Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1C=CC=CN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Br
Agent: BrCc1ccccn1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccn3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)pyridine hydrobromide and isolated as light-yellow solid (4.2 mg, 27%). MS (m/e): 374.4 (MH+).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]([CH3:35])[CH2:24][C:25]2[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([NH:12][C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]([CH3:35])[CH2:24][C:25]2[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])=[CH:15][CH:14]=1)=[O:11])([OH:6])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(NC(=O)c2ccccc2C(=O)O)nc1
Reaction time: 48 h
Yield: 15.6 %

Procedure:
Phthalic anhydride (0.81 g, 5.48 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.44 g, 1.37 mmole) and sodium bicarbonate (0.58 g, 6.85 mmole) in THF (70 mL) at RT, and the reaction was heated at reflux under nitrogen. After 48 hr, the reaction was concentrated in vacuo and the residue was diluted with water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Plash chromatography on silica gel (10% MeOH/CHCl3) gave the title compound (0.10 g, 16%) as a light yellow solid: MS (ES) m/e 469 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Si:8]([O:25][CH2:26][CH:27]1[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[Si:8]([O:25][CH2:26][CH:27]1[CH2:30][NH:29][CH2:28]1)([C:21]([CH3:24])([CH3:22])[CH3:23])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](OCC1CNC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
2,2,2-Trifluoroacetic acid (42.9 mL, 556.53 mmol) was added to tert-butyl 3-((tert-butyldiphenylsilyloxy)methyl)azetidine-1-carboxylate (Intermediate BG4) (9.87 g, 23.19 mmol) in anhydrous DCM (50 mL) at 0° C. then allowed to stirred at room temperature for 1 hour. The solution was concentrated and made basic using sodium hydroxide (250 mL, 2M) was added. the suspension was extracted with DCM and dried with Na2SO4 to afford the product (7.46 g, 99%)
Reaction SMILES: [CH3:1][N:2]([C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:22])[C:17]([O:19]CC)=[O:18])[N:15]=1)[C:3]([O:5][C:6]([CH2:9][CH3:10])([CH3:8])[CH3:7])=[O:4].[OH-].[Na+]>C(O)C>[CH3:1][N:2]([C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:22])[C:17]([OH:19])=[O:18])[N:15]=1)[C:3]([O:5][C:6]([CH2:9][CH3:10])([CH3:7])[CH3:8])=[O:4]
Reactant: CCOC(=O)C(=O)c1csc(N(C)C(=O)OC(C)(C)CC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(C)(C)OC(=O)N(C)c1nc(C(=O)C(=O)O)cs1
Yield: 84.7 %

Procedure:
To a solution of ethyl 2-[2-(N-methyl-N-tert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]glyoxylate (3.1 g.) in ethanol (40 ml.) was added 1 N sodium hydroxide aqueous solution (14.2 ml.) under ice-cooling and stirring, and the mixture was further stirred for 30 minutes at the same temperature. After the reaction, ethanol was distilled off from the reaction mixture below 20° C. under reduced pressure. To the residue was added water (50 ml.), and after layering with ethyl acetate, the mixture was adjusted to pH 3 with 2 N hydrochloric acid. The ethyl acetate layer was separated from the mixture, washed with water, dried over magnesium sulfate and then treated with an activated charcoal. The solvent is distilled off from the resulting ethyl acetate layer to give solid of 2-[2-(N-methyl-N-tert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]glyoxylic acid (2.4 g.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([O:26]CC)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:29][CH2:30][C:31]([F:34])([F:33])[CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([OH:26])=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:29][CH2:30][C:31]([F:34])([F:33])[CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC(C)(F)F)C2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OCC(C)(F)F)nc1Cl
Yield: 66.4 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(2,2-difluoropropoxy)piperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (130a) (0.20 g, 0.49 mmol), 2 N lithium hydroxide (6 mL, 12 mmol) and methanol (5 mL), to obtain 0.16 g of the title compound as a light brown solid (74%).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[F:14][C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[CH2:16][CH2:17][CH2:18][OH:19]>CC(C)=O>[F:14][C:15]([F:24])([C:20]([F:21])([F:22])[F:23])[CH2:16][CH2:17][C:18]([OH:3])=[O:19]
Reactant: CC(C)=O
Reactant: OCCCC(F)(F)C(F)(F)F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a stirred solution of Jones reagent (20 ml, 160 mmol) in acetone (20 ml), cooled in an ice bath, a solution of 4,4,5,5,5-pentafluoro-1-pentanol (7.12 g, 40 mmol) in acetone (30 ml) was added dropwise. After remaining ice bath, the mixture was stirred continuously at room temperature for 1 h. The mixture was poured into ice/water and extracted with diethyl ether. Crude ether washed was extracted with aqueous 2 N sodium hydroxide. On the inorganic layer was acidified with aqueous 6 N hydrochloric acid and the organic layer was extracted with diethyl ether. The final extract was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude 4,4,5,5,5-pentafluoropentanoic acid as colorless liquid (6.31 g, 82%), which was used in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]([C@H:15]([OH:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl.C(OCC)C>ClCCl>[CH3:16][C@H:15]1[O:17][C:19](=[O:21])[NH:9][C@@H:10]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H]1NC(=O)O[C@@H]1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (7.40 mL, 53.1 mmol) was added slowly to a mixture of (2S,3R)-methyl 2-amino-3-hydroxybutanoate hydrochloride (3.0 g, 17.7 mmol) in dichloromethane (41 mL) at 0° C. The mixture was stirred for 15 minutes. A mixture of triphosgene (1.79 g, 6.01 mmol) in dichloromethane (15 mL) was added drop wise via addition funnel. The mixture was allowed to warm to room temperature for 14 hours. Diethyl ether (20 mL) was added, and the mixture was cooled to −78° C. for 15 minutes. The solids were filtered and the filtrate was concentrated under reduced pressure to about 10 mL. The mixture was then added to a plug of silica gel and washed slowly with ethyl acetate (˜75 mL). The filtrate was then concentrated under reduced pressure and dried under vacuum to afford (4S,5R)-methyl 5-methyl-2-oxooxazolidine-4-carboxylate. 1H NMR (500 MHz, CDCl3) δ 5.96 (s, 1H), 4.77-4.71 (m, 1H), 3.99 (d, J=5.4 Hz, 1H), 3.81 (s, 3H), 1.56 (d, J=6.3 Hz, 3H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:20][C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:15]([NH:17][O:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(NCC2C=CSC=2)CC1)=O)(C)(C)C.[O:46]=[C:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49](=[O:56])[N:48]1[CH2:57][CH2:58]C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(O)(=O)C>[O:46]=[C:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49](=[O:56])[N:48]1[CH2:57][CH2:58][CH2:6][N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:20][C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:15]([NH:17][O:18][CH3:19])=[O:16])[CH2:12][CH2:13]1
Reactant: CONC(=O)N(Cc1ccsc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=CCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1CCC(NCc2ccsc2)CC1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Product: CONC(=O)N(Cc1ccsc1)C1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
4-(3-Methoxy-1-thiophen-3-ylmethyl-ureido)-piperidine-1-carboxylic acid tert-butyl ester (0.950 g, 2.69 mmol) was dissolved in a 3:1 mixture of CH2Cl2 and TFA and the mixture was stirred at rt for 1 h. The solvent was removed in vacuo and the resulting brown oil pumped in vacuo (high vacuum system) for 2 h. Using general procedure A, the crude amine, 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde (0.561 g, 2.75 mmol), acetic acid (20 drops, cat.) and sodium triacetoxyborohydride (0.792 g, 3.75 mmol) were combined in CH2Cl2 (40 ml) and the resulting mixture was stirred at rt for 16 h. Standard basic workup gave the crude product as a tan oil. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 94:5:1, v/v/v) gave 1-{1-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-piperidin-4-yl}-3-methoxy-1-thiophen-3-ylmethyl-urea as a white foam (0.692 g, 62%). 1H NMR (CDCl3) δ 1.36 (m, 2H), 1.59 (m, 2H), 1.85 (p, 2H, J=4.5 Hz), 1.91 (t, 2H, J=9.0 Hz), 2.39 (t, 2H, J=6.0 Hz), 2.88 (d, 2H, J=12.0 Hz), 3.62 (s, 3H), 3.75 (t, 2H, J=6.0 Hz), 4.04 (s, 2H), 4.23 (m, 1H), 6.90 (d, 1H, J=3.0 Hz), 6.99 (s, 1H), 7.06 (s, 1H), 7.36 (m, 1H), 7.62 (m, 2H), 7.81 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[C:21]([C:22]([OH:24])=O)=[C:20]([C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[CH:27][CH:26]=4)[N:19](COCC[Si](C)(C)C)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:46][N:47](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C1COCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[C:21]([C:22]([NH:47][CH3:46])=[O:24])=[C:20]([C:25]4[CH:26]=[CH:27][C:28]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[CH:29][CH:30]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(CCc2cnc3c(n2)c(C(=O)O)c(-c2ccc(N4CCN(C)CC4)cc2)n3COCC[Si](C)(C)C)cc(OC)c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(N3CCN(C)CC3)cc2)[nH]c2ncc(CCc3cc(OC)cc(OC)c3)nc12
Reaction time: 1 h
Yield: 21.5 %

Procedure:
To a stirred solution of crude 2-[2-(3,5-dimethoxyphenyl)ethyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (20 mg, 31.6 μmol) in N,N-dimethylformamide (2 mL), HATU (12.0 mg, 31.6 μmol), 2.0 M methylamine in THF (15.8 μL, 31.6 μmol) and N,N-diisopropylethylamine (11.0 μL, 63.3 mmol) were added sequentially at ambient temperature. After 1 hour, the reaction was quenched with saturated aqueous NH4Cl, extracted with methylene chloride. The combined organic layers were dried over MgSO4, concentrated. The residue was dissolved in methylene chloride (1 mL) and trifluoroacetic acid (1 mL) was added at ambient temperature. After 2 hours, the volatiles were removed under vacuum and the residue was dissolved in methanol (1 mL), followed by the addition of ethylenediamine (0.1 mL). After another 1 hour, the reaction mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (3.5 mg) as its TFA salt. LCMS calculated for C29H35N6O3 (M+H)+: m/z=515.3. Found: 515.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[NH:12][CH:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:9]2)=[CH:4][CH:3]=1.[C:19]1(C)C=CC=C[CH:20]=1>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>[CH:19]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[NH:12][CH:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:9]2)=[CH:4][CH:3]=1)=[CH2:20]
Reactant: Brc1ccc(N2NC=C(c3ccccc3)O2)cc1
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1ccc(N2NC=C(c3ccccc3)O2)cc1

Procedure:
2-(4-Bromophenyl)-5-phenyl-oxadiazole (2.0 g, 6.64 mmol) was dissolved in degassed toluene (30 ml). Pd(PPh3)4 (0.15 g, 0.133 mmol) and nBu3Sn(CHCH2)(2.11 g, 6.64 mmol) were added under dry nitrogen. The solution was refluxed for 4 hours, cooled, and evaporated to give a yellow solid. This solid was dissolved in toluene (20 ml), silica added (20 g) and the solvent removed in vacuo. This solid was placed on top of a short column of silica and flushed with hexane to remove nBu3SnBr, and the column then stripped with methanol. The methanol was evaporated, and the residue recrystallised from hexane to give white crystals of 2-(4-vinylphenyl)-5-phenyloxadiazole, (m.pt. 83-84° C., lit.ii 82-84° C.)1.1 g, 67%. 1H NMR (CDCl3, 300 MHz) δ 8.1-8.0 (m, 4H, aromatic CH), 7.6-7.6 (m,5H, aromatic CH), 6.77 (d of d, 3JHH 17.4 Hz and 10.8 Hz, ChCH2), 6.90 (d, 3JHH 17.4 Hz, CHCH2), (d of d, 3JHH 10.8 Hz, CHCH2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([N:22](C(OC(C)(C)C)=O)[CH3:23])[CH2:18][CH2:17]2)[CH2:14][CH3:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:14][CH3:15])[C@H:16]2[CH2:21][CH2:20][C@H:19]([NH:22][CH3:23])[CH2:18][CH2:17]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 5-bromo-3-(((trans)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate (30 g, 62.24 mmol) in methanol (100 mL) at 0° C., methanolic HCl (500 mL) was added and reaction was stirred for 2 h at room temperature. After completion, reaction was concentrated to dryness. The residue was basified with Na2CO3 (aq.) to pH 8 and aqueous layer was extracted with 10% methanol in DCM (200 mL×3). Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford the title compound as colorless oil (25 g, crude). The isolated compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]([CH3:30])=[C:12]([CH2:14][O:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH2:17]3)[N:13]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]([CH3:30])=[C:12]([CH2:14][O:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:17]3)[N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCC[C@H]1CCC[C@@H](OCc2nc(-c3cccc(OC)c3)oc2C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(-c2nc(CO[C@@H]3CCC[C@H](CCCC(=O)O)C3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.4 %

Procedure:
110 mg of ethyl 4-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}butyrate are dissolved in 5 ml of a mixture of tetrahydrofuran and water in a ratio of 2:1, and 20 mg of lithium hydroxide are added. The mixture is stirred at room temperature for 12 hours. The mixture is acidified by addition of 1 N HCl and extracted with ethyl acetate. The organic phase is dried over MgSO4, and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. Freeze-drying gives 24 mg of 4-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}butyric acid as a lyophilizate. C22H29NO5 (387.48), MS(ESI): 388 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]3[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:17]=3)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]#[CH:32].O>CN(C)C=O>[O:1]=[C:2]1[N:7]([CH2:32][C:31]#[CH:30])[C:6]2[CH:8]=[C:9]([C:12]3[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:17]=3)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc3c(c2)NC(=O)CO3)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2ccc(-c3ncc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Then, 0.15 g of 3-(3-oxo-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 2-1) was dissolved in 0.92 ml of N,N-dimethylformamide, to which 0.127 g of potassium carbonate and 70 μl of propargyl bromide were added, and the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.12 g (yield, 74%) of 3-(3-oxo-4-propargyl-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 2-13; m.p., 129.2° C.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1.[OH:25][CH2:26][CH2:27][NH2:28].CO.O>CN(C)C=O>[OH:25][CH2:26][CH2:27][NH:28][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: NCCO
Reactant: N#Cc1c(Cl)nc(Sc2ccccc2)c(C#N)c1-c1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(NCCO)nc(Sc2ccccc2)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under argon, 0.7 g (2 mmol) of 2-chloro-4-phenyl-6-(phenylsulfanyl)-3,5-pyridine-dicarbonitrile (1st step) is dissolved in 2 ml of dimethylformamide (DMF), 0.27 g (4.5 mmol) of 2-hydroxyethylamine is added and the mixture is stirred at room temperature for 15 minutes. After addition of 2 ml of methanol, about 1 ml of water is added dropwise and the precipitate is filtered off with suction. The crystals are purified by boiling with 4 ml of methanol.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([O:32]C)=[O:31].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:29][C:30]([OH:32])=[O:31])=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cc1
Reactant: COC(=O)Cc1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2ccccc2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-2-(2-furyl)-5-methyloxazole (1.84 g), methyl 2-(2-hydroxyphenyl)acetate (1.00 g), anhydrous potassium carbonate (1.66 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature overnight. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. To a mixture of the obtained residue, tetrahydrofuran (10 mL) and methanol (10 mL) was added a 1N aqueous sodium hydroxide solution (10 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to the residue. The precipitated solid was collected by filtration and dried with air to give crystals (2.08 g, 82%) of 2-[2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 167-168° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH2:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1)[C:9]2=[O:14])([O-])=O.CO>[Pd]>[C:23]([O:22][C:20]([N:18]1[CH2:19][CH:16]([CH2:15][N:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[NH2:1])[C:9]2=[O:14])[CH2:17]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC(Cn2ccc3c([N+](=O)[O-])cccc3c2=O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(Cn2ccc3c(N)cccc3c2=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round bottom flask was combined tert-butyl 3-((5-nitro-1-oxoisoquinolin-2(1H)-yl)methyl)azetidine-1-carboxylate (0.56 g, 0.0015 mol), palladium on C (0.16 g, 0.0015 mol) and methanol (50 mL, 1 mol). The reaction mixture was stirred under hydrogen balloon at room temperature overnight. The mixture was filtered over celite, MeOH was removed and purified by silica-gel column twice (DCM:MeOH and EtOAc:Hexane). A white solid was obtained (190 mg). MS m/z=330.0 (M+1).