Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O>[Cl:14][CH2:15][CH2:16][C:17]([C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:18]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: O=C(CCCl)c1ccc2[nH]c3ccccc3c2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a 90 ml solution of 5.0 g of carbazole and 4.2 g of 3-chloropropionyl chloride in nitromethane, 4.8 g of aluminum chloride was added portionwise, followed by stirring at 45° C. for 1 hour. The reaction mixture was poured over 100 ml of ice water, and the organic layer was separated and then washed by sequential additions of a 50 ml saturated aqueous sodium hydrogen carbonate solution and 50 ml of distilled water. After the mixture was dried over anhydrous sodium sulfate, the solvent was distilled off to yield a crystalline residue. The residue was collected by filtration and dried under reduced pressure to yield 4.8 g of the title compound as a light red crystal having a melting point of 148° to 151° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH:18]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([CH:18]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)CC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., trifluoroacetic acid (10 ml) was added to a methylene chloride (30 ml) solution of t-butyl 3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propionate (3.10 g, 7.43 mmol). The resulting mixture was stirred at room temperature for 2 hours. To the residue obtained by concentrating the reaction mixture was added toluene and the resulting mixture was concentrated. The residue thus obtained was recrystallized from ethyl acetate-hexane, whereby the title compound (2.29 g, 85%) was obtained as colorless needle crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.C1C(=O)N([Br:26])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1ccccc1-c1ccc(C)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1-c1ccc(CBr)cn1

Procedure:
Under nitrogen, the crude ethyl 2-(5-methyl-2-pyridinyl)benzoate from step 6 was treated with 1.7 g (9.5 mmol) of NBS and 160 mg (0.66 mmol) of benzoyl peroxide in 145 mL of anhydrous carbon tetrachloride at reflux for 2.5 h. The reaction was filtered under nitrogen and concentrated in vacuo to give crude ethyl 2-(5-bromomethyl-2-pyridinyl)benzoate; no purification was attempted.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([O:22][CH3:23])=[C:15]([O:24][CH3:25])[C:14]=1[O:26][CH3:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)(N)C(C)(C)N.Cl[CH2:37][CH2:38][CH2:39][CH2:40][OH:41].O1CCCCC1OC1CCCCO1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1.CCCCCC>[CH3:27][O:26][C:14]1[C:15]([O:24][CH3:25])=[C:16]([O:22][CH3:23])[C:17]([O:20][CH3:21])=[C:18]([CH3:19])[C:13]=1[CH:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:37][CH2:38][CH2:39][CH2:40][OH:41]
Reactant: COc1c(C)c(Cc2ccccc2)c(OC)c(OC)c1OC
Reactant: OCCCCCl
Agent: C1CCC(OC2CCCCO2)OC1
Agent: CC(C)(N)C(C)(C)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C)c(C(CCCCO)c2ccccc2)c(OC)c(OC)c1OC
Reaction time: 0.42 h
Yield: 68.9 %

Procedure:
A 3.1 ml (5.0 mmole) of n-butyllithium.hexane solution was added dropwise to 1.51 g (5.0 mmole) of 1-benzyl-2,3,4,5-tetramethoxy-6-methylbenzene and 0.83 ml (5×1.1 mmole) of 1,1,2,2-tetramethylethylenediamine dissolved in anhydrous tetrahydrofuran (15 ml), under an atmosphere of argon at -5° C. over the period of 5 minutes, followed by stirring at -5° to 0° C. for 25 minutes. Then, a solution of 0.96 g (5.0 mmole) of 4-chlorobutanol.tetrahydropyranyl ether in tetrahydrofuran (5 ml) was added to the mixed solution over the period of 5 minutes, followed by stirring for further 15 minutes under ice-cooling. Subsequently, the cooling bath was removed, and stirring was effected at room temperature for 20 minutes. The reaction solution was cooled with ice, and made acid by adding a 10% aqueous phosphoric acid solution, and the product was extracted with isopropyl ether. The organic layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate). The solvent was distilled off and the residue was dissolved in methanol (15 ml), followed by addition of 48 mg (5×1/20 mmole) of p-toluenesulfonic acid and stirring at 70° C. for 15 minutes. After cooling by standing at room temperature, the mixed solution was neutralized by adding an aqueous sodium hydrogen-carbonate solution, and the solvent was distilled off. Isopropyl ether and water were added to the residue to effect extraction. The isopropyl ether layer was washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residual solution was chromatographed on a silica gel column to perform purification (elution with isopropyl ether) to thereby give 1.29 g (69%) of 5-(2,3,4,5-tetramethoxy-6-methylphenyl)-5-phenylpentane-1-ol. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 14.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C1COCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: COc1cccc(N)c1
Solvent: C1CCOC1
Product: COc1cccc(NC(C(=O)O)c2ccccc2)c1
Yield: 98.9 %

Procedure:
A solution of 2-bromo-2-phenylacetic acid (0.5 g, 2.28 mmol) and 3-methoxyaniline (0.54 mL, 4.56 mmol) in THF (12 mL) is refluxed for 4 hours. Solvent is removed under vacuum, the residue is taken up with 1M HCl and extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and evaporated. The crude is purified by flash chromatography (DCM/MeOH=98/2 to 9/1) to obtain intermediate I116 as a white solid (0.58 g, 99% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[N:16][OH:17])[CH3:15])=[CH:4]1)[CH3:2].[Li][CH2:19]CCC.CN(C=O)C.OS(O)(=O)=O>C1COCC1.O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:15]=[CH:19][O:17][N:16]=2)=[CH:4]1)[CH3:2]
Reactant: [Li]CCCC
Reactant: CCn1cc(C(C)=NO)c2ccc(OC)cc21
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCn1cc(-c2ccon2)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 12.5 %

Procedure:
1-(1-Ethyl-6-methoxy-1-H-indole-3-yl)ethanone oxime (100 mg, 0.43 mmol) is dissolved in THF (900 μL) at 0° C. n-BuLi (450 μL, 2.5 M in hexanes, 1.12 mol) is added dropwise, resulting in instant precipitation of solids. DMF (70 μL, 0.9 mol) in 260 μL, of THF is then added dropwise. This is stirred at 0° C. for 1 h, then at room temperature for 1 h. The reaction mixture is pipetted into a mixture containing 1 mL of H2O, 1 mL of THF, and 100 μL, of concentrated H2SO4. This mixture is heated at 75° C. for 1 h and then is partitioned between H2O and EtOAc. The organic phase is dried and concentrated. Purification by column chromatography (CH2Cl2) yields 1-ethyl-3-isoxazol-3-yl-6-methoxy-1-H-indole product as a white solid (13 mg, 12%).
Reaction SMILES: C(O[C:4]([N:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]1[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:11][C@H:9]1[CH2:10][N:6]([CH3:4])[C@H:7]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:8]1
Reactant: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1cc(C)ccc1CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(CCc2ccccc2)c(OCC[C@@H]2C[C@@H](O)CN2C)c1
Yield: 79 %

Procedure:
1150 mg of (2R,4R)-1-ethoxycarbonyl-4-hydroxy-2-{2-[5-methyl-2-(2-phenylethyl)phenoxy]ethyl}pyrrolidine [prepared as described in step (b) above], 18 ml of tetrahydrofuran and 330 mg of lithium aluminum hydride were allowed to react together and subsequently treated in the same manner as described in step (b) of Example 1. The concentrated substance thus obtained was purified by silica gel column chromatography, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 776 mg (yield 80%) of the title compound as a colorless solid substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: C1CNCCN1
Reactant: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNCC3)nn12
Temperature: 170 °C
Reaction time: 1 h

Procedure:
6-[(S)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate B, 200 mg, 0.569 mmol), KF (371 mg, 6.26 mmol) and piperazine (490 mg, 5.69 mmol) were suspended in NMP (2.85 mL). The RM was stirred at 170° C. for 1 h. The mixture was diluted with EtOAc and washed with 1M Na2CO3 (1×) and water (2×). The aqueous was further extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a yellow foam (tR 2.78 min (conditions 1), MH+=395, 1H-NMR in DMSO-d6: 8.95 (d, 1H); 8.45 (d, 1H); 7.77 (d, 1H); 7.61 (d, 1H); 7.59 (s, 1H); 7.58 (m, 1H); 7.02 (d, 1H); 4.95 (m, 1H); 3.23 (m, 2H); 3.07 (m, 2H); 2.62 (m, 2H); 2.56 (m, 2H); 1.87 (d, 3H)).
Reaction SMILES: [C:1]([CH:3]1[CH2:11][CH:10]2[CH:5]3[CH2:6][CH:7]4[CH:9]2[CH:8]4[CH:4]13)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:13].O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1([Cl:13])[CH2:11][CH:10]2[CH:5]3[CH2:6][CH:7]4[CH:9]2[CH:8]4[CH:4]13)#[N:2]
Reactant: N#CC1CC2C3CC4C2C4C13
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#CC1(Cl)CC2C3CC4C2C4C31
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 8-cyanotetracyclo-[4,3,0,02,4,03,7 ]nonane (87 g.) in carbon tetrachloride (600 ml.) was added phosphorus pentachloride (168 g.). The mixture was heated under reflux for 60 hours, cooled and poured into a mixture of crushed ice and water (1.1). The mixture was stirred for 30 minutes and the organic layer separated. This was washed with a 10% w/v aqueous solution of sodium carbonate (200 ml.), saturated brine (100 ml.) and then dried over anhydrous potassium carbonate. The filtrate was then evaporated in vacuo to remove solvent and then distilled in vacuo to give 8-cyano-8-chlorotetracyclo[4,3,0,02,4,03,7 ]nonane, b.p. 136°-140° C./20 mm., in 83% yield.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[C:10]([NH:11][C:12]2[C:17]3[CH:18]([CH3:21])[CH2:19][CH2:20][C:16]=3[N:15]=[C:14]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[F:29])[N:13]=2)=[CH:9][CH:8]=[N:7][CH:6]=1)C.[OH-].[Na+]>CO>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]([F:29])=[C:22]([C:14]2[N:13]=[C:12]([NH:11][C:10]3[C:5]([C:4]([OH:30])=[O:3])=[CH:6][N:7]=[CH:8][CH:9]=3)[C:17]3[CH:18]([CH3:21])[CH2:19][CH2:20][C:16]=3[N:15]=2)[CH:27]=1
Reactant: CCOC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1C(C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CCc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(=O)O)c21
Temperature: 25 °C
Yield: 95.5 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluoro-phenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-nicotinic acid ethyl ester (180 mg, 0.42 mmol, 1 eq) in MeOH (5 ml) was added a 1 N NaOH(aq) solution (634 μl, 0.63 mmol, 1.5 eq) and the reaction mixture was heated to reflux for 1 h. The solution was cooled to r.t. and concentrated in vacuo. Water (20 ml) was added to the crude material and the aqueous layer was acidified to pH 4. The solid was filtered, washed with water (2×5 ml) and dried overnight to give 4-[2-(5-chloro-2-fluorophenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-nicotinic acid, compound of formula (49) (160 mg, 95%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[ClH:22]>CO.O=[Pt]=O>[ClH:22].[F:20][C:2]([F:1])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11][NH:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)CC1CCNC(c2ccc(C(F)(F)F)cc2)C1
Reaction time: 5 h

Procedure:
A mixture of methyl {2-[4-(trifluoromethyl)phenyl]pyridin-4-yl}acetate (6.2 g, 21 mmol), PtO2 (200 mg, 0.9 mmol) and HCl solution (4N in dioxane, 5.8 ml, 23 mmol) in MeOH (100 ml) was hydrogenated at 20 psi on a Parr® apparatus for 5 hours. The catalyst was removed by filtration and the filtrate evaporated in vacuo to give the desired piperidine as white solid (7.1 g, quant). 1H NMR (400 MHz, CD3OD) δ: 1.58-1.72 (1H, m), 1.75-1.85 (1H, m), 2.08 (1H, d, J 14.2), 2.19 (1H, t, J 14.2), 2.28-2.38 (1H, m), 2.45 (2H, d, J 6.9), 3.24-3.32 (1H, m), 3.51-3.57 (1H, m), 3.67 (3H, s), 4.46 (1H, d, J 10.2), 7.72 (2H, d, J 8.3), 7.79 (2H, d, J 8.4).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([S:21](=[O:30])(=[O:29])[NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:13][CH:12]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>ClCCl>[CH2:42]([O:41][C:39]([N:26]1[CH2:25][CH2:24][CH:23]([NH:22][S:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([C:9](=[O:10])[NH:8][CH:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)=[CH:12][CH:13]=2)(=[O:30])=[O:29])[CH2:28][CH2:27]1)=[O:40])[CH3:43]
Reactant: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)NC3CCCCC3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexylamide hydrochloride F-2 (87 mg, 0.19 mmol) was dissolved and stirred in dichloromethane (2 mL). Triethylamine (58 mg, 0.08 mL, 0.57 mmol) was added followed by ethyl chloroformate (41 mg, 0.037 mL, 0.39 mmol). The reaction was stirred overnight at room temperature, then charged directly to a flash column. Elution with 99:1 dichloromethane:methanol afforded the titled compound the title compound as a white solid. Wt.: 60 mg (65%). 1H NMR (300 MHz, CDCl3) δ 8.59 (m, 1H), 8.28 (m, 1H), 8.19 (d, 1H), 7.64 (m, 2H), 7.54 (d, 1H), 4.10 (m, 1H), 4.03 (q, 2H), 3.80 (m, 2), 3.64 (m, 1H), 3.18 (m, 1H), 2.68 (m, 2H), 2.12 (m, 2H), 1.79 (m, 2H), 1.68 (m, 1H), 1.58 (m, 2H), 1.47 (m, 2H), 1.24 (m, 6H), 1.18 (t, 3H); LC/MS m/z 488 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7]1)[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:43]3[CH2:42][CH2:41][N:40]([C:37]4[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=4)[CH2:45][CH2:44]3)=[NH:24])=[CH:19][C:18]=2[F:25])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C#N)cc2F)CC1
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCN(c4ccc(F)cc4)CC3)cc2F)CC1
Yield: 19.2 %

Procedure:
The same procedure as in Example 45 was performed with ethyl-N-(N-(4-cyano-2-fluorobenzoyl)-β-ethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (1.48 g, 3.3 mmol) by using 1-(4-fluorophenyl) piperazine (5.9 g) as an amine to yield the titled compound (396 mg, 19%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][O:39][CH3:40]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:38][O:39][CH3:40])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCc1ccccc1CI
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: COCc1ccccc1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and 1-iodomethyl-2-methoxymethylbenzene analogous to Example 57, step B.
Reaction SMILES: [BrH:1].[Br:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][C:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=[CH:8]CC1C=CC=C(Br)C=1>C(O)(=O)C>[Br:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][C:7]([CH2:8][C:26]1[CH:25]=[CH:5][CH:4]=[C:3]([Br:2])[CH:27]=1)([CH2:6][C:5]1[CH:25]=[CH:26][CH:27]=[C:3]([Br:2])[CH:4]=1)[Br:1]
Reactant: Brc1cccc(CC=C(Cc2cccc(Br)c2)Cc2cccc(Br)c2)c1
Reactant: Br
Solvent: CC(=O)O
Product: Brc1cccc(CC(Br)(Cc2cccc(Br)c2)Cc2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
500 ml of a 30% by weight solution of hydrogen bromide in glacial acetic acid were added dropwise to a solution of 140.7 g (270 mmol) of 1,1,2-tris(3-bromobenzyl)-ethene in 1000 ml of glacial acetic acid. After the mixture had been stirred at room temperature for 48 h, the colourless precipitate was filtered off with suction, washed twice with 200 ml of glacial acetic acid each time and subsequently dried under reduced pressure. The yield, with a purity of about 97%, was 157.2 g (261 mmol), corresponding to 96.7% of theory.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][P:9]([CH2:14][CH:15]([CH2:25][OH:26])[CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])(=[O:13])[O:10][CH2:11][CH3:12])[CH3:7].C(N(CC)CC)C>ClCCl>[CH2:19]([O:18][P:17]([CH2:16][CH:15]([CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14][P:9](=[O:13])([O:10][CH2:11][CH3:12])[O:8][CH2:6][CH3:7])(=[O:24])[O:21][CH2:22][CH3:23])[CH3:20]
Reactant: CCOP(=O)(CC(CO)CP(=O)(OCC)OCC)OCC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC(COS(C)(=O)=O)CP(=O)(OCC)OCC)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
Methanesulfonylchloride (2.2 ml, 28.6 mmol) was added dropwise at 0° C. to a solution of 2-hydroxymethyl-1,3-propylene-bisphosphonic acid tetraethylester (9.0 g, 26.0 mmol) and triethylamine (4.0 ml, 28.6 mmol, 1.1 eq.) in anhydrous dichloromethane (90 ml). The reaction mixture was stirred for 30 min at 0° C. and for 2 h at room temperature. After concentrating in vacuo deionized water (100 ml) was added and the mixture was extracted with ethylacetate (3×100 ml). The combined organic phases were dried with anhydrous sodium sulphate. After removal of the solvent under reduced pressure the obtained crude product was purified by column chromatography (eluent: ethylacetate/methanol 9:1). 9.37 g (85% yield) of the product was obtained as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][N:23]([CH2:2][CH2:3][CH2:4][CH3:5])[C:22](=[O:26])[CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCBr
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCn1ccc(OCc2ccccc2)cc1=O
Yield: 97.9 %

Procedure:
1-Bromobutane (3.75 g, 27.33 mmol) and potassium carbonate (10.3 g, 74.52 mmol) were added to a solution of 4-benzyloxy-1H-pyridin-2-one (5.0 g, 24.84 mmol) in acetonitrile (200 ml) and the mixture was heated at reflux for 16 hours. The reaction mixture was filtered through diatomaceous earth and concentrated in vacuo. The crude residue was then triturated with diethylether to yield pure D4 (6.26 g, 98%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH:29]1([CH2:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH2:2][C:3]3[N:4]([CH3:28])[C:5]4[C:10]([N:11]=3)=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]=[C:7]([N:18]3[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[N:20]=[C:19]3[CH3:27])[N:6]=4)[CH2:35][CH2:34]2)[CH2:31][CH2:30]1
Reactant: C1CN(CC2CC2)CCN1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CC4CC4)CC3)n(C)c2n1

Procedure:
4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 1-(cyclopropylmethyl)piperazine via General Procedure E to give 23.5 mg of 277 following reverse phase purification. MS (Q1) 502.3 (M)+
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]([C:16]#[N:17])[CH:3]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>O1CCOCC1>[C:16]([C:4]1[CH:3]=[C:2]([NH:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=1)#[N:17]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N#Cc1cc(O)c2cc(C(F)(F)F)ccc2n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNc1cc(C#N)nc2ccc(C(F)(F)F)cc12
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-6-(trifluoromethyl)quinoline-2-carbonitrile (2 g, 8.4 mmol) from example 21, step D, in dry dioxane was added TEA (2.9 mL, 21 mmol) and PyBroP (4.75 g, 10 mmol) and stirred at 50 C for 2 hour. To this solution tert-butyl 2-aminoacetate (1.3 g, 10.1 mmol) was added and stirred at 30° C. for 24 h. The solution was concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The ethyl acetate was removed under vacuum and the residue was purified by flash chromatography (silica gel, 0 to 80% EtOAc in hexane) to give the title compound.