Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1(CCCC1)(=O)=O.P(Cl)(Cl)([Cl:10])=O.C(N(CC)CC)C.O=[C:21]1[NH:26][CH:25]=[N:24][C:23]2[S:27][C:28]3[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30][C:29]=3[C:22]1=2>[Cl-].[Na+]>[Cl:10][C:21]1[C:22]2[C:29]3[CH2:30][CH2:31][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][C:28]=3[S:27][C:23]=2[N:24]=[CH:25][N:26]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3nc[nH]c(=O)c23)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=S1(=O)CCCC1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To sulfolane (3.19 L) was added phosphoryl chloride (785 g, 5.12 mol) at rt. Triethylamine (518 g, 5.12 mol) was added dropwise with water-bath cooling. tert-Butyl 4-oxo-3,5,6,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(4H)-carboxylate from Example 10A (525.5 g, 1.706 mol) and additional sulfolane (1.34 L) were added, and the mixture was heated to 70° C. for 2.5 h. The mixture was cooled to it, and triethylamine (967 g, 9.56 mol) was added. A semi-saturated aqueous sodium chloride solution (10 L) was added during which the mixture was cooled with an ice-bath. After stirring at rt for 2 h, the precipitate was collected by suction filtration and washed three times with water (1.5 L). The residue was dried to yield 517 g (93%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[C:15]1[N:20]=[C:19]([C:21]2[CH:26]=[C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:24]([OH:33])=[CH:23][C:22]=2[OH:34])[N:18]=[C:17]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:16]=1.[OH-].[K+].Br[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>C(OCCO)C>[CH2:27]([C:25]1[C:24]([O:33][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:23][C:22]([OH:34])=[C:21]([C:19]2[N:20]=[C:15]([C:3]3[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:6]([O:8][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:7][C:2]=3[OH:1])[N:16]=[C:17]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:18]=2)[CH:26]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCc1cc(-c2nc(-c3ccccc3)nc(-c3cc(CCCCCC)c(O)cc3O)n2)c(O)cc1O
Reactant: CCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCOCCO
Product: CCCCCCOc1cc(O)c(-c2nc(-c3ccccc3)nc(-c3cc(CCCCCC)c(OCCCCCC)cc3O)n2)cc1CCCCCC
Temperature: 90 °C

Procedure:
To a 350 mL sulfonation flask equipped with a mechanical stirrer, condenser, dropping funnel and a nitrogen atmosphere are charged 16.2 g (30 mmol) of the product of Example 62, 3.7 g (66 mmol) of powdered potassium hydroxide and 100 mL of 2-ethoxyethanol. To the resulting red solution are then added 10.9 g (66 mmol) of 1-bromohexane are added dropwise over 30 minutes. The mixture is heated to 90° C. for 20 hours and filtered hot. The filtrate is warmed to 100° C. and 1 mL of acetic acid is added. The solution is cooled to 0° C. to give a precipitate. The crude yellow product is recrystallized from 70 mL of 2-ethoxyethanol to give the title compound in a yield of 13.1 g as a yellow solid melting at 118°-121° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[CH2:9](C(CC)(CC)C([O-])([O-])[O-])[CH3:10]>C1(C)C=CC=CC=1>[CH2:9]([O:7][C:6]([CH:4]1[CH2:5][C:2](=[O:1])[CH2:3]1)=[O:8])[CH3:10]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: O=C1CC(C(=O)O)C1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC(=O)C1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of 3-oxo-cyclobutanecarboxylic acid (6.0 g, 52.4 mmol; J. Org. Chem. 1988 53, 3841-3843), triethylorthoacetate (28.8 mL, 157 mmol) and toluene (120 mL) was heated at 110° C. for 5 hours. The reaction mixture was cooled to room temperature and quenched with 1.0 N HCl (120 mL). The organic phase was separated, washed with a saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound (6.5 g, 80% yield) as an oil.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[C:8]([C:11]1[CH:30]=[CH:29][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([CH3:28])=[CH:25][C:26]=2[Br:27])[NH2:23])=[C:13]([CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])[C:12]=1[OH:37])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[C:8]([C:11]1[CH:30]=[CH:29][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([NH:23][C:1](=[O:6])[C:2]([O:4][CH3:5])=[O:3])[C:24]([CH3:28])=[CH:25][C:26]=2[Br:27])=[C:13]([CH2:31][CH2:32][C:33]([F:34])([F:35])[F:36])[C:12]=1[OH:37])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(OCCCOc2cc(N)c(C)cc2Br)c(CCC(F)(F)F)c1O
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)Nc1cc(OCCCOc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.36 ml (3.57 mmol) of methyl chlorooxalate in 5 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 1.75 g (3.57 mmol) of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-aniline (Example 1) and 0.55 ml (3.57 mmol) of triethylamine in 15 ml of methylene chloride in the course of 5 minutes. The reaction mixture is subsequently stirred at room temperature for 90 minutes and poured onto ice-water and the organic phase is separated off. The organic phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. Crystallisation of the residue from methylene chloride/ether gives methyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-phenyl}}-oxamate of melting point 139°-140°.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:10][S:11][C:7]=2[CH:6]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[C:8]3[CH:19]=[CH:20][C:5]([O:4][CH2:3][CH2:2][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:6][C:7]=3[S:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: C1CCNC1
Reactant: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: Brc1ccc(-c2nsc3cc(OCCN4CCCC4)ccc23)cc1

Procedure:
According to the method in example 4, 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and pyrrolidine were converted to yield 3-(4-Bromo-phenyl)-6-(2-pyrrolidin-1-yl-ethoxy)-benzo[d]isothiazole, MS: 404 (MH+, 1Br).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=O)=[CH:12][C:7]=2[N:6]=[C:5]1[NH:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=2[N:21]=1.[CH2:31]([O:33][CH2:34][CH2:35][NH2:36])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:31]([O:33][CH2:34][CH2:35][NH:36][C:13]([C:11]1[CH:10]=[CH:9][C:8]2[N:4]([CH2:3][CH2:2][F:1])[C:5]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:30])([F:28])[F:29])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:6][C:7]=2[CH:12]=1)=[O:15])[CH3:32]
Reactant: CCOCCN
Reactant: O=C(O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCF
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCF
Yield: 43 %

Procedure:
1-(2-Fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (50.0 mg) was prepared by following General Procedure F starting from 1-(2-fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-ethoxy-ethylamine (31.0 mg), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 513.
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[CH3:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>C(#N)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:23]2[CH:24]=[C:20]([CH3:19])[N:21]=[CH:22]2)=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1c[nH]cn1
Reactant: O=[N+]([O-])c1cc(C(Br)c2ccccc2)ccc1Cl
Solvent: CC#N
Product: Cc1cn(C(c2ccccc2)c2ccc(Cl)c([N+](=O)[O-])c2)cn1
Reaction time: 24 h
Yield: 54.5 %

Procedure:
A mixture of 31.9 parts of 4-(bromophenylmethyl)-1-chloro-2-nitrobenzene, 49.3 parts of 4-methyl-1H-imidazole and 120 parts of acetonitrile was stirred for 24 hours at reflux temperature. The reaction mixture was concentrated and the concentrate was taken up in 150 parts of water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (98:1:1 by volume) as eluent. The desired fractions were collected and the eluent was evaporated. The residue was converted into the ethanedioate salt in 80 parts of 2-propanol. The salt was filtered off, washed with 2-propanol and dried, yielding 22.8 parts (54.5%) of 1-[(4-chloro-3-nitrophenyl)phenylmethyl]-4-methyl-1H-imidazole ethanediotate(1:1); mp. 105° C. (int. 133).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[CH3:11][C:12](OC(C)=O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH3:12]
Reactant: NCCCCCCCCN
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCNCCCCCCCCN
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ten mmole of 1,8 diaminooctane is dissolved in 50 ml of pyridine. Five mmole of Ac2O is added to the solution dropwise at 10° C. The organic solvent is then evaporated. Using column chromatography, N-monoacetoamide-1,8-diaminooctane subsequently is separated out. The N-monoacetoamide-1,8-diaminooctane is dissolved in 25 ml 1,2-dichloroethane. To this solution, 6 mmole of LiAlH4 is added. The solution is then stirred under nitrogen gas at room temperature for 1 day. Subsequently, the solution is diluted with 100 ml of ethyl acetate. The resulting solution is washed with 20 ml of saturated sodium chloride solution. The solution is dried over MgSO4 and evaporated to produce a residue of N-monoethyl-1,8-diaminooctane. The obtained N-monoethyl-1,8-diaminooctane is dissolved in 80 ml of 1,2-dichloroethane containing about 15 mmole of 2-methyl-5-nitro-imidazolyl-1-yl-acetaldehyde. This reaction mixture is stirred for 30 minutes and then acidified with 15 mmole of acetic acid. Eighteen mmole of sodium triacetoxyborohydride is added as a reducing agent and the solution is stirred for 48 hours at room temperature. The resulting mixture is diluted with 80 ml of ethyl acetate, and the mixture solution is washed with 100 ml of saturated aqueous NaHCO3 and 50 ml of water. The organic layer is dried over anhydrous MGSO4, and the solvent is evaporated to leave residual oil which solidified at 4° C. for 2 days. The obtained solid is recrystallized from ethyl acetate/hexane to give N, N, N'-tri[2'-(2-methyl-5-nitro-1-imidazolyl) ethyl]-N'-ethyl-1,8-octanediamine.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3([C:23]([OH:25])=O)[CH2:22][CH2:21]3)=[O:19])=[C:13]([F:26])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>O1CCCC1>[F:26][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[NH:17][C:18]([C:20]1([C:23](=[O:25])[NH:32][C:31]2[CH:33]=[CH:34][C:28]([F:27])=[CH:29][CH:30]=2)[CH2:22][CH2:21]1)=[O:19])[O:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)O)CC3)c(F)c2)ccn1
Reactant: Nc1ccc(F)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 87.1 %

Procedure:
To a suspension of 1-[4-(2-carbamoylpyridin-4-yl)oxy-2-fluorophenylaminocarbonyl]cyclopropanecarboxylic acid (743 mg) and 4-fluoroaniline (459 mg) in tetrahydrofuran (30 ml) was added 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (1.22 g), followed by stirring at room temperature for 7.5 hr. The reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium hydrogencarbonate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the resultant residue was suspended by addition of tert-butyl methyl ether—ethyl acetate (1:1, 20 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as a white solid (815 mg, 87%).
Reaction SMILES: [C:1]([CH:5]1[C:9](=[O:10])[CH2:8][CH2:7][S:6]1)([O:3][CH3:4])=[O:2].[CH2:11](O)[CH2:12][OH:13]>C1C=CC=CC=1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:13]1[C:9]2([CH2:8][CH2:7][S:6][CH:5]2[C:1]([O:3][CH3:4])=[O:2])[O:10][CH2:11][CH2:12]1
Reactant: COC(=O)C1SCCC1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C1SCCC12OCCO2
Yield: 72.5 %

Procedure:
A solution of 1.60 g (10.0 mmol) of 2-carbomethoxy-2,3,4,5-tetrahydrothiophen-3-one (contained 15% of the 4-carbomethoxy isomer, Pfaltz and Bauer), 1.4 g (24.0 mmol) of ethylene glycol, and 0.02 g of p-toluenesulfonic acid dihydrate in 20 ml of benzene was heated at reflux in a flask equipped with a Dean-Stark trap for 40 hours. The cooled solution was washed with saturated sodium bicarbonate solution (10 ml), water (3×5 ml), and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.48 g of an oil. The oil was flash chromatographed on silica gel eluting with hexane:ether (3:1) to give 1.23 g (60%) product as an oil, a 5:1 mixture of the 6-carboxylate: 4-carboxylate; NMR (deuteriochloroform): δ 4.0 (m, 3H), 3.75 (S, 3H), 2.95 (m, 2H), 2.60 (d of d, 1H), 2.05 (d of d, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:18]C)=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)[CH3:2].Cl.C(Cl)(Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH2:20]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)[CH3:21]
Reactant: CCN(CC)CCOCCc1ccc(OC)c(C(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCOCCc1ccc(O)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
In 5.0 mL of ethyl acetate is dissolved 1.20 g of 1-(5-{2-[2-(diethylamino)ethoxy]ethyl}-2-methoxyphenyl)-1-ethanone, to which is added 1.1 mL of 3.7 mol/L solution of dry hydrogen chloride in ethyl acetate. The solvent is distilled off under reduced pressure. The residue is dissolved in 6.0 mL of methylene chloride, to which are successively added at an ice-cooled temperature 1.60 g of aluminum chloride and 0.70 g of sodium iodide. The mixture thus obtained is stirred at ambient temperature for 2 hours. Ice water and chloroform are added to the reaction mixture, pH is adjusted to 8.0 with 1.0 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. Thus, 1.10 g of 1-(5-{2-[2-(diethylamino)ethoxy]ethyl}-2-hydroxyphenyl)-1-ethanone is obtained as an oily product.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[H-].[Na+].[Br:18][C:19]1[C:23]2[N:24]=[CH:25][N:26]=[C:27](Cl)[C:22]=2[N:21]([CH3:29])[CH:20]=1>CN(C=O)C>[Br:18][C:19]1[C:23]2[N:24]=[CH:25][N:26]=[C:27]([O:15][CH:12]3[CH2:11][CH2:10][N:9]([C:6]4[N:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=4)[CH2:14][CH2:13]3)[C:22]=2[N:21]([CH3:29])[CH:20]=1
Reactant: Cn1cc(Br)c2ncnc(Cl)c21
Reactant: CCc1cnc(N2CCC(O)CC2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(Oc3ncnc4c(Br)cn(C)c34)CC2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(5-ethylpyrimidin-2-yl)piperidin-4-ol (93 mg) was added to DMF (5 mL), and cooled to 0° C. Then, NaH (27 mg) was added thereto, and stirred for 30 min. 7-bromo-4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (100 mg) was added thereto, and stirred at room temperature for 12 hours. The reaction mixture was extracted with ethyl acetate and distilled water, and the organic layer thus obtained was washed with water and a saline solution. Subsequently, the washed organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: CO[CH:3]1[CH2:10][CH2:9][O:8][C:6](=[O:7])[CH2:5][CH2:4]1.[NH3:11]>>[OH:8][CH2:9][CH2:10][CH:3]1[NH:11][C:6](=[O:7])[CH2:5][CH2:4]1
Reactant: COC1CCOC(=O)CC1
Reactant: N
Product: O=C1CCC(CCO)N1

Procedure:
30 g of 4-methoxycaprolactone were stirred at 330° C. for 1 hour together with 100 g of 25% strength aqueous ammonia in the same manner as described in Example 4. After cooling and depressurizing the autoclave and working up the reaction mixture by distillation, 9.1 g of 5-hydroxyethylpyrrolidone were obtained (34%, based on the 4-methoxycaprolactone employed) and identified by NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:17]=[CH:16][C:15]2[N:14]([CH3:18])[C:13](=[O:19])[C@@H:12]([CH2:20][CH3:21])[N:11]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:10]=2[N:9]=1.Cl[CH2:28][O:29][C:30](=O)[O-:31].O>N1C=CC=CC=1>[CH:22]1([N:11]2[C:10]3[N:9]=[C:8]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[NH:1][C:30](=[O:31])[O:29][CH3:28])[N:17]=[CH:16][C:15]=3[N:14]([CH3:18])[C:13](=[O:19])[C@H:12]2[CH2:20][CH3:21])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C([O-])OCCl
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3N)nc2N1C1CCCC1
Solvent: c1ccncc1
Solvent: O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3NC(=O)OC)nc2N1C1CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91, 1 eq) and chloromethylcarbonate (10 eq) in dry pyridine under Ar was stirred at 80° C. overnight. The mixture was cooled to rt and water was added, then extracted with EtOAc. The organic layer was dried with Na2SO4, then concentrated and the residue was purified by a silica gel column to give the title compound. LCMS (0.05% TFA): 411.1 m/z (M+H)+; 1H-NMR (DMSO-d6, 500 MHz): δ: 12.22 (s, 1H), 9.56 (s, 1H), 8.43 (d, 1H, J=5 Hz), 8.30 (s, 1H), 8.26 (d, 1H, J=5 Hz), 4.48 (m, 2H), 3.79 (s, 3H), 3.39 (s, 3H), 2.12-1.69 (m, 10H), 0.82 (t, 3H, J=7.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12](OCC)(=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CC(O)=O>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:6][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:1]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC(=O)c1ccc(F)cc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(O)c2ccc(F)cc2n1
Yield: 22 %

Procedure:
A solution of 2-amino-4-fluorobenzamide (750 mg, 4.40 mmol), diethyl oxalate (20 mL), and AcOH (8 mL) was stirred at 140° C. for 16 h. The solid was collected by filtration and dried under reduced pressure to afford ethyl 7-fluoro-4-hydroxyquinazoline-2-carboxylate as a solid (235 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ 1.36 (t, J=7.08 Hz, 2H), 4.39 (q, J=7.08 Hz, 2H), 7.52 (m, 1H), 7.67 (m, 1H), 8.25 (m, 1H), 11.97 (br s, 1H), 12.77 (br s, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[C:2]1=[O:11].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[CH:15][CH:14]=1>O1CCCC1>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:2](=[O:11])[C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[OH:1])=[CH:18][CH:17]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: O=C1Oc2ccccc2C1=O
Reactant: COc1ccc(CCc2ccc(N)cc2)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(CCc2ccc(NC(=O)C(=O)c3ccccc3O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
A mixture of 2,3-benzofurandione (Fries and Pfaffendorf, Ber, 45, 156 (1912); Valentine, Titoff, Muller, and Reichstein, Helv. Chim. Acta, 20, 883 (1937)) (10 g, 0.0675 mol) and 4-[2-(4-aminophenyl)ethyl]-1,2-dimethoxybenzene (15.6 g, 0.0606 mol) in dry tetrahydrofuran is stirred at room temperature under nitrogen for 18 hours in the dark. The solvent is removed under reduced pressure on a rotary evaporator below 35° and the resulting solid is recrystallized from tetrahydrofuran-ethanol to give 22.2 g (90.6%) of a light-yellow solid, mp 124°-125° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8](=[O:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:3][CH:2]=1.Cl.[H][H]>[Pd].C(O)C>[NH:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:8](=[O:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:5][CH2:6]1
Reactant: O=c1[nH]c2ccccc2cc1-c1ccncc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccccc2cc1C1CCNCC1

Procedure:
A mixture of 8.6 g (0.0387 mol) of 3-(4-pyridinyl)-2(1H)-quinolone, 1.2 1 of ethanol, 39 ml (0.039 mol) of 1N hydrochloric acid and 8.0 g of 10% palladium/charcoal was hydrogenated at a temperature of 40° C. until about 0.08 mol of hydrogen had been taken up. The mixture was freed from catalyst, the filtrate was evaporated down in vacuo, the residue was taken up in 200 ml of water and made ammoniacal. Common salt was added up to saturation point and the mixture was continuously extracted with dichloromethane using a perforator. The dichloromethane phase was evaporated down, the residue remaining was separated from by-products by chromatography over silica gel using FM1 as eluant. The appropriate fractions were combined, freed from solvent, dissolved in a little isopropanol and converted with ethanolic hydrogen chloride solution into the hydrochloride. Colourless crystals. Yield: 2.68 g (26.2% of theory).
Reaction SMILES: [N:1]1([C:19]([O:21]C(C)(C)C)=O)[C@H:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:4][C@@H:3]2[CH2:16][CH2:17][CH2:18][C@H:2]12.[CH3:26][O:27][C:28]([NH:30][C@@H:31]([C@@H:35]([CH3:38])[CH2:36][CH3:37])C(O)=O)=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:26][O:27][C:28]([NH:30][C@@H:31]([C@@H:35]([CH3:38])[CH2:36][CH3:37])[C:19]([N:1]1[C@H:5]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:4][C@@H:3]2[CH2:16][CH2:17][CH2:18][C@H:2]12)=[O:21])=[O:29]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Reaction time: 8 h
Yield: 132.1 %

Procedure:
To a solution of commercially available (2S,3aS,6aS)-2-benzyl 1-tert-butyl hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (10.0 g, 35.489 mmol) in methylene chloride (100 mL) was added (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid (10.072 g, 53.23 mmol), HATU (21.59 g, 56.78 mmol), and DIPEA (18.59 mL, 106.46 mmol). The reaction was stirred overnight, at which time it was concentrated in vacuo, diluted in ethyl acetate and washed with HCl (1N). The aqueous layer was backextracted with ethyl acetate, and the combined organics were dried over sodium sulphate, filtered and concentrated. The resulting oil was diluted in a small amount of chloroform and filtered to remove tetramethyl urea precipitate. The resulting oil was purified by normal phase chromatography (50% ethyl acetate in hexanes) to give (2S,3aS,6aS)-benzyl 1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)octahydrocyclopenta[b]pyrrole-2-carboxylate (19.53 g, >99% yield) which was used without further purification. LCMS-ESI+ calc'd for C23H33N2O5: 417.23. Found: 417.37.