Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]([CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([C:46]2[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=2)=[O:45])[C:10]([NH:12][C@@:13]2([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:17][CH2:16][N:15]([C@H:18]([C:26](=[O:29])[NH:27][CH3:28])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]2=[O:30])=[O:11])=CC=1.C1(OC)C=CC=CC=1>ClCCl>[SH:8][C@@H:9]([CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1)=[O:45])[C:10]([NH:12][C@@:13]1([CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:17][CH2:16][N:15]([C@H:18]([C:26](=[O:29])[NH:27][CH3:28])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]1=[O:30])=[O:11]
Reactant: CNC(=O)[C@H](Cc1ccccc1)N1CC[C@](CCc2ccccc2)(NC(=O)[C@H](CCCCNC(=O)c2ccncc2)SCc2ccc(OC)cc2)C1=O
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CNC(=O)[C@H](Cc1ccccc1)N1CC[C@](CCc2ccccc2)(NC(=O)[C@@H](S)CCCCNC(=O)c2ccncc2)C1=O
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Combine (S)-3-((S)-2-(p-methoxybenzylthio)-6-(pyrid-4-ylcarbonylamino)hexamido)-3-phenethyl-1-((S)-1-methylcarbamoyl-2-phenylethyl)pyrrolidin-2-one (122 mg, 0.166 mmol), mercuric acetate (66 mg, 0.207 mmol), and anisole (0.18 mL, 1.7 mmol) in dichloromethane (5 mL). Cool in an ice bath and degas by repeated cycles of vacuum and filling with nitrogen. Add trifluoroacetic acid (2 mL). After 3 hours, bubble hydrogen disulfide gas through the reaction mixture for about 15 minutes to give a black precipitate. Remove the precipitate by filtration and rise with dichloromethane. Evaporate the filtrate in vacuo and remove residual trifluoroacetic acid by coevaporation with carbon tetrachloride to give a residue. Triturate the residue sequentially with hexane, diethyl ether, and then hexane to give the title compound as a solid (102 mg, 84%). 13C NMR (CDCl3) d 24.4, 26.5, 27.6, 29.4, 33.9, 35.2, 36.9, 39.8, 42.0, 46.2, 61.7, 61.9, 123.8, 126.8, 126.9, 128.3, 128.6, 128.86, 128.93, 137.7, 140.2, 145.1, 147.0, 163.6, 169.3, 173.0, 173.5. MS Calculated for C34H41N5O4S.C2HF3O2=615.8.114.0. Found (M+H)+=616.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[C:12]([C:16]1[CH:40]=[CH:39][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[C:24]=2[CH3:38])=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C1C=CC([P]([Pd]([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)=CC=1>[NH2:11][C:4]1[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=[C:2]([C:25]2[C:24]([CH3:38])=[C:23]([NH:22][C:20](=[O:21])[C:19]3[CH:18]=[CH:17][C:16]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:40][CH:39]=3)[CH:28]=[CH:27][CH:26]=2)[CH:3]=1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1cc(Br)cn2ccnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(N)c2nccn2c1
Temperature: 170 °C
Reaction time: 0.33 h
Yield: 67.7 %

Procedure:
A mixture of 6-Bromo-imidazo[1,2-a]pyridin-8-ylamine (0.72 g, 3.43 mmol), 4-tert-Butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl)-phenyl]-benzamide (1.0 g, 2.54 mmol), Pd(PPh3)4 (0.29 g, 0.25 mmol) in 5 ml 1M Na2CO3 and 10 mL of ethylene glycol dimethyl ether was stirred at 170° C. in a microwave for 20 min. The resulting suspension was filtered through celite and then partitioned between 100 mL of water and 100 mL of ethyl acetate, and the aqueous layer was further extracted with 50 mL of ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated to a residue. Column chromatography (0-6% MeOH/CH2Cl2) afforded 0.685 g of product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[Br:35][C:36]1[CH:37]=[C:38](F)[C:39]([Cl:43])=[C:40]([F:42])[CH:41]=1>CS(C)=O.C1COCC1>[Br:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([Cl:43])=[C:38]([O:8][C:7]2[C:6]([F:9])=[C:5]([CH3:10])[CH:4]=[CH:3][C:2]=2[Cl:1])[CH:37]=1
Reactant: Fc1cc(Br)cc(F)c1Cl
Reactant: Cc1ccc(Cl)c(O)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Temperature: 130 °C
Yield: 38.1 %

Procedure:
6-chloro-2-fluoro-3-methylphenol (9.96 g, 62.0 mmol) and 18-crown-6 (4.5 g, 17.03 mmol) were dissolved in dry DMSO (100 mL) and treated with 20% potassium t-butoxide in THF (34.8 g, 62.0 mmol) in THF for 15 minutes at room temperature. 5-bromo-2-chloro-1,3-difluorobenzene (14.11 g, 62.0 mmol) was added in one portion and the reaction mixture heated at 130° C. for 3 days. The reaction mixture was filtered through Celite™, cooled to ambient temperature and water was added to afford the crude product as a black precipitate which was filtered off, washed with water and air dried. The crude product was dissolved in DCM, dried over MgSO4, and filtered through a plug of 45 g silica gel which was eluted with 500 mL DCM. The filtrate was concentrated to an amber oil and crystallized by addition of EtOH (150 mL). The precipitate was cooled in an ice bath and filtered to afford 2-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (8.7 g, 23.64 mmol, 38.1% yield) as a white solid. The mother liquor was concentrated to dryness and crystallized from IPA (70 mL) to give a second batch of the desired product (4.55 g, 12.36 mmol, 19.93% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.61 (dd, J=8.56, 1.97 Hz, 1H), 7.30-7.47 (m, 2H), 6.74 (s, 1H), 2.29 (d, J=1.56 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[S:12][C:11](Br)=[C:10]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2[CH3:23])[CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].C([Li])CCC.O>C1COCC1>[CH2:1]([NH:4][S:5]([C:8]1[S:12][CH:11]=[C:10]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2[CH3:23])[CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNS(=O)(=O)c1cc(-c2sc(NC(C)=O)nc2C)c(Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C=CCNS(=O)(=O)c1cc(-c2sc(NC(C)=O)nc2C)cs1
Temperature: -70 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
N-(5-{5-[(allylamino)sulfonyl]-2-bromo-3-thienyl}-4-methyl-1,3-thiazol-2-yl)acetamide obtained in Step I as described above (35 mg; 0.08 mmol; 1 eq), is dissolved in dry THF (5 ml) at −70° C. under an inert atmosphere. n-Butyllithium (0.18 ml; 1 M; 0.18 mmol; 2.20 eq) is added slowly and reaction stirred at −70° C. for 1 hour before being hydrolyzed with water (0.3 ml). Reaction is warmed up to room temperature before being concentrated to dryness. Residue is taken up with water (2 ml) and EtOAc (10 ml). The organic phases are decanted, dried over MgSO4, filtrated and evaporated. Title compound is purified by reverse preparative HPLC, affording Compound (49) as a white powder (3 mg; 10%).
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:30]=[CH:31][C:32]5[N:33]([C:35]([C:38]([F:41])([F:40])[F:39])=[N:36][N:37]=5)[N:34]=4)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)(=[O:7])[CH3:6].CCOCC>[Pd].CCO>[C:5]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH2:30][CH2:31][C:32]5[N:33]([C:35]([C:38]([F:39])([F:40])[F:41])=[N:36][N:37]=5)[N:34]=4)[CH2:27][CH2:28]3)=[CH:21][CH:22]=2)[CH2:12][CH2:13]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 74.6 %

Procedure:
Ammonium formate (99 g, 1568.94 mmol) was added to 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (81.2 g, 156.89 mmol) and 10% palladium on carbon (8.35 g, 7.84 mmol) in EtOH (810 mL) under nitrogen. The resulting mixture was stirred at 70° C. for 6 hours, then ammonium formate (50 g) was added. The mixture was stirred at 70° C. for 2 hours then further portions of 10% palladium on carbon (8.35 g, 7.84 mmol) and ammonium formate (50 g) were added and stirring continued at 70° C. for a further 10 hours. Ammonium formate (50 g) was added and the reaction mixture was stirred at 70° C. for 24 hours then cooled to room temperature. The catalyst was removed by filtration and the reaction charged with further 10% palladium on carbon (8.35 g, 7.84 mmol) and stirred at 70° C. for 16 hours. Further ammonium formate (50 g) was added and the stirring continued for 5 hours. The reaction mixture was cooled to room temperature and a further portion of 10% palladium on carbon (8.35 g, 7.84 mmol) was added. The mixture was heated to 70° C. for a 30 hours, cooled to room temperature and the catalyst removed by filtration and washed with EtOH. The solvent was evaporated and the residue dissolved in DCM (500 mL) and the solution washed with water (500 mL). The aqueous layer was re-extracted with DCM (500 mL), then EtOAc (500 mL×2). The combined extracts were dried over MgSO4, filtered and evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford a gum, which was slurried with ether (300 mL) and re-evaporated. Methyl tert-butyl ether (250 mL) was added and the mixture was stirred vigorously for 3 days. The solid was collected by filtration and dried to afford 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (60.8 g, 75%) as a solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[C:7](=[S:8])[CH2:6][CH:5]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23].C1CCCCC1>CC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][S:8][C:7]1[CH:6]=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[CH:10][C:9]=1[O:11][CH3:12]
Reactant: ClCCCBr
Reactant: COC1=CC(C(C)=O)=CCC1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCCCC1
Product: COc1cc(C(C)=O)ccc1SCCCCl
Temperature: 25 °C

Procedure:
A mixture of 1-(4-thio-3-methoxyphenyl)ethanone (10.0 g, 54.9 mmol), potassium carbonate (9.0 g, 65.1 mmol), and acetone (100 ml) was stirred at reflux under nitrogen for 30 minutes. The reaction was cooled to ambient temperature and a solution of 1-bromo-3-chloropropane (6.5 ml, 9.5 g, 60.4 mmol) dissolved in acetone (25 ml) was dripped into the reaction. After complete addition, the reaction was heated to reflux and stirred under nitrogen for 17 hours. After the reaction was carried to substantial completion, the reaction mixture was filtered and the resulting filter cake was washed with acetone. The filtrate was concentrated to provide an amber oil. A small sample was solidified by trituration with hot cyclohexane to provide 1-[4-[(3-chloropropyl)thio]-3-methoxyphenyl]ethanone as a yellow solid, 11.7 g, m.p.=53°-55° C.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].C([O-])([O-])=O.[K+].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[C:15]1([CH2:14][N:1]2[C:5](=[O:6])[CH2:4][CH2:3][C:2]2=[O:7])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1Cc1ccccc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To 2,5-pyrrolidinedione (2.5 g, 25.2 mmol) in DMF (50 mL) was added K2CO3 (4.18 g, 30.3 mmol) followed by benzyl bromide (3.00 mL, 25.2 mmol), and the reaction mixture was stirred overnight at 55° C. Water was added to the reaction mixture (˜200 mL) and a precipitate was immediately observed. The precipitate was filtered, and the white solid was washed with water and dried to afford the title compound (2.7 g, 57%). 1H NMR (400 MHz, CDCl3): δ 2.73 (s, 4H), 4.68 (s, 2H), 7.28-7.37 (m, 3H), 7.39-7.44 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[S:17]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24](Cl)=O)=[CH:18]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52]>C(OCC)(=O)C>[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52].[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:24](/[CH:23]=[CH:22]/[C:19]3[CH:20]=[CH:21][S:17][CH:18]=3)=[N:16][C:5]=2[CH:4]=1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Reactant: O=C(Cl)/C=C/c1ccsc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/c1ccsc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-amino-N-(2-pyridyl)aniline and (E)-3-(3-thienyl)acryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [CH2:1]([N:3]1CN(C)C[N:5]([C:10]2[S:11][C:12]3[C:18]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:17][C:16]([C:25]4[CH:26]=[N:27][C:28]([N:31]5[CH2:36][CH2:35][C:34]([CH3:42])([C:37]([O:39]CC)=[O:38])[CH2:33][CH2:32]5)=[N:29][CH:30]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:43])[CH3:2].[OH-].[Na+].Cl>CCO>[CH2:1]([NH:3][C:4]([NH:5][C:10]1[S:11][C:12]2[C:18]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:17][C:16]([C:25]3[CH:26]=[N:27][C:28]([N:31]4[CH2:32][CH2:33][C:34]([CH3:42])([C:37]([OH:39])=[O:38])[CH2:35][CH2:36]4)=[N:29][CH:30]=3)=[CH:15][C:13]=2[N:14]=1)=[O:43])[CH3:2]
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(COCCOC)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(COCCOC)c2s1
Temperature: 70 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
Ethyl 1-[5-[2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-7-(2-methoxyethoxymethyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (86 mg, 0.141 mmol) was dissolved in EtOH (15 mL) and 2M aqueous NaOH (5 mL) added. The reaction was then stirred at 70° C. for 2 h then cooled to rt, 2M HCl (10 mL) was added and the mixture was stirred for 1 h. The mixture was then extracted with EtOAc (3×25 mL) and the combined organic fractions, washed with brine, separated, dried (Na2SO4) and concentrated under reduced pressure to afford Compound 202 (60 mg, 81%) as an off-white solid. 1H NMR (DMSO-d6): δ=12.40 (bs, 1H), 10.76 (bs, 1H), 8.75 (s, 2H), 7.82 (d, J=1.5 Hz, 1H), 7.41 (d, J=1.4 Hz, 1H), 6.84 (bt, J=5.4 Hz, 1H), 4.68 (s, 2H), 4.28 (dt, J=13.8 and 4.2 Hz, 2H), 3.39-3.30 (m, 2H), 3.35 (s, 3H), 3.25-3.17 (m, 2H), 2.05-2.00 (m, 2H), 1.39 (ddd, J=13.8, 10.2 and 3.9 Hz, 2H), 1.20 (s, 3H), 1.12 (t, J=7.2 Hz, 3H). MS: 529.16 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:10][CH2:11][CH2:12][CH2:13][CH2:14]C.C([Li])CCC.CCC(=O)CC>O.C1COCC1>[C:1]([C:5]1[CH:9]=[CH:8][C:7](=[C:12]([CH2:13][CH3:14])[CH2:11][CH3:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC=CC1
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCC(=O)CC
Product: CCC(CC)=C1C=CC(C(C)(C)C)=C1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To a THF solution of 1.53 g (13 mmol) of tert-butylcyclopentadiene, 9.0 ml (14 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. Then, 1.7 ml (16 mmol) of 3-pentanone was further added at −78° C., followed by stirring at room temperature for 2 days. To the reaction solution, water was added. The mixture was subjected to extraction with ether, then the solvent was distilled off, and the residue was subjected to column chromatography (silica gel, developing solvent: hexane) to obtain 1.50 g of a yellow liquid (yield: 63%) The analyzed values are given below.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]=1.[N-:15]=[N+]=[N-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CS(C)=O.C1COCC1.O.CCOC(C)=O>[NH2:15][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(N)ccn1
Temperature: 130 °C
Yield: 52.1 %

Procedure:
A mixture of tert-butyl 4-chloropicolinate (3.8 g, 17.8 mmol) and sodium azide (1.74 g, 26.8 mmol) in DMSO (20 mL) was heated at 130° C. for 15 h. The mixture was poured into water (80 mL), extracted three times with EtOAc. The combined organic solutions was dried over MgSO4. The solid was filtered off, and the filtrate was concentrated in vacuo to give a residue which was heated with PPh3 in THF/H2O (9:1,40 mL) at 70° C. overnight. The mixture was diluted with EtOAc, washed with sat. K2HPO4 aq. solution. The organic layer was dried over MgSO4 and the product was purified by flash column chromatography (SiO2, 5% MeOH in EtOAc) to afford a white solid (1.8 g, 52%). LC-MS: m/z 195 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH2:14]C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([CH3:14])[CH:18]2[CH2:19][CH2:20][O:16][CH2:17]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCC1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CC1CN(C(=O)OC(C)(C)C)C1)C1CCOC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
A mixture of 3-ethylaminomethyl-azetidine-1-carboxylic acid tert-butyl ester (200 mg, 1.0 mmol), dihydrofuran-3-one (0.155 mL, 2.0 mmol), diisopropylethylamine (0.347 mL, 2.0 mmol) and 4 Å molecular sieves (600 mg) in DCM (10 mL) was stirred at RT for 30 min. Sodium triacetoxyborohydride (424 mg, 2 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 60 h. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 5:95) to afford the title compound as a colourless oil (257 mg, 95%). 1H NMR (400 MHz, CDCl3): δ 4.04-3.92 (3H, m), 3.83 (1H, dd, J=8.89, 6.90 Hz), 3.75 (1H, q, J=8.07 Hz), 3.64 (1H, dd, J=8.87, 6.21 Hz), 3.56-3.55 (2H, m), 3.14 (1H, m), 2.67-2.66 (2H, m), 2.51 (1H, dd, J=12.33, 7.20 Hz), 2.17 (3H, s), 2.05 (1H, s), 1.89-1.79 (1H, m), 1.44 (9H, s).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[CH:16]=[N:17][N:18]([CH3:21])[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].CO.CC(N(C)C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[CH:16]=[N:17][N:18]([CH3:21])[C:19]=5[CH3:20])[C:5]=4[C:4]=3[CH:3]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Cc1c(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)cnn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cnn(C)c2C)c(=O)n4C)cc1OC
Temperature: 105 °C
Reaction time: 1.5 h

Procedure:
A mixture of 8-bromo-1-(1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate J, 50 mg, 0.132 mmol), 3,4-dimethoxyphenylboronic acid (Aldrich, Buchs, Switzerland, 29 mg, 0.156 mmol) and PdCl2(PPh3)2 (6 mg, 0.0085 mmol) in DMF (1.2 ml) and 1 M aqueous K2CO3 (0.329 ml) was stirred under argon at 105° C. for 1.5 h. Then the RM was cooled to rt, diluted with MeOH/DMA+3 drops TFA and purified directly by Prep. HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 55:45). The fractions containing product were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as an off-white solid. (HPLC: tR 2.66 min (Method A); M+H=430 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.08-8.01 (m, 1H), 7.95-7.88 (m, 1H), 7.76 (s, 1H), 7.60-7.55 (m, 1H), 7.13-7.08 (m, 1H), 7.05-7.00 (m, 1H), 6.99-6.94 (m, 1H), 3.88-382 (m, 6H), 3.78 (s, 3H), 3.56 (s, 3H), 2.11 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.N1C=CC=[C-]1.Cl.[NH2:16][CH2:17][C@@H:18]([OH:34])[CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C:28]2=[O:33])=[CH:23][CH:22]=1.Cl>C(Cl)Cl>[OH:34][C@H:18]([CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C:28]2=[O:33])=[CH:25][CH:26]=1)[CH2:17][NH:16][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: NC[C@@H](O)CNc1ccc(N2CCOCC2=O)cc1
Agent: Cl
Agent: [c-]1ccc[nH]1
Solvent: ClCCl
Product: O=C(NC[C@H](O)CNc1ccc(N2CCOCC2=O)cc1)c1ccc(Cl)s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of nitrogen to a suspension of 1.65 g of 5-chloro-thiophene-2-carboxylic acid (MW=162.60; 1.2 eq.) in 50 mL of methylenechloride were added 1.62 g N,N′-carbonyldiimidazole (MW=162.15; 1.2 eq.) and the reaction mixture was stirred for 2 h. To the resulting solution of the azolide were added 2.41 g of 4-[4-((R)-3-amino-2-hydroxy-propylamino)-phenyl]-morpholin-3-one hydrochloride (MW=301.78; 1 eq.) and stirring at ambient temperature was continued for 4 h. Then 50 mL of 1 M aqueous hydrochloride were added. After 5 min of stirring, the layers were separated. The organic layer was extracted once more with 25 mL of 1 M hydrochloric acid. The combined aqueous layers were washed with 25 mL of methylenechloride and neutralized by the addition of approx. 15 mL of 5 M sodium hydroxide. The resulting suspension was stirred for 1 h at ambient temperature, then cooled to 0° C. After stirring in an ice bath for 2 h, the precipitate was isolated by filtration, washed with 10 mL of water and the wet product was dried in vacuo at 40° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([SH:11])[N:3]=1.O1C[CH2:15][CH2:14][CH2:13]1>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([S:11][CH2:13][CH2:14][CH3:15])[N:3]=1
Reactant: Nc1nc(S)c2nc[nH]c2n1
Reactant: C1CCOC1
Product: CCCSc1nc(N)nc2[nH]cnc12

Procedure:
2-Amino-6-propylthio-9H-purine was prepared by nucleophilic displacement of the iodo group on 1-iodopropane (Aldrich Chemical Co.) by 2-amino-6-mercapto-9H-purine (Aldrich Chemical Co.) in tetrahydrofuran.