Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:22]([NH:24][C@H:25]([C:29]([NH:31][C@H:32]([C:40]([NH:42][C@H:43]([C:46]([NH:48][C@H:49]([C:55]([NH:57][C@H:58]([C:64]([NH:66][C@H:67]([C:71]([NH:73][C@H:74]([C:76]([NH:78][C@H:79]([C:85]([NH:87][C@H:88]([C:101]([NH:103][C@H:104]([C:109]([OH:111])=[O:110])[CH2:105][C:106](=[O:108])[NH2:107])=[O:102])[CH2:89][C:90]1[C:98]2[C:93](=[CH:94][CH:95]=[CH:96][CH:97]=2)[N:92](C=O)[CH:91]=1)=[O:86])[CH2:80][CH2:81][CH2:82][CH2:83][NH2:84])=[O:77])[CH3:75])=[O:72])[C@@H:68]([CH3:70])[OH:69])=[O:65])[CH2:59][CH2:60][CH2:61][CH2:62][NH2:63])=[O:56])[CH2:50][CH2:51][CH2:52][CH2:53][NH2:54])=[O:47])[CH2:44][OH:45])=[O:41])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:39])[NH2:38])=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:20][OH:21])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[OH-].[NH4+]>C(O)(=O)C>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:22]([NH:24][C@H:25]([C:29]([NH:31][C@H:32]([C:40]([NH:42][C@H:43]([C:46]([NH:48][C@H:49]([C:55]([NH:57][C@H:58]([C:64]([NH:66][C@H:67]([C:71]([NH:73][C@H:74]([C:76]([NH:78][C@H:79]([C:85]([NH:87][C@H:88]([C:101]([NH:103][C@H:104]([C:109]([OH:111])=[O:110])[CH2:105][C:106](=[O:108])[NH2:107])=[O:102])[CH2:89][C:90]1[C:98]2[C:93](=[CH:94][CH:95]=[CH:96][CH:97]=2)[NH:92][CH:91]=1)=[O:86])[CH2:80][CH2:81][CH2:82][CH2:83][NH2:84])=[O:77])[CH3:75])=[O:72])[C@@H:68]([CH3:70])[OH:69])=[O:65])[CH2:59][CH2:60][CH2:61][CH2:62][NH2:63])=[O:56])[CH2:50][CH2:51][CH2:52][CH2:53][NH2:54])=[O:47])[CH2:44][OH:45])=[O:41])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:38])[NH2:39])=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:20][OH:21])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](CC(N)=O)C(=O)O)[C@@H](C)O)C(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(N)=O)C(=O)O)[C@@H](C)O)C(C)C
Yield: 98 %

Procedure:
H-Ile-Lys-Ser-Val-Arg-Ser-Lys-Lys-Thr-Ala-Lys-Trp(CHO)-Asn-OH (3) (460 mg) was treated with 0.15M ammonium hydroxide (200 mg) at room temperature for 40 minutes. The reaction mixture was neutralized with acetic acid (2.5 ml) and concentrated. The concentrate was chromatographed on a Sephadex LH-20 column (3.2×65 cm, 1% acetic acid) for desalting and lyophilized to give crude H-Ile-Lys-Ser-Val-Arg-Ser-Lys-Lys-Thr-Ala-Lys-Trp-Asn-OH (4) (443 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:10]([O:12]C)=[O:11])=[CH:9][C:5]=2[CH:4]=1.O.[OH-].[Li+].O>CO>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1
Reactant: COC(=O)c1cc2cc(C(F)(F)F)ccc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2cc(C(F)(F)F)ccc2s1
Temperature: 75 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A mixture of 300 mg of methyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 66 mg of lithium hydroxide monohydrate, 2 ml of water and 6 ml of methanol was stirred at 75° C. for 1 hour. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. To the residue was added water, and then washed with tert-butyl methyl ether 3 times. To the aqueous layer was added concentrated hydrochloric acid, and then extracted with tert-butyl methyl ether 3 times. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 280 mg of 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid (the present compound 1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12]N=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl-].[Ca+2].[Cl-].[CH2:22](O)C>>[CH3:1][C:2]1[C:7]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:22]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCO
Reactant: Cc1ncccc1CSc1ccc([N+](=O)[O-])cn1
Agent: [Ca+2]
Agent: [Cl-]
Product: Cc1ncccc1CSc1ccc(N)cc1
Temperature: 25 °C

Procedure:
To 2-methyl-3-[[(5-nitro-2-pyridinyl)sulfanyl]methyl]pyridine (4.0 g) was added 85% aqueous solution of ethanol (80 ml), calcium chloride (0.86 g) and reduced iron (4.3 g) were added to the mixture, and the mixture was heated to reflux for 3 hours. After allowing the mixture to be cooled to room temperature, and the solvent was removed under reduced pressure. The mixture was filtered with. Celite, and washed with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[[(2-methyl-3-pyridinyl)methyl]sulfanyl]aniline (3.2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8](I)[N:7]=1.[CH3:29][O:30][C:31](=[O:36])[CH2:32][CH2:33][C:34]#[CH:35]>C(N(CC)CC)C.[Cu]I>[CH3:29][O:30][C:31](=[O:36])[CH2:32][CH2:33][C:34]#[C:35][C:8]1[N:7]=[C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:28])[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Reactant: C#CCCC(=O)OC
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)CCC#Cc1ccc(OCCCC/C=C/c2ccc(OC)cc2)c(CCC(=O)OC)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.4 %

Procedure:
11 mg of bis-triphenylphosphine-palladium(II) chloride and 1.5 mg of copper(I) iodide are added to a solution of 300 mg of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester and 68 mg of 4-pentynoic acid methyl ester in 5 ml of triethylamine, and the mixture is stirred for 20 hours at room temperature. The reaction mixture is filtered, the filter residue is washed with ethyl acetate and the filtrate is concentrated by evaporation. The residue is taken up in water, shaken out with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. The crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate and for complete purification subjected to high-pressure liquid chromatography on reversed-phase silica gel (Nova-Pak HR C18) with acetonitrile/water=75/25. 280 mg of 5-{2-(2-methoxycarbonylethyl)-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-6-pyridyl}-4-pentynoic acid methyl ester is obtained as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:27]=[C:11]3[N:12]=[C:13]([CH3:26])[C:14]([C@H:20]([OH:25])[C:21]([O:23][CH3:24])=[O:22])=[C:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O[C:32]([CH3:35])([CH3:34])[CH3:33])(=O)C>C(Cl)Cl.CCOCC>[C:32]([O:25][C@@H:20]([C:14]1[C:13]([CH3:26])=[N:12][C:11]2[N:10]([N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:27]=2)[C:15]=1[CH2:16][CH:17]([CH3:19])[CH3:18])[C:21]([O:23][CH3:24])=[O:22])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1CC(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1CC(C)C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a stirred solution of (S)-methyl 2-(2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (0.059 g, 0.152 mmol) and tert-butyl acetate (1 ml, 7.40 mmol) in CH2Cl2 (3 mL) was added 70% perchloric aci (0.039 ml, 0.456 mmol) at rt. After 2 h, the reaction was diluted with Et2O (50 mL), washed with sat. Na2CO3 (2×5 mL), dried (Na2SO4), filtered and concentrated to give yellow solid which was purified by prep-HPLC to afford (S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.0357 g, 0.080 mmol, 52.9% yield) as brown paste. 1H NMR (500 MHz, CDCl3) δ: 7.97 (t, J=1.7 Hz, 1H), 7.86 (dt, J=7.6, 1.3 Hz, 1H), 7.40-7.31 (m, 2H), 6.79 (s, 1H), 5.36 (s, 1H), 3.70 (s, 3H), 3.53 (dd, J=13.4, 7.6 Hz, 1H), 3.14 (dd, J=13.4, 7.0 Hz, 1H), 2.69 (s, 3H), 2.65-2.54 (m, 1H), 1.25 (s, 9H), 1.03 (d, J=6.7 Hz, 3H), 0.98 (d, J=6.7 Hz, 3H). LCMS (M+H) calcd for C24H31ClN3O3: 444.21. found: 444.3.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:7]1[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccccc1CNc1cccnc1Cl
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccccc1CNc1cccnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
To a 22 L three neck round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel, and nitrogen inlet, were added 3.84 L of tetrahydrofuran, 91.6 grams (0.17 moles) of bis(diphenylphosphino)ethanenickel (II) chloride, and 96 grams (0.39 moles) of 2-chloro-3-(2-methoxybenzylamino)pyridine. The orange slurry was stirred at 25° C. for about 30 minutes. Phenylmagnesium bromide (3M in ether, 231.6 mL, 0.69 moles) was added over a 4 hour period and the resulting black slurry was stirred for 22 hours at 25° C. During this time, the reaction was monitored by thin layer chromatography assay, and a total of 86 mL (0.26 moles) of additional phenylmagnesium bromide solution was added to the system. The reaction mixture was cooled to 10° C. and the reaction was quenched with 3.84 L of 20% aqueous HCl over 30 minutes. Ethyl acetate (3.84 L) was added and the reaction mixture was stirred an additional 10 minutes. The layers were separated and the organic layer was washed with 4 L of 25% aqueous HCl. The pH of the aqueous layer was, adjusted from 0.98 to 11.6 with 1.6 L of 50% aqueous sodium hydroxide. Diatomaceous earth (Celite®) (1 kg) and 7 L of ethyl acetate were added. The mixture was stirred for 15 minutes, filtered through diatomaceous earth (Celite®) and the cake was washed with about 1 L of ethyl acetate. The layers were separated, the aqueous layer washed twice with 2 L of ethyl acetate, and the organic layers were combined and dried with sodium sulfate. The drying agent was removed by filtration, the cake was washed with ethyl acetate, and the filtrate was vacuum concentrated to about 2 L volume. This solution was treated with 510 g of silica gel for 30 minutes at 20°-25° C., filtered, and the silica gel was washed twice with 2 L of ethyl acetate. The filtrate was vacuum concentrated to a yellow slurry and displaced with 1 L of isopropanol to a final volume of about 275 mL. The slurry was granulated at 0°-5° C. for 30 minutes, filtered, washed with cold isopropanol, and dried giving 83.8 g (74.8%) of crude material (Mp 122°-125° C). A portion (48.3 g) of this material was purified by chromatography to give 38.6 g of the title compound as a yellow solid. Mp 124°-128° C. Spectral data for this compound are identical to the data reported in step 1 of Example 4.
Reaction SMILES: C([O:4][C:5]1[C:28]([CH3:29])=[CH:27][C:8]([O:9][CH2:10][CH2:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:14][CH:13]=2)=[C:7]([CH3:30])[C:6]=1[CH3:31])(=O)C.[OH-].[Na+]>C(O)C>[OH:4][C:5]1[C:28]([CH3:29])=[CH:27][C:8]([O:9][CH2:10][CH2:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][C:17]([CH3:24])([CH3:23])[C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)=[C:7]([CH3:30])[C:6]=1[CH3:31]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCOc2cc(C)c(OC(C)=O)c(C)c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCCc2ccc(OC(C)(C)C(=O)O)cc2)c(C)c(C)c1O
Yield: 68.3 %

Procedure:
10.5 g (0.0245 mol) of the ethyl 2-{4-[2-(4-acetoxy-2,3,5-trimethylphenoxy)ethyl]phenoxy}isobutyrate so obtained are introduced with 500 ml of ethanol and 50 ml of 1N sodium hydroxide solution into a three-necked flask that is equipped with a stirrer and a condenser and is placed under a nitrogen atmosphere. The whole is heated under reflux for 3 hours and then concentrated to dryness. The residue is taken up in water and extracted several times with ether. The aqueous phase is acidified with 55 cm3 of 1N hydrochloric acid and then extracted several times with ether. The combined ethereal phases are washed with water, dried over sodium sulphate and concentrated to dryness. The residue is chromatographed on 1.4 liters of Amicon silica (0.035-0.070 mm) while eluting with a mixture of methylene chloride and ethyl acetate (70:30). The desired fractions are concentrated to dryness. The residue is dissolved in 20 ml of ether. The whole is diluted with petroleum ether and cooled. Crystallisation is observed. The crystals are filtered off with suction and dried at 45° C. under 133 Pa to yield 6 g of 2-{4-[2-(4-hydroxy-2,3,5-trimethylphenoxy)ethyl]phenoxy}isobutyric acid in the form of white crystals melting (K) at 69° C. Yield: 68%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH3:16])=[C:6]([C:17]([O-:19])=[O:18])[C:5]=1[C:20]([O:22]CC)=[O:21])[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:15]([O:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:20]([OH:22])=[O:21])[C:6]=1[C:17]([OH:19])=[O:18])[CH3:16]
Reactant: CCOC(=O)c1c(C(=O)[O-])c(OCC)c2ccccc2c1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1c(C(=O)O)c(C(=O)O)c(OCC)c2ccccc12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
Ethyl 1,4-diethoxy-2,3-naphthalenedicarboxylate (32 g, 89 mmol) was added to a solution of sodium hydroxide (20 g) in ethanol (200 ml) and water (40 ml) and stirred for 1.5 h at 60° C. The reaction was cooled and the thick white suspension was filtered. The solid was dissolved in a mixture of ethyl acetate (200 ml) and water (800 ml). The layers were separated and the aqueous was acidified with hydrochloric acid (2M, 120 ml). The aqueous was extracted with ethyl acetate (2×) and the combined organics were dried (MgSO4). Evaporation of the solvent under vacuum gave the title compound as a white solid (25 g, 92%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([N:22]3[CH2:27][C@@H:26]4[CH2:28][C@H:23]3[CH2:24][N:25]4C(OC(C)(C)C)=O)=[O:21])=[CH:17][CH:18]=2)[N:13]([C:36]2[N:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)=[CH:38][N:37]=2)[CH:12]=1)=[O:10]>ClCCl>[C@H:23]12[CH2:28][C@H:26]([NH:25][CH2:24]1)[CH2:27][N:22]2[C:20]([C:16]1[CH:15]=[C:14]2[C:19]([C:11]([S:9]([CH3:8])=[O:10])=[CH:12][N:13]2[C:36]2[N:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)=[CH:38][N:37]=2)=[CH:18][CH:17]=1)=[O:21]
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccn3)cn2)c2cc(C(=O)N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)c1cn(-c2ncc(-c3ccccn3)cn2)c2cc(C(=O)N3C[C@@H]4C[C@H]3CN4)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4 M solution of trifluoroacetic acid in dichloromethane (5.1 mL, 20.78 mmol, 40 eq) was added at 0° C. to 244d) (0.29 g, 0.51 mmol, 1 eq) in dichloromethane (10 mL). The reaction mixture was then stirred for 3 h at room temperature. The solvent was removed under vacuum and the residue was co-distilled twice with dichloromethane, diluted with dichloromethane (50 mL) and washed with saturated potassium carbonate solution (2×20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, concentrated and finally chromatographed by preparative HPLC. White solid. Yield: 0.200 g (84% by theory)
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=CC(C([O:27][CH2:28][C@H:29]2[O:33][C@@H:32]([N:34]3[CH:41]=[C:40]([CH3:42])[C:38](=[O:39])[NH:37][C:35]3=[O:36])[C@H:31]([O:43][CH2:44][CH2:45][O:46][CH3:47])[C@@H:30]2[CH3:48])(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)(Cl)Cl>[CH3:48][C@@H:30]1[C@@H:29]([CH2:28][OH:27])[O:33][C@@H:32]([N:34]2[CH:41]=[C:40]([CH3:42])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[C@@H:31]1[O:43][CH2:44][CH2:45][O:46][CH3:47]
Reactant: COCCO[C@@H]1[C@H](C)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccc(OC)cc2)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COCCO[C@@H]1[C@H](C)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
Trifluoroacetic acid (1.5 mL) was added dropwise to a stirred solution of 3′-deoxy-5′-O-(4-methoxytrityl)-3′-methyl-2′-O-(2-methoxyethyl)-5-methyluridine (370 mg, 0.63 mmol) in 50 mL of chloroform at 0° C. The mixture was stirred at rt for 30 min, concentrated, and then dissolved in ethyl acetate. The solution was washed with dilute sodium bicarbonate and brine. The organic phase was dried (Na2SO4) and concentrated. The resulting residue was purified by flash chromatography on a silica gel column. Elution with 1:1, 1:3 and then 0:1 hexanes-EtOAc provided 170 mg of the title compound as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:46][CH3:47])=[O:5])[CH3:2].I[CH2:49][CH2:50][OH:51].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[CH:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:39])([F:37])[F:38])[CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=3)[C:22]([N:40]3[CH2:45][CH2:44][N:43]([CH2:49][CH2:50][OH:51])[CH2:42][CH2:41]3)=[CH:21][N:20]=2)[CH2:8][CH:7]1[CH2:46][CH3:47])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCNCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2C(Nc2ncc(N3CCN(CCO)CC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)CC1CC
Temperature: 50 °C
Reaction time: 5 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(piperazin-1-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in N,N-dimethylformamide (1 ml), then thereto are added 2-iodoethanol (26 μl) and excess potassium carbonate, and the mixture is heated to 50° C. under nitrogen flow and stirred for 5 hours. After adding distilled water, the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=19:1→9:1) to give (2R*,4-{[3,5-bis(trifluoromethyl)benzyl]-[5-[4-(2-hydroxyethyl)piperazin-1-yl]pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (128 mg). MS (m/z): 712 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[NH:10][C:9]1=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:20][CH3:21]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[N:10]([CH2:20][CH3:21])[C:9]1=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)NC2CCCC21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)N(C(=O)OC(C)(C)C)C2CCCC21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.9 %

Procedure:
To a solution of (3aSR,6aRS)-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester (Example 1, step 1) (1.50 g, 6.63 mmol) in 25 ml of DMF was added a 60% suspension of sodium hydride in mineral oil (207 mg, 8.62 mmol, 1.3 equiv.). The suspension was stirred for 45 minutes at room temperature (gas evolution), then iodoethane (1.34 g, 0.696 ml, 8.62 mmol, 1.3 equiv.) was added and the mixture was stirred at room temperature overnight. After concentration in vaccuo and workup with ethyl acetate/water, 1.60 g of a yellow oil were obtained containing mineral-oil drops which was directly used in the next step without further characterization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.O[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:22]1([NH:18][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:16])[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=1
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (107 mg, 0.49 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (75 mg, 0.56 mmol) and PS-DCC (511 mg, 1.28 mmol/g, 0.65 mmol) in DMF (8 mL) is shaken at room temperature for 15 min. Aniline (30.4 mg, 0.33 mmol) is added. The mixture is shaken at room temperature for 18 hours. PS-trisamine (392 mg, 3.75 mmol/g, 1.47 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with EtOAc. The filtrate is concentrated to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide as a solid in quantitative yield. MS: 294 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:28])[CH2:4][CH2:3]1.[O:29]1[C:38]2[CH:37]=[C:36]([CH:39]=O)[N:35]=[CH:34][C:33]=2[O:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:29]1[C:38]2[CH:37]=[C:36]([CH2:39][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[C:15]([C:22]6[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=6)[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:28])[CH2:6][CH2:7]3)[N:35]=[CH:34][C:33]=2[O:32][CH2:31][CH2:30]1
Reactant: COc1cc(-c2ccncc2)c2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2ccncc2)c2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
To 3 mL of a chloroform solution containing 160 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-5-(pyridin-4-yl)quinoxalin-2(1H)-one and 63 mg of 2,3-dihydro-1,4-dioxino[2,3-c]pyridine-7-carbaldehyde, 0.04 mL of acetic acid was added, and stirred at room temperature for 4 hours. To the reaction mixture, 140 mg of sodium triacetoxyborohydride was added, and stirred for 13 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=4:1] to give 139 mg of 1-(2-(4-((2,3-dihydro-1,4-dioxino[2,3-c]pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxy-5-(pyridin-4-yl)quinoxalin-2(1H)-one as a white foam.