Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[C:24]1([C:22]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[CH:3]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:19])[F:20])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: BrCc1ccncc1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccncc2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-Bromomethyl-pyridine following the procedure of Example 478: MS (ESI) m/z 485.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Mg].C(=O)([O:15][CH2:16][CH3:17])OCC.Cl>C(OCC)C>[CH2:2]([C:16]([CH2:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[OH:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCBr
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCCCCC(O)(CCCCCCCC)CCCCCCCC
Temperature: 30 °C
Reaction time: 1 h

Procedure:
This compound may be prepared in the following manner. Three moles of 1-bromooctane are slowly added to 3 moles of magnesium turnings in 0.6 liters of anhydrous ethyl ether (nitrogen atmosphere). One mole of diethyl carbonate in 0.151 anhydrous ethyl ether is slowly added to the mixture. The mixture is stirred for one hour at 30° C., then the mixture is slowly poured into 1.8 liters of a cold 10% HCl solution. The organic layer is dried with magnesium sulfate and the ethyl ether is evaporated off to give tri-n-octylcarbinol. One mole of tri-n-octylcarbinol is added to a mixture of 0.2 liters of methylene chloride and 0.32 moles calcium chloride. Approximately 1.5 moles of HCl gas is slowly bubbled through the solution. The product mixture is then washed with 1 liter of a 10% sodium carbonate solution. The organic layer is dried with magnesium sulfate and the methylene chloride is evaporated off. One mole of tri-n-octylmethylchloride is added to 0.75 liters of methylene chloride and the solution is blanketed with nitrogen and is cooled to 0° C. 0.33 moles of trimethylaluminum is then added and the mixture is allowed to warm to room temperature. The mixture is slowly quenched with 50 ml of water followed by washing with 1 liter of a 10% HCl solution. The organic layer is dried with magnesium sulfate and the solvent is evaporated to give tri-n-octylmethylmethane.
Reaction SMILES: Br[C:2]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CO>[O:17]([C:14]1[CH:15]=[CH:16][C:11]([C:2]2([CH:28]3[CH2:29][NH:30][CH2:31][CH2:32][N:27]3[CH2:26][CH2:25][OH:24])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]2=[O:10])=[CH:12][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1NC(=O)C(Br)(c2ccc(Oc3ccccc3)cc2)C(=O)N1
Reactant: OCCN1CCNCC1
Solvent: CO
Product: O=C1NC(=O)C(c2ccc(Oc3ccccc3)cc2)(C2CNCCN2CCO)C(=O)N1
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A solution of 5-Bromo-5-(4′-phenoxyphenyl)barbituric Acid (50 mg) in 0.2 ml of methanol is added dropwise with a solution of N-(2-hydroxyethyl)piperazine (52 mg) in 0.6 ml of methanol and the mixture is stirred for 2 hours. The white precipitate is recovered by filtration and dried under vacuum at 60° C. overnight. 42.6 mg of the product are obtained, m.p. >240° C. 1H-NMR in d6-DMSO: 2.2-2.45 ppm (m, 6H); 2.55 ppm (m, 4H); 3.45 ppm (m, 2H); 4.4 ppm (t, 1H); 6.9-7.7 ppm (m, 9H); 11.6 ppm (s, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][C:7]=1[CH3:22].[CH2:23]([NH:27][CH2:28][CH2:29][CH2:30]C)[CH2:24][CH2:25]C>>[CH2:23]([N:27]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][C:7]=1[CH3:22])[CH2:28][CH2:29][CH3:30])[CH2:24][CH3:25]
Reactant: Cc1cc(-c2cn3cccc(C)c3n2)ccc1OCCCCl
Reactant: CCCCNCCCC
Product: CCCN(CCC)CCCOc1ccc(-c2cn3cccc(C)c3n2)cc1C

Procedure:
The product of Step C (3.0 g) and dibutylamine (10.0 mL) were heated at reflux temperature for 18 hours. The reaction was evaporated and the residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:30][CH3:31])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]>C(OCC)(=O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:30][CH3:31])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCN4CCOCC4)cc23)c1
Solvent: CCOC(C)=O
Product: CCc1cccc(Nc2ncnc3cc(OC)c(OCCCN4CCOCC4)cc23)c1
Temperature: 67.5 °C
Yield: 83 %

Procedure:
Into a three liter three necked round bottomed flask equipped with a mechanical stirrer, reflux-condenser and thermometer socket were charged ethyl acetate (2000 ml), followed by N-(3-ethynylphenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4-quinazolinamine (25 g) obtained from the process described in the above given Example-(1). The reaction mass was slowly heated to 65-70° C., so that the solid material completely dissolved and carbon treatment was given and filtered the reaction mass. The filtrate was transferred into another round-bottomed flask and slowly cooled to 10-15° C. and maintained for 30 minutes at that temperature. The crystalline mass was filtered and after washing the cake with chilled ethyl acetate dried to get 20.95 g of N-(3-ethylphenyl)-6-(3-morpholino propoxy)-7-methoxy-4-quinazolinamine as a white crystalline solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=2)[N:4]([CH3:14])[N:3]=1.C([Mg]Cl)(C)C.[CH2:20]([Sn:24]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])Cl)[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH3:14])[N:3]=[C:2]2[Sn:24]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:20][CH2:21][CH2:22][CH3:23])([CH3:13])[CH3:12]
Reactant: CC(C)c1ccc2c(c1)c(I)nn2C
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C(C)C)cc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-iodo-5-isopropyl-1-methyl-1H-indazole (0.3 g, crude) in 100 mL of dry THF at −16° C. under nitrogen was added i-PrMgCl (0.69 mL, 1.38 mmol, 2M in THF) drop-wise. Then the mixture was stirred at −16° C. for 20 minutes. Tributylchlorostannane (0.39 g, 1.2 mmol) was added slowly and the mixture was stirred at room temperature for 2.5 hours. The solution was quenched by 40 mL of water, extracted with ethyl acetate (2×100 mL), washed with water (2×50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was evaporated under reduced pressure to give crude 5-isopropyl-1-methyl-3-(tributylstannyl)-1H-indazole as an oil, which was used into next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:21])[C:12](=[O:20])[C:13]([CH3:19])=[CH:14][C:15]=1[C:16]([OH:18])=[O:17].O[N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29].C1CCC(N=C=NC2CCCCC2)CC1>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:21])[C:12](=[O:20])[C:13]([CH3:19])=[CH:14][C:15]=1[C:16]([O:18][N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29])=[O:17]
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1cc(C(=O)O)c(Nc2ccc(I)cc2F)n(C)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: Cc1cc(C(=O)ON2C(=O)CCC2=O)c(Nc2ccc(I)cc2F)n(C)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
A 250 ml round-bottom flask was charged with 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2.0 g, 5.00 mmol) and dioxane (100 mL). To the resulting suspension was added 1-hydroxypyrrolidine-2,5-dione (0.63 g, 5.5 mmol) and DCC (0.63 g, 5.5 mmol). The reaction mixture was stirred at room temperature for 16 hours and filtered. The residue was concentrated under reduced pressure and purified by flash chromatography (Biotage system) using a gradient of EtOAc (0-50%) in hexane to afford the title product (2.1 g, 85%).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][NH2:45])[CH:34]=1>O1CCCC1>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:10])[CH:29]=[CH:28][CH:27]=1
Reactant: NCCCCCCc1cccnc1
Reactant: COc1cccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Solvent: C1CCOC1
Product: COc1cccc(C(=C/C=C/C(=O)NCCCCCCc2cccnc2)c2cccc(OC)c2)c1
Yield: 76.4 %

Procedure:
As in Example 134. a solution of (E)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (3.0 g) and 3-pyridinehexanamine (1.25 g) in tetrahydrofuran (20 mL) was stirred for 1.5 hours at room temperature and was then worked up in the usual manner. The product was purified by HPLC (ethyl acetate) and triturated with ether to give 2.5 g of (E)-5,5-bis(3-methoxyphenyl)-N-[6-(3-pyridinyl)hexyl]-2,4-pentadienamide mp 66°-70° C. Crystallization of a portion from ethyl acetate-hexane afforded of the pure amide, mp 71°-72° C. Anal. Calculated for C30H34N2O3 : C, 76.57; H, 7.28; N, 5.98 Found: C, 76.39; H, 7.28; N, 5.90.
Reaction SMILES: C([O:14][C:15]1[C:16]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:33][C:17]=2[C:18]([O:25][S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[F:44][C:41]1[CH:40]=[CH:39][C:38]([CH2:37][N:34]2[C:35](=[O:36])[C:16]3[C:15]([OH:14])=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[N:23]4)=[C:18]([O:25][S:26]([C:29]([F:30])([F:31])[F:32])(=[O:28])=[O:27])[C:17]=3[CH2:33]2)=[CH:43][CH:42]=1
Reactant: O=C1c2c(c(OS(=O)(=O)C(F)(F)F)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2c(c(OS(=O)(=O)C(F)(F)F)c3cccnc3c2O)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 46 (28 mg, 0.045 mmol) dissolved in dichloromethane (2 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was triturated with diethyl ether/hexane (1/1) to afford trifluoro-methanesulfonic acid 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 274, (13.7 mg, 0.03 mmol, 67%) as a yellow solid: 1H NMR (CDCl3) δ 9.0 (d, 1H), 8.4 (d, 1H), 7.7 (dd, 1H), 7.3 (dd, 2H), 7.1 (t, 2H), 4.8 (s, 2H), 4.6 (s, 2H); MS: 457 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[NH:10][C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[I:17]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:1]([C:8]1[C:13](=[O:14])[C:12]([I:17])=[C:11]([CH3:15])[NH:10][C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1c(C)[nH]c(C)cc1=O
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCc1c(C)[nH]c(C)c(I)c1=O
Temperature: 70 °C
Reaction time: 7 h

Procedure:
To a solution of 3 (100 mg, 0.45 mmol) in acetonitrile (2.5 mL) was added ceric ammonium nitrate (25 mg, 0.045 mmol) followed by iodine (126 mg, 0.495 mmol). The reaction mixture was stirred at 70° C. under nitrogen for 7 h. After completion of the reaction, the mixture was cooled to room temperature and treated with an ice-cold aqueous solution of sodium thiosulfate with stirring. The mixture was extracted with portions of ethyl ether. The combined organic phase was dried over anhydrous MgSO4 and concentrated under diminished pressure to afford a crude residue. The residue was purified by chromatography on a silica gel column. Elution with hexane/ethyl acetate gave 3-heptyl-5-iodo-2,6-dimethylpyridin-4(1H)-one (5) as a light yellow solid: yield 119 mg (74%); silica gel TLC Rf 0.45 (1:1 hexane/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 0.88-0.91 (m, 3H), 1.29-1.35 (m, 10H), 2.33 (s, 3H) and 2.54-2.56 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([CH2:23][N:13]2[CH:14]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[CH:11][C:12]2=[O:15])=[CH:21][CH:22]=1
Reactant: COc1ccc(-c2ccc(=O)[nH]c2)cc1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)nc3)c2)cc1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
5-(4-Methoxyphenyl)pyridine-2(1H)-one (4.20 mmol, 0.85 g), 2-chloro-5-(chloromethyl)pyridine (1.5 eq, 6.30 mmol, 1.02 g), K2CO3 (2 eq, 8.40 mmol, 1.17 g) in THF (10 mL) were heated at 70° C. for 2 hours. Then, the reaction was cooled to room temperature. The suspension was filtered off and the filtrate was evaporated under reduced pressure. The residue was puridied by short open column chromatography CH2Cl2/MeOH(NH3)sat. 1% yielding 1-((6-chloropyridin-3-yl)methyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one as white solid (1.04 g, 75%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](O)[N:5]2[CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[N:11]=[C:4]2[CH:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[N:5]2[CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[N:11]=[C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: CN(C)Cc1cn2c(O)nc(Cl)cc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CN(C)Cc1cn2c(Cl)nc(Cl)cc2n1

Procedure:
In analogy to Example 11A, 30 mg (18% of theory) of the product are obtained from 131 mg (0.58 mmol) of 7-chloro-2-[(dimethylamino)methyl]imidazo[1,2-c]pyrimidin-5-ol (Example 98A) by reaction with phosphoryl chloride.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:18](=[O:29])[N:17]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=1)[C:16]2=[O:41])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([N:26]1[CH2:27][CH2:28][CH:23]([N:19]2[C:20]3[C:15](=[CH:14][C:13]([O:12][CH2:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)=[CH:22][CH:21]=3)[C:16](=[O:41])[N:17]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=3)[C:18]2=[O:29])[CH2:24][CH2:25]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCNCC3)c2=O)cc1OC
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCN(C(C)=O)CC3)c2=O)cc1OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
0.14 g of acetyl chloride is added to a mixture of 0.6 g of 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(piperidin-4-yl)quinazoline-2,4(1H,3H)-dione obtained according to stage 1.6 and 0.24 g of NEt3 in 10 ml of DCM cooled to 0° C. The mixture is stirred at AT overnight. It is washed twice with a saturated NH4Cl solution and filtered, and then the filtrate is evaporated under reduced pressure to give 0.64 g of the expected product.
Reaction SMILES: CC(OC(=O)[NH:7][CH:8]([C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]([CH2:24][CH:25]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:29]3[CH:38]=[CH:39][CH:40]=[CH:41][C:28]=3[NH:27][C:26]2=[O:42])[CH2:16]1)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)C.[ClH:44]>C(OCC)(=O)C>[ClH:44].[NH2:7][CH:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]([CH2:24][CH:25]2[N:31]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:29]3[CH:38]=[CH:39][CH:40]=[CH:41][C:28]=3[NH:27][C:26]2=[O:42])[CH2:16]1)=[O:14]
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)N1CC(CC2N=C(c3ccccc3)c3ccccc3NC2=O)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CC(N)C(=O)N1CC(CC2N=C(c3ccccc3)c3ccccc3NC2=O)c2ccccc21

Procedure:
The procedure of Example 2 was carried out in which (1-[(3-[(2,3-dihydro-2-oxo-5-phenyl-1,4-benzodiazepin-3-yl)methyl]-2,3-dihydro-1H-indol-1-yl) carbonyl]-3-methylbutyl]-carbamic acid-1,1-dimethylethyl ester was reacted with excess HCl gas in ethyl acetate at 0° C. to give the title compound as a foam.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([OH:13])=[CH:6][C:5]=1[NH2:14])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23].O>CN(C)C=O>[CH2:23]([O:13][C:7]1[CH:6]=[C:5]([C:4]([C:1](=[O:3])[CH3:2])=[CH:9][C:8]=1[C:10](=[O:12])[CH3:11])[NH2:14])[CH:22]=[CH2:21]
Reactant: CC(=O)c1cc(C(C)=O)c(O)cc1N
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(N)c(C(C)=O)cc1C(C)=O

Procedure:
Treatment of the product of step (b) (1.5 g) with K2CO3 (1 equivalent) and allyl bromide (2 equivalents) in dimethylformamide (20 ml) at 70° C. for 21/2 hours followed by dilution with water at 70° C. afforded the sub-title product, as a pale yellow solid (83%) mp 131°-134°.
Reaction SMILES: Br[C:2]1[N:3]([CH3:23])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[CH3:23][N:3]1[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=[C:2]1[C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24]
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(C#C[Si](C)(C)C)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Yield: 100 %

Procedure:
2-(2-Bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 26) (52 mg), PdCl2dppf (10 mg), copper(I) iodide (2 mg), trimethylsilyl acetylene (0.11 mL) and triethylamine (0.2 mL) were heated in DMF (4 mL) at 80° C. for 1 hour under an inert atmosphere. The reaction mixture was concentrated in vacuo, EtOAc (20 mL)/MeOH (0.3 mL)/water (10 mL) added and the aqueous layer removed. The organic layer was dried (MgSO4), filtered, concentrated in vacuo, then purification by flash chromatography on silica eluting with 4% MeOH/DCM gave the title compound as a light brown solid (48 mg, 100%);
Reaction SMILES: [C:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14](/[C:18](/[CH3:25])=[CH:19]\[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>[Pd].C(O)C>[C:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]([CH3:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)/C=C(/C)c1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(C)c1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Yield: 100.5 %

Procedure:
A mixture of ethyl 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)crotonate [9 g, Reference Example 7(c)] and 5% palladium on charcoal (2.5 g) in ethanol (250 ml) was hydrogenated at room temperature and pressure overnight. The spent catalyst was removed by filtration through Celite and the filtrate was evaporated to give the title compound (9.1 g) as a colourless oil.
Reaction SMILES: CC([O-])(C)C.[K+].Cl[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[CH:15][S:16][C:9]=12.COC(=O)CC[S:22][C:23]1[CH:24]=[C:25]([O:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:26]([NH:29][C:30]2[S:31][CH:32]=[C:33]([CH2:35][CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)[N:34]=2)=[N:27][CH:28]=1>CS(C)=O>[O:49]([C:25]1[C:26]([NH:29][C:30]2[S:31][CH:32]=[C:33]([CH2:35][CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)[N:34]=2)=[N:27][CH:28]=[C:23]([S:22][C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[CH:14]=[CH:15][S:16][C:9]=23)[CH:24]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(CC3CCN(C(=O)OC(C)(C)C)CC3)cs2)c(Oc2ccccc2)c1
Reactant: Clc1ccnc2ccsc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2csc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Reaction time: 2 h
Yield: 97.1 %

Procedure:
Added potassium 2-methylpropan-2-olate (0.443 g, 3.95 mmol) to a solution of 7-chlorothieno[3,2-b]pyridine (0.268 g, 1.58 mmol) and tert-butyl 4-((2-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate (0.77 g, 1.32 mmol) in DMSO (8 mL). The reaction was stirred for two hours, then set aside to react at ambient temperature for 60 hours. The reaction was partitioned between ethyl acetate and saturated ammonium chloride. Washed the organic layer twice with water and brine, dried, and concentrated. The residue was purified by MPLC (Biotage) eluting with 1:1 hexane:ethyl acetate. The major UV active component with an Rf of 0.3 was collected and concentrated to afford the title compound (0.810 g, 97.4% yield) as a white powder: 1H NMR (CDCl3) δ 8.88 (s, 1H), 8.46 (d, 1H), 8.32 (s, 1H), 7.72 (d, 1H), 7.54 (d, 1H), 7.38 (t, 2H), 7.20 (t, 1H), 7.18 (s, 1H), 7.04 (d, 2H), 6.73 (d, 1H), 6.51 (s, 1H), 4.09 (m, 2H), 2.68 (m, 2H), 2.59 (d, 2H), 1.87 (m, 1H), 1.66 (m, 2H), 1.45 (s, 9H), 1.16 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:25])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[CH:3][C:4]([NH:6][CH2:7][CH2:8][OH:9])=[O:5]>[Pd].C(O)C>[CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][C:4]([NH:6][CH2:7][CH2:8][OH:9])=[O:5]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)NCCO
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)NCCO
Yield: 100.7 %

Procedure:
6.5 g of N-(3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoyl)-ethanolamine obtained in Example 1 was hydrogenated in the presence of a catalyst composed of palladium on carbon in 40 ml of ethanol. The ethanol layer was then separated from the catalyst and the solvent was distilled off to afford 6.7 g (yield 94%) of the title compound as a colorless oil.