0 g, 27 mmol) and dimethyl malonate (3.1 mL, 27 mmol) were dissolved in 30% w/v solution of sodium methoxide in methanol. The reaction mixture was refluxed for four hours before being allowed to cool to ambient temperature overnight. The resultant white precipitate was filtered and dried in vacuo yielding 4.2 g (quantitative yield) of the title compound.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[CH:10]=[C:9]([Br:17])[CH:8]=1.CN([CH:21]=[O:22])C.O>CCOCC>[Br:17][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[CH:10]=1)[CH:21]=[O:22]
Reactant: COCOc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COCOc1cc(Br)cc(C=O)c1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
n-BuLi (8.34 mL of a 1.6 M solution in Et2O, 13.34 mmol) was added dropwise to a solution cooled to −78° C. of 1,3-dibromo-5-methoxymethoxy-benzene (3.59 g, 12.13 mmol) in anhydrous Et2O (40 mL) under a nitrogen atmosphere. The solution was aged at −78° C. for 45 m, anhydrous DMF (1.03 mL, 13.34 mmol) was added, and the reaction mixture was slowly warmed to RT. The mixture was poured into H2O (50 mL), and the aqueous phase was extracted with Et2O (2×75 mL). The combined organic fractions were washed with brine (50 mL) and dried over anhydrous MgSO4. The solvents were evaporated, and the remaining oil was purified by flash chromatography over silica gel (0% to 10% EtOAc/hexanes) to afford 2.18 g (74%) of 3-bromo-5-methoxymethoxy-benzaldehyde (113b).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18](O)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[ClH:33].O>C(O)CCC>[ClH:33].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15](=[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(Br)cc1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: Brc1ccc(C=CCCN2CCC(=C(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A mixture of 10 g (0.02 mole) of α-(p-bromophenyl)-4-(α-hydroxy-α-phenylbenzyl)-1-piperidinebutanol, 150 ml of conentrated HCl, 150 ml of water and 50 ml of n-butanol was heated for 2 hours at reflux. The solvent was removed under vacuum, and the remaining residue was recrystallized from ethyl acetate to give the desired product, M.P. 215°-217° C. Alternatively, the title compound may be prepared by a similar acid dehydration reaction of α-(p-bromophenyl)-4-(diphenylmethylene)-1-(piperidinebutanol hydrochloride, M.P. 215°-217° C.
Reaction SMILES: [ClH:1].O[C@@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[S:8][CH2:9][C:10]([OH:12])=[O:11].[Cl-].[Na+]>O>[Cl:1][C@@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[S:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: Cl
Reactant: O=C(O)CS[C@@H]1CCC[C@H]1O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CS[C@@H]1CCC[C@H]1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Concentrated hydrochloric acid (50 ml) was added to the product of Example 3 (8.4 g) and stirred for 20 hours at room temperature. The reaction mixture was poured into a solution of water (50 ml) containing sodium chloride and extracted three times with 75 ml of diethyl ether. The combined diethyl ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The product was purified by silica gel chromatography, and the structure was supported by NMR spectroscopy. The NMR spectrum showed a small amount of the cis-product as well.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 78.4 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 04 mmol), (prepared as described for the starting material in Example 10), was reacted with 5-hydroxy-2-methylindole (74 mg, 0.5 mol) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (137 mg, 79%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:6](=O)[CH3:7])[CH3:5].O.[NH2:10][NH2:11]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:6](=[N:10][NH2:11])[CH3:7])[CH3:5]
Reactant: CON=C(C)C(C)=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CON=C(C)C(C)=NN
Yield: 29.8 %

Procedure:
3 g (0.026 mol) of butane-2,3-dione mono-(O-methyl oxime) are heated at 60° C. in 20 ml of ethanol with 2.6 g (0.052 mol) of hydrazine hydrate for 1 hour. The reaction mixture is poured onto water and extracted with diethyl ether, the organic phase is dried over sodium sulphate and the solvent is distilled off in vacuo. The residue is stirred with petroleum ether and the crystals are filtered off. 1 g (29.7% of theory) of 3-hydrazono-butan-2-one O-methyl oxime is obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:70][CH2:71][C:72]([NH2:74])=[O:73]>CN(C=O)C>[NH2:74][C:72](=[O:73])[CH2:71][NH:70][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:35]([CH3:36])=[C:27]([C:10]2[C:11]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]4[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=4[F:25])[C:12]=3[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:37][CH3:38])[N:9]=2)[CH:28]=1
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: NCC(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCC(N)=O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and glycinamide (11.1 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9 mg, 31%).
Reaction SMILES: [CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][C:15]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[N:8]2[C:17]([C:16]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:15]=2[CH3:14])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)NN(C2CCCCC2)C1=O
Reactant: Cc1ccc(C)c(C(=O)Cl)c1
Product: Cc1ccc(C)c(C(=O)N2N(C3CCCCC3)C(=O)C2(C)C)c1

Procedure:
2-Cyclohexyl-4,4-dimethyl-1,2-diazetidin-3-one and 2,5-dimethylbenzoyl chloride were used for a similar reaction and treatment as Example 96, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:20]([OH:22])=[S:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:22][C:20]([C:11]1[N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[C:18]2[C:13]([CH:12]=1)=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)=[S:21]
Reactant: Cc1ccc2c(c1)cc(C(O)=S)n2S(=O)(=O)c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=S)c1cc2cc(C)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 1-benzenesulfonyl-5-methylthioindole-2-carboxylic acid (3.5 g), sulfuric acid (10 ml) and methanol (10 ml) was heated under reflux for 12 hours. The reaction mixture was poured into ice-water and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane) to obtain 3.4 g of the desired product as a white crystal.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:8])([CH3:7])[CH2:4][O:5][CH3:6].[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O>C1(C)C=CC=CC=1>[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]=[N:2][C:3]([CH3:8])([CH3:7])[CH2:4][O:5][CH3:6]
Reactant: COCC(C)(C)N
Reactant: O=Cc1ccc(F)cc1F
Agent: Cl
Solvent: Cc1ccccc1
Product: COCC(C)(C)N=Cc1ccc(F)cc1F
Yield: 115.8 %

Procedure:
To a solution of the obtained 2-amino-2-methyl-1-methoxypropane hydrochloride (422 mg, 2.08 mmol) in toluene (7 ml) was added 2,4-difluorobenzaldehyde (310 mg, 2.18 mmol) and stirred under reflux using a Dean-Stark trap to remove water for 1 hour. Then triethylamine (1.0 ml) was added to the mixture and stirred for 6 hours. The precipitated hydrochloride was filtered off and the solvent was evaporated to give the crude title compound (547.5 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:5][N:6]([CH3:8])[CH3:7])[CH:3]=O.CC(N)C.[NH2:14][CH2:15][CH2:16][CH2:17][Si:18]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>>[CH3:1][C:2]([CH3:9])([CH2:5][N:6]([CH3:8])[CH3:7])[CH:3]=[N:14][CH2:15][CH2:16][CH2:17][Si:18]([O:25][CH2:26][CH3:27])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24]
Reactant: CN(C)CC(C)(C)C=O
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: CC(C)N
Product: CCO[Si](CCCN=CC(C)(C)CN(C)C)(OCC)OCC

Procedure:
13.57 g 2,2-dimethyl-3-dimethylaminopropanal, 7.45 g 2-propanamine and 22.14 g 3-aminopropyltriethoxysilane were reacted according to the general manufacturing procedure (iminosilanes). Yield: 32.3 g of a clear, colorless oil having an amine content of 5.97 mmol N/g and a purity of 98%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=O)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=N[CH2:40][CH2:41][CH2:42][N:43](C)C)C.ON1C2C=CC=CC=2N=N1.C1(N)CC1>CN(C)C=O.O>[CH:42]1([NH:43][C:22]([C:21]2[CH:20]=[C:19]([S:16]([N:14]3[C:13]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:12][C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:15]3)(=[O:18])=[O:17])[CH:27]=[CH:26][CH:25]=2)=[O:24])[CH2:40][CH2:41]1
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(=O)O)c2)c1)C(=O)OC(C)(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(=O)NC3CC3)c2)c1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution (5 mL) of 3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoic acid (150 mg) in N,N-dimethylformamide were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (92 mg), 1-hydroxy-1H-benzotriazole (73 mg) and cyclopropylamine (27 mg) at room temperature. After stirring at the same temperature for 30 min, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as a colorless amorphous (yield 162 mg, quantitative).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[S:21][CH3:22].[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[S:21][CH3:22]
Reactant: CCOC(=O)CBr
Reactant: CSc1cc(C(C)C)ccc1-n1c(=O)[nH]c2c(Cl)nc(C)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(=O)n(-c2ccc(C(C)C)cc2SC)c2nc(C)nc(Cl)c21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 97.4 %

Procedure:
In 5 ml of dimethylformamide, 0.70 g of 6-chloro-9-(4-isopropyl-2-methylthiophenyl)-2-methyl-8,9-dihydropurin-8-one was dissolved, and 80 mg of sodium hydride in an oil was added thereto with ice-cooling, followed by stirring for 40 minutes. Subsequently, 0.39 g of ethyl bromoacetate was added thereto, and the reaction mixture was warmed up to room temperature and was stirred for 20 minutes. Water was poured into the reaction mixture. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and was then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to yield 0.85 g of ethyl 2-[6-chloro-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetate as an oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]3[N:15]([CH3:28])[C:16](=[O:27])[N:17]([CH2:18][C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]#[N:22])[C:9]=23)[CH2:3]1.[C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br)#[N:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]3[N:15]([CH3:28])[C:16](=[O:27])[N:17]([CH2:18][C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]#[N:22])[C:9]=23)[CH2:3]1)#[N:30]
Reactant: Cc1cc(N2CCC[C@@H](N)C2)c2c(n1)n(C)c(=O)n2Cc1ccccc1C#N
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCC[C@@H](NCc3ccccc3C#N)C2)c2c(n1)n(C)c(=O)n2Cc1ccccc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
15.1 g (R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile (40.1 mmol) was added in a reaction bottle, to which 30 mL DMF was added. 8.6 g 2-cyano-benzyl bromide (44 mmol) and 11 g potassium carbonate (80 mmol) were added at 0° C. The reaction was continued for 3 h by stirring at room temperature. The reaction solution was extracted with dichloromethane, and washed with saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, and evaporated to dryness to afford 19.68 g crude product with a yield of 99.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][CH:8]=[C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([I:19])[CH:17]=3)[C:12](=[O:20])[NH:11][C:10]2=[O:21])=[CH:4][C:3]=1[OH:24].C(N(CC)CC)C.[CH3:32][N:33]([CH2:35][C:36](O)=[O:37])[CH3:34].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:24][C:3]1[CH:4]=[C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)[CH:22]=[CH:23][C:2]=1[NH:1][C:36](=[O:37])[CH2:35][N:33]([CH3:34])[CH3:32]
Reactant: CN(C)CC(=O)O
Reactant: Nc1ccc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
4-[(4-Amino-3-hydroxy-benzylamino)-methylene]-6-iodo-4H-isoquinoline-1,3-dione (89 mg, 0.20 mmol) is dissolved in N,N-dimethylformamide (3.56 mL), followed by addition of triethylamine (0.236 mL, 1.69 mmol), dimethylamino-acetic acid (30.58 mg, 0.30 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (42.6 mg, 0.22 mmol) and 1-hydroxybenzotriazole (13.8 mg, 0.10 mmol). It is stirred at room temperature overnight. It is then evaporated to dryness, and the residue is washed with ether, and then acetonitrile to yield 21 mg (20%) of the title compound as a solid. MS (ESI) m/z 521 (M+H)+1
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1.Br[C:13]1[S:14][C:15]([C:19]2[C:20]([CH3:34])=[N:21][N:22]3[C:27]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:26][C:25]([CH3:33])=[N:24][C:23]=23)=[C:16]([Br:18])[N:17]=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[Br:18][C:16]1[N:17]=[C:13]([C:11]2[N:7]([CH3:6])[N:8]=[CH:9][N:10]=2)[S:14][C:15]=1[C:19]1[C:20]([CH3:34])=[N:21][N:22]2[C:27]([CH:28]([CH2:29][CH3:30])[CH2:31][CH3:32])=[CH:26][C:25]([CH3:33])=[N:24][C:23]=12
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Br)nc3Br)c(C)nn12
Reactant: Cn1cncn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nc2c(-c3sc(-c4ncnn4C)nc3Br)c(C)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
Under nitrogen atmosphere, add n-butyl lithium (2.5 M in hexane, 0.6 mL, 1.5 mmol) to a solution of 1-methyl-1,2,4-triazole (124.5 mg, 1 5 mmol) in THF (3 mL) at −78° C. and stir for 30 min. Add anhydrous zinc chloride (409 mg, 3 0 mmol), continue stirring for 30 min, warm up to room temperature and stir for 2 h. Add 3-(2,4-dibromo-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (229 mg, 0.5 mmol), followed by tetrakis(triphenylphosine)palladium (58 mg, 0.05 mmol) and reflux overnight. Cool to room temperature, dilute with ethyl acetate, and wash with saturated ammonia chloride. Dry the organic portion over sodium sulfate, filter, and concentrate to a residue. Purify the crude material by flash chromatography, eluting with hexanes:ethyl acetate (10:2.5) to give the title compound as a yellow foam (77 mg). MS (APCI) m/z (79Br) 460.4 (M+1)+.