Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([F:26])[CH:20]=1>C1(O)CCCCC1>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:21]([F:26])[CH:20]=1
Reactant: COC(=O)c1cc2c(Cl)ccnc2cc1OC
Reactant: Nc1ccc(Cl)cc1F
Solvent: OC1CCCCC1
Product: COC(=O)c1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OC
Temperature: 130 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
4-Chloro-7-methoxy-6-methoxycarbonylquinoline (1.4 g, 5.5 mmol) was dissolved in cyclohexanol (30 ml) and 4-chloro-2-fluoroaniline (0.786 g, 5.8 mmol) was added. The mixture was heated at 130° C. for 1 hour then at 160° C. for 3hours. The solvent was removed by evaporation and the residue was purified by flash chromatography eluting with methylene chloride/ethylacetate (100/0 increasing to 50/50). The solvent was removed by evaporation and the solid was triturated with ether/isohexanes. The solid was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-methoxy-6-methoxycarbonylquinoline (570 mg, 28%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([S:20](Cl)(=[O:22])=[O:21])=[CH:15][CH:16]=2)[CH2:11]1)(=[O:9])[CH3:8].C(NC(C)C)(C)C.Cl.N1(S(C2C=C3C(CCNC3)=CC=2)(=O)=O)CCOCC1>C1COCC1>[C:7]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([S:20]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)(=[O:21])=[O:22])=[CH:15][CH:16]=2)[CH2:11]1)(=[O:9])[CH3:8]
Reactant: C1COCCN1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Agent: Cl
Agent: O=S(=O)(c1ccc2c(c1)CNCC2)N1CCOCC1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCc2ccc(S(=O)(=O)N3CCOCC3)cc2C1

Procedure:
was obtained as described in Example 4A by reacting morpholine with 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride in the presence of diisopropylamine in THF and by heating with 50% concentrated hydrochloric acid and, after alkaline workup, converted into the corresponding 7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: OO.O[Li].O.C([C@@H]1COC(=O)N1[C:19](=[O:37])[C@@H:20]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])C1C=CC=CC=1.C[O:39]C1C=C(OC)C=CC=1C=O.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:25]([O:24][C:23]([NH:22][CH2:21][C@H:20]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C:19]([OH:37])=[O:39])=[O:29])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)cc1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 93.8 %

Procedure:
35% H2O2 (0.240 mL, 2.91 mmol) was added to a solution of LiOH—H2O (0.0978 g, 2.33 mmol) in 2:1 THF:H2O (33 mL). The reaction mixture was stirred at room temperature for 35 minutes, and then cooled to 0° C. A solution containing a mixture of tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropylcarbamate (0.535 g, 1.17 mmol) and 2,4-dimethoxybenzaldehyde (0.194 g, 1.17 mmol) in THF (7 mL) was added dropwise by addition funnel. The ice bath was allowed to slowly warm, and the reaction mixture was stirred overnight. The reaction mixture was then cooled to 0° C., and 1M Na2SO3 (7 mL) was added. The mixture was stirred for 5 minutes, and then warmed to room temperature and stirred an additional 20 minutes. The reaction mixture was then transferred to a separatory funnel and washed with ether (3×). The aqueous layer was acidified with KHSO4(s), and the mixture was extracted with DCM (2×). The combined extracts were dried (Na2SO4), filtered, and concentrated to give (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (0.329 g, 94.2% yield) as a white residue. LC/MS (APCI+) m/z 200 [M−BOC+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([NH:22][NH:23][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:11][CH:10]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSc1ccc(C(=O)O)cc1
Reactant: NNc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CSc1ccc(C(=O)NNc2ccccc2)cc1
Temperature: 31 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
A mixture consisting of 21.88 g. (0.130 mole) p-(methylthio)benzoic acid and 25 ml. thionyl chloride was heated at the reflux temperature until evolution of gas ceased and a clear solution was obtained. After removing the excess thionyl chloride on a rotary evaporator and then under substantially complete vacuum, the solid residue that remained was dissolved in 35 ml. dioxane. The dioxane solution was mixed with a solution consisting of 14.06 g. (0.130 mole) phenylhydrazine in 100 ml. pyridine initially at 5° to 10°C. Inadvertently, about one-third of the acid chloride was added rapidly and the mixture was heated to 31°C. by the exothermic reaction. The reaction mixture was set aside at 25°C. with continuous stirring for three days. It was then poured into 1.5 l. water in order to precipitate the desired p-(methylthio)benzoic acid 2-phenylhydrazide. The precipitate was collected on a filter, washed with water, washed with 1N hydrochloride acid, and finally washed with water. The washed filter cake was then recrystallized from 3A alcohol to give 23.2 g. (69% yield) of p-(methylthio)benzoic acid 2-phenylhydrazide having a melting point at 165.5° to 167.5°C. Recrystallization from 250 ml. ethyl acetate gave the compound melting at 167° to 168°C. (shrinks at 162°C.) Two further recrystallizations from ethyl acetate gave the compound melting at 167° to 168.5°C. with shrinkage at 161.5°C.
Reaction SMILES: C([N:8]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27](O)[C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[OH:11])C1C=CC=CC=1>Cl.O1CCOCC1>[Cl:18][C:14]1[CH:13]=[C:12]([C@@H:10]([OH:11])[CH2:9][NH:8][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)=[CH:25][CH:26]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccc(C(O)c2ccc(CCN(Cc3ccccc3)C[C@H](O)c3cccc(Cl)c3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Oc1ccc(Cc2ccc(CCNC[C@H](O)c3cccc(Cl)c3)cc2)cc1
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
A mixture of 4-[[4-[2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl](hydroxy)-methyl]phenol (545 mg) in 4N hydrogen chloride in 1,4-dioxane (1.0 ml) was stirred for 5 minutes. The solvent was removed by evaporation. A suspension of the residue in ethanol (2.2 ml) and chlorobenzene (5.2 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 55 mg) under hydrogen atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was evaporated. The residue was diluted with ethyl acetate and saturated sodium biscarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 4-[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]benzyl]phenol (395 mg).
Reaction SMILES: O1C2C=CC=CC=2N=C1.C(OC([N:17]1[CH2:22][CH2:21][CH2:20][C@H:19]([CH2:23][NH:24][C:25](=[O:46])[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[O:33][C:34]4[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][C:38]([C:44]#[N:45])=[CH:37][C:35]=4[N:36]=3)=[CH:28][CH:27]=2)[CH2:18]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:44]([C:38]1[CH:39]=[C:40]([CH:41]([CH3:43])[CH3:42])[C:34]2[O:33][C:32]([C:29]3[CH:28]=[CH:27][C:26]([C:25]([NH:24][CH2:23][C@H:19]4[CH2:20][CH2:21][CH2:22][NH:17][CH2:18]4)=[O:46])=[CH:31][CH:30]=3)=[N:36][C:35]=2[CH:37]=1)#[N:45]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CCCN(C(=O)OC(C)(C)C)C4)cc3)oc12
Agent: c1ccc2ocnc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CCCNC4)cc3)oc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110.7 %

Procedure:
To a solution of tert-butyl(3R)-3-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)piperidine-1-carboxylate benzoxazole (201 mg, EXAMPLE 94) in 15 ml dichloromethane was added trifluoroacetic acid (5 ml). The mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo, diluted with 40 ml of ethyl acetate, and basified by slow and cautious addition of 40 ml of saturated aqueous sodium carbonate. The phases were separated and the aqueous phase was extracted with 40 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound (144 mg, 89%). Mass spectrum (ESI) 403.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:9]1(=[O:13])[CH2:12][CH2:11][CH2:10]1>C1COCC1>[Br:8][C:6]1[CH:7]=[C:2]([C:9]2([OH:13])[CH2:12][CH2:11][CH2:10]2)[CH:3]=[N:4][CH:5]=1
Reactant: O=C1CCC1
Reactant: Brc1cncc(Br)c1
Solvent: C1CCOC1
Product: OC1(c2cncc(Br)c2)CCC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a cooled (−20° C.) solution of 3,5-dibromopyridine (592 mg, 2.5 mmol) in THF (2 mL) is added a solution of isopropylmagnesium chloride-lithium chloride complex in THF (1.7 M, 1.4 mL, 2.4 mmol). The resultant mixture is stirred warming to −10° C. for 30 min. The mixture is recooled to −20° C. and cyclobutanone (230 μL, 3.0 mmol) is added. After stirring for 1 h, the reaction is quenched with saturated aqueous ammonium chloride solution and is extracted with EtOAc. The combined organic extracts are washed with water and brine, dried (MgSO4) and concentrated under reduced pressure. Purification by silica gel column chromatography (0-10% MeOH in DCM) provided 1-(5-bromo-pyridin-3-yl)-cyclobutanol (322 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][CH2:7][C:8]3[C:9]([C:14](O)=[O:15])=[CH:10][CH:11]=[CH:12][C:13]=3[C:2]1=2>O1CCCC1.O>[S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][CH2:7][C:8]3[C:9]([CH2:14][OH:15])=[CH:10][CH:11]=[CH:12][C:13]=3[C:2]1=2
Reactant: O=C(O)c1cccc2c1CCc1ccsc1-2
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc2c1CCc1ccsc1-2
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
To a stirred solution of 4,5-dihydronaphtho[1,2-b]thiophen-6-carboxylic acid (3.4 g, 0.015 mole) in 50 ml of tetrahydrofuran under an argon atmosphere was added dropwise borane-tetrahydrofuran complex (2.5 g, 0.030 mole). Upon complete addition, the reaction mixture was stirred at room temperature for 18.5 hours. The reaction mixture was then taken up in water and concentrated under reduced pressure to a residue. The residue was washed into a separatory funnel with aqueous 2N sodium hydroxide and methylene chloride. The aqueous layer was extracted with two 100 ml portions of methylene chloride. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 4,5-dihydronaphtho[1,2-b]thiophen-6-methanol; 2.8 g, mp 99°-100°.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)C(=O)C2=CC=CC=C12.NN>>[NH2:5][CH2:6][CH:7]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2
Reactant: O=C1c2ccccc2C(=O)N1CC1Nc2ccccc2Cc2ccccc21
Agent: NN
Product: NCC1Nc2ccccc2Cc2ccccc21

Procedure:
reacting the 6-(phthalimidomethyl)-6,11-dihydro-5H-dibenz[b,e]azepine with hydrazine, to produce 6-aminomethyl-6,11-dihydro-5H-dibenz[b,e]azepine;
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:26]C(OC(C)(C)C)=O)[CH2:7][O:8][C:9]1[C:13]2[CH:14]=[C:15]([NH:18]C(OC(C)(C)C)=O)[CH:16]=[CH:17][C:12]=2[O:11][N:10]=1)(=[O:3])[NH2:2].O1CCOCC1.[ClH:40]>CO>[ClH:40].[NH2:18][C:15]1[CH:16]=[CH:17][C:12]2[O:11][N:10]=[C:9]([O:8][CH2:7][CH:6]([NH2:26])[CH2:5][O:4][C:1](=[O:3])[NH2:2])[C:13]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2onc(OCC(COC(N)=O)NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)OCC(N)COc1noc2ccc(N)cc12

Procedure:
To a solution of 0.47 g of 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-tert-butoxycarbonylamino-1,2-benzoisoxazole in 10 ml of methanol is added 5.0 ml of a dioxane solution (2.2N) of hydrogen chloride at 5°-10° C. and they are subjected to reaction at 20°-25° C. overnight. The solvent is removed from the reaction mixture by distillation under reduced pressure, and the residue obtained is crystallized from 2-propanol, after which the crystals are collected by filtration, to obtain 0.21 g of colorless, crystalline 5-amino-3-(2-amino-3-carbamoyloxypropoxy)-1,2-benzoisoxazole hydrochloride having a melting point of 230°-231° C.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:15]([C:18]1[N:19]([CH2:31][CH2:32][CH2:33][OH:34])[C:20]2[C:29]3[N:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:30]=1)[CH2:16][CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:55]1[C:59](=[O:60])[C:58]2=[CH:61][CH:62]=[CH:63][CH:64]=[C:57]2[C:56]1=[O:65]>O1CCCC1.C(OCC)(=O)C.ClCCl>[CH2:15]([C:18]1[N:19]([CH2:31][CH2:32][CH2:33][O:34][N:55]2[C:59](=[O:60])[C:58]3[C:57](=[CH:64][CH:63]=[CH:62][CH:61]=3)[C:56]2=[O:65])[C:20]2[C:29]3[N:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:30]=1)[CH2:16][CH3:17]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc2cnc3cccnc3c2n1CCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
Diisopropyl azodicarboxylate (8.10 mL, 48.4 inmol) was added dropwise over ten minutes to a stirred solution of 3-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propan-1-ol (10.9 g, 40.3 mmol), triphenylphosphine (12.7 g, 48.4 mmol), and N-hydroxyphthalimide (7.89 g, 48.4 mmol) in tetrahydrofuran (160 mL) at 0° C. The reaction was allowed to warm to room temperature and was stirred overnight. The solvent was removed under reduced pressure to afford an oil that was dissolved in ethyl acetate (200 mL) and extracted with 2 M HCl (3×100 mL). The aqueous layers were combined, and the pH was adjusted to 7 with the addition of solid sodium bicarbonate. A precipitate formed, was isolated by filtration, and was dissolved in dichloromethane (300 mL). The solution was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 17.38 g of 2-[3-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propoxy]-1H-isoindole-1,3(2H)-dione as a tan solid.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[K+].[C:13]([C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][CH2:22][CH2:23]Br)=[C:18]([CH2:27][CH2:28][CH3:29])[C:17]=1[OH:30])(=[O:15])[CH3:14]>C(O)C.ClCCl.O>[C:13]([C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][CH2:22][CH2:23][S:1][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[C:18]([CH2:27][CH2:28][CH3:29])[C:17]=1[OH:30])(=[O:15])[CH3:14]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCCc1c(OCCCSc2nc3ccccc3[nH]2)ccc(C(C)=O)c1O
Yield: 81.4 %

Procedure:
To a suspension of 1.2 g of 2-mercaptobenzimidazole in 30 ml of ethanol was added 580 mg of potassium hydroxide under stirring and stirred at room termperature for 10 minutes. To this solution was added 2.8 g of 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylbromide at one time, and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure and resulting residue was diluted with dichloromethane-water, then extracted with dichloromethane three times. The organic layer was combined, then washed with water saturated with sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was recrystallized from dichloromethane-n-hexane to give 2.5 g (yield 81%) of the aimed compound as colorless powder. mp 149°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH:12]1(/[CH:18]=[C:19](\B2OC(C)(C)C(C)(C)O2)/[CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[F-].[Cs+]>O1CCOCC1.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](/[C:19](/[CH2:20][OH:21])=[CH:18]\[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(/C(=C\C2CCCCC2)CO)cc1
Yield: 74.7 %

Procedure:
Following the method of example 46a, Suzuki coupling of 4-bromo-benzoic acid methyl ester (1.05 g, 4.88 mmol) with (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (1.48 g, 5.56 mmol) in the presence of tetrakis(triphenylphosphino)palladium(0) (0.35 g, 0.30 mmol) and cesium fluoride (2.1 g, 14 mmol) in dioxane (15 mL) gives the title compound (1.0 g). MS (m/e): 275 (M+H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]([O:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[C:16]([O:28]C)[N:17]2[CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:13]([NH2:30])[N:12]=1)[CH2:7][CH2:8][CH3:9].CCN(C(C)C)C(C)C.CS(C)=O>CN(C=O)C>[NH2:30][C:13]1[N:12]=[C:11]([O:10][CH2:6][CH2:7][CH2:8][CH3:9])[N:19]=[C:18]2[C:14]=1[NH:15][C:16](=[O:28])[N:17]2[CH2:20][CH2:21][CH:22]1[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:26][CH2:27]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Reactant: CCCCI
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(CCCC)CC3)c2n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 12.3 %

Procedure:
1-Iodobutane (0.1 mmol) was weighed into a tube and an aliquot (0.4 ml, 0.12 mmol) of a solution of 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine (0.418 g mg, 1.2 mmol) suspended in DMF (4.8 ml) was added. DIPEA (40 μl, 0.229 mmol) was added and the tube was heated at 50° C. for 18 hours. An additional portion of 1-iodobutane (15 μl) and DIPEA (20 μl) was added and heating continued for a further 18 hours. DMSO (200 uL) was added and the mixture purified by Mass Directed AutoPrep (Method A). The solvent was evaporated in vacuo using the Genevac. The residue was redissolved in 4M HCl/dioxane (0.2 ml), capped and stood at room temperature for 18 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The sample was dissolved in 1:1 DMSO:MeOH and purified by MDAP (Method C) and the solvent was evaporated in vacuo using the Genevac. The material was redissolved in methanol (0.5 ml), and applied to a 0.1 g aminopropyl SPE (preconditioned with methanol, 1.5 ml). The cartridge was eluted with methanol (1.5 ml), the solvent was removed to give the title compound (4.8 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:8][C:7]=12.[C:17]1([N:23]2[C:27]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][N:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([N:31]3[CH2:32][CH2:33][N:28]([C:27]4[N:23]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[N:24]=[N:25][N:26]=4)[CH2:29][CH2:30]3)=[O:14])=[CH:9][NH:8][C:7]=12
Reactant: Nc1ncc(F)c2c(C(=O)C(=O)O)c[nH]c12
Reactant: c1ccc(-n2nnnc2N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
2-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (2.3 g, 10.0 mmol) was dissolved in DMF (66 mL) and treated with 1-(1-phenyl-1H-tetrazol-5-yl)piperazine (2.31 g, 10.0 mmol), triethylamine (2.8 mL, 20.0 mmol) and TBTU (3.5 g, 11.0 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred at rt for 18 h. Solvent was removed in vacuum and water was added. A white solid precipitated out and it was collected by filtration and recrystallized with MeOH to afford the title compound (2.4 g) as a yellow solid. 1HNMR (500 MHz, DMSO-D6) δ 8.53 (s, 1H), 7.81 (d, J=4.0 Hz; 1H), 7.75-7.54 (m, 5H), 3.69 (m, 2H), 3.44 (m, 2H), 3.33 (m, 2H), 3.17 (m, 2H). LCMS: m/e 436 (M+H)+, ret time 1.73 min (method 2).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:8]2)=[CH:4][CH:3]=1.Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]Cl)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C.O1CCCC1.O.CN(C)C=O>[C:12]1([C:10]2[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:34][C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[CH:11]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: O=C(O)CCc1cn(Cc2ccc(OCc3cccnc3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (1.35 g), 3-picolyl chloride hydrochloride (0.76 g), potassium carbonate (0.85 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and an oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). A mixture of the oily substance obtained, 1N aqueous sodium hydroxide solution (8 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After adding water, the residue was neutralized by adding 1N hydrochloric acid. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-(3-pyridylmethoxy)benzyl]-3-pyrrolyl]propionic acid (0.76 g, yield: 48%). This was recrystallized from ethanol-water. Melting point: 131–132° C.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[N:17]=[N:16]2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[CH3:30][C:26]1([CH3:31])[CH2:25][CH2:24][C:23]([CH3:32])([CH3:33])[C:22]2[CH:21]=[C:20]([C:18]3[N:17]=[N:16][N:15]([CH:12]4[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]4)[CH:19]=3)[CH:29]=[CH:28][C:27]1=2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)nn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(-c3cn(C4CCNCC4)nn3)ccc21

Procedure:
The protecting group was cleaved off as already described using HCl in dioxane starting from 120 mg (0.27 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,3-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester from step a. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.