Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].C([Li])CCC.IC>C1COCC1>[F:7][C:8]1[CH:16]=[C:15]([CH3:1])[C:14]([O:17][CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COc1ccc(F)c(C(=O)O)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)c(F)cc1C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Potassium tert-butoxide (7.92 g, 70.5 mmol) was dissolved in THF (150 mL) and cooled to −78° C. 2-Fluoro-5-methoxybenzoic acid (3.00 g, 17.6 mmol) in THF (100 mL) was added followed by n-butyl lithium (2.5 N in hexanes, 28.2 mL, 70.5 mmol). After 40 minutes, iodomethane (2.2 mL, 35.4 mmol) was added and allowed to stir at −78° C. for 70 minutes before warming to room temperature. The reaction was quenched with saturated ammonium chloride (100 mL) and extracted with ether. The aqueous layer was acidified using 6 N HCl then extracted with ether. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified by Gilson reverse-phase HPLC (acidic mobile phase) to yield 2-fluoro-5-methoxy-4-methylbenzoic acid as a white solid. MS m/z=185 [M+1]+. Calc'd for C9H9FO3: 184.20.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][N:11]([C:23]2[C:32]([N:33]3[CH2:38][C@@H:37]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C@@H:35]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:34]3)=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH:55][C:56](=[O:66])[C:57]4[CH:62]=[CH:61][C:60]([N+:63]([O-])=O)=[CH:59][CH:58]=4)[CH:29]=3)[N:24]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NN>CCOC(C)=O.CO.[Ni]>[NH2:63][C:60]1[CH:61]=[CH:62][C:57]([C:56]([NH:55][C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[N:24]=[C:23]([N:11]2[CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][C@@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[C:32]([N:33]2[CH2:38][C@@H:37]([NH:39][C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[CH2:36][C@@H:35]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:34]2)=[N:31]3)=[O:66])=[CH:58][CH:59]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Agent: [Ni]
Agent: NN
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc(NC(=O)c4ccc(N)cc4)cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 100.6 %

Procedure:
N-(2,3-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-quinoxalin-6-yl)-4-nitro-benzamide (251) (0.063 g, 0.068 mmol) was dissolved in a mixture of EtOAc (3 mL) and MeOH (3 mL). The solution was heated to 60° C. and Raney Nickel (0.25 mL, 50% slurry in water) and hydrazine (0.5 mL, anhydrous) were added. Bubbling was observed. The mixture continued to stir for 15 minutes at 60° C. The mixture was passed through a plug of silica gel and concentrated to give an orange powder. The solid was dissolved in EtOAc (30 mL), washed with water (2×20 mL) and brine (2×20 mL) via extraction, dried over MgSO4 and concentrated to give the desired product as an orange powder (0.061 g, 0.0684 mmol, 99% yield). LC-MS (ESI): (exact mass: 890.50) m/e=891.9 [M+1]+.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[C@@H:8]([CH2:20][CH2:21][CH:22]([OH:31])[C:23]([F:30])([F:29])[CH2:24][C@@H:25]([CH3:28])[CH2:26][CH3:27])[C@H:7]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:6]1)(=O)C.[OH-].[Na+]>C(O)C>[F:30][C:23]([F:29])([CH2:24][C@@H:25]([CH3:28])[CH2:26][CH3:27])[CH:22]([OH:31])[CH2:21][CH2:20][C@H:8]1[C@H:7]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:6][C@H:5]([OH:4])[C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CC[C@H](C)CC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC[C@H](C)CC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((6S)-4,4-difluoro-6-methyl-3-hydroxyoctyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (E) (132.5 mmol) in ethanol (213 ml) was cooled on ice, and an 24% sodium hydroxide aqueous solution (135 ml, 1029 mmol) was added thereto dropwise. After stirring at room temperature for approximately 3.5 hours, the reaction mixture was concentrated under reduced pressure. The residue was mixed with water (281 ml) and t-butyl methyl ether (141 ml), and cooled on ice. After 6M-hydrochloric acid was added dropwise to adjust to pH 3 to 4, the solution was extracted three times with ethyl acetate (281 ml). The organic layers were combined and sequentially washed with water (281 ml) twice and saturated aqueous sodium chloride (338 ml). After drying with anhydrous magnesium sulfate (50 g), the solution was concentrated under reduced pressure to give crude 7[(1R,2R,3R,5S)-2-((6S)-4,4-difluoro-6-methyl-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid (F) as white solid. The entire amount was used in the following step without purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:14]1([C:20]2[O:24][N:23]=[CH:22][C:21]=2[CH2:25][C:26](O)=[O:27])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:26](=[O:27])[CH2:25][C:21]3[CH:22]=[N:23][O:24][C:20]=3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Reactant: O=C(O)Cc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1cnoc1-c1ccccc1)Nc1nc(-c2ccc(Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A mixture of 2-amino-4-(4-chlorophenyl)thiazole (0.65 g), 5-phenyl-4-isoxazolylacetic acid (0.60 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.51 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.59 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-(4-chlorophenyl)-2-thiazolyl]-5-phenyl-4-isoxazolylacetamide (0.92 g, yield 79%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 210–211° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[NH2:10][CH2:11][CH2:12][C:13]1[N:14]=[C:15]([F:37])[N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1>>[F:37][C:15]1[N:16]([C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:17]=[C:13]([CH2:12][CH2:11][NH:10][C:7]([C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[O:9])[N:14]=1
Reactant: Cc1cc(C(=O)O)no1
Reactant: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Product: Cc1cc(C(=O)NCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)n2)no1

Procedure:
5-Methylisoxazole-3-carboxylic acid and 4-(2-aminoethyl)-2-fluoro-1-triphenylmethylimidazole were reacted by the mixed anhydride procedure described for the starting material of Example 24, to give 2-fluoro-4-[2-(5-methylisoxazole-3-carboxamido)ethyl]-1-triphenylmethylimidazole. It had the following n.m.r. spectrum in d6DMSO: 2.5 (s, 3H); 2.7 (t, 2H); 3.7 (q, 2H); 6.3 (s, 1H); 6.4 (s, 1H); 7.0-7.4 (m, 15H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9](=[O:25])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:19])[F:18])=[C:12]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH:11]=1.O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:37].[Mg+2].C(OCC)(=O)C>C(Cl)Cl.CO>[Cl:26][C:6]1[CH:5]=[N+:4]([O-:37])[CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9](=[O:25])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:18])[F:19])=[C:12]([O:20][CH2:21][CH:22]2[CH2:23][CH2:24]2)[CH:11]=1
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 63.8 %

Procedure:
A mixture of N-(3,5-Dichloropyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide (3.0 g, 7.4 mmol) and magnesium monoperoxyphthalate hexahydrate (“MMPP”) (7.36 g, 14.9 mmol) in CH2Cl2/MeOH (10 mL) was stirred under reflux for 48 h. An additional amount of magnesium monoperoxyphthalate hexahydrate (7.4 g, 15 mmol) was added and the reaction mixture was stirred under reflux for an additional 24 h. Ethyl acetate was then added and the organic phase was washed by 25% aqueous NH4OAc, water and brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica (EtOAc) to yield N-(3.5-Dichloro-1-oxido-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide (Compound I) as a white solid (1.98 g, 63%). 1H NMR (500 MHz, acetone-d6): δ 0.40 (m, 2H), 0.60 (m, 2H), 1.30 (m, 1H), 4.0 (d, 2H), 7.05 (t, 1H), 7.35 (d, 1H), 7.7 (m, 1H), 7.75 (s, 1H), 8.40 (s, 2H), 9.6 (bs, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:25][CH2:24]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(F)cc2[N+](=O)[O-])CC1
Yield: 97 %

Procedure:
Method 1 was followed using 2,5-difluoronitrobenzene (1.0 eq), 4-(N-Boc-amino) piperidine (1.4 eq), and TEA (2.0 eq) at 55° C. overnight yielding tert-butyl 1-(4-fluoro-2-nitrophenyl)piperidin-4-ylcarbamate (97%). LCMS (m/z): 340.1 (MH+); LC Rt=3.28 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:12]([Cl:28])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
167 g of 3,5-dibenzyloxybenzoic acid and 400 ml of redistilled thionyl chloride were refluxed on an oil bath for 1 hour. Excess thionyl chloride was distilled off at reduced pressure, and the remaining mass crystallized. The product was recrystallized from petroleum ether (B.p., 60°-85°C.) : M.P. 73°-74°C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH:16]1([C:20]2[C:28]([C:29](=[O:32])[NH:30][CH3:31])=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([CH3:33])[CH:21]=2)[CH2:19][CH2:18][CH2:17]1.CCN=C=NCCCN(C)C.Cl.CCOC(C)=O>CN(C)C1C=CN=CC=1.CN(C)C=O>[O:1]1[C:5]2[CH:6]=[C:7]([CH:10]3[CH2:15][CH2:14][N:13]([C:24]([C:23]4[C:22]([CH3:33])=[CH:21][C:20]([CH:16]5[CH2:19][CH2:18][CH2:17]5)=[C:28]([CH:27]=4)[C:29]([NH:30][CH3:31])=[O:32])=[O:25])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: c1cc2ccc(C3CCNCC3)cc2o1
Reactant: CNC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(C(=O)N2CCC(c3ccc4ccoc4c3)CC2)c(C)cc1C1CCC1
Temperature: 15 °C
Reaction time: 2 h
Yield: 19.4 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 4-(benzofuran-6-yl)piperidine (compound 63.6) (110 mg, 0.55 mmol), 4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3, 135 mg, 0.55 mmol), EDC.HCl (210 mg, 1.10 mmol) and 4-dimethylaminopyridine (133.5 mg, 1.09 mmol) in N,N-dimethylformamide (3 mL). The resulting solution was stirred for 2 h at 15° C. then diluted EtOAc (60 mL). The resulting mixture was washed with aqueous saturated NH4Cl (2×20 mL) and brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product (110 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (51.0% CH3CN up to 60.0% in 9 min, up to 100.0% in 5 min, down to 51.0% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield the title compound as a white solid (46.0 mg, 20%). m/z (ES+) 431 (M+H)+.
Reaction SMILES: Cl.N[C@@H]1CC[C@H](O)CC1.[NH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[CH3:28])[C:24](=[O:29])[NH:23][CH:22]=[CH:21]3)[CH2:13][CH2:12]1.Cl.N[C@@H]1CC[C@H](OC2C=C3C(=CC=2C)C(=O)NC=C3)CC1>>[NH2:10][C@@H:11]1[CH2:12][CH2:13][C@H:14]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[CH3:28])[C:24](=[O:29])[NH:23][CH:22]=[CH:21]3)[CH2:15][CH2:16]1
Reactant: Cc1cc2c(=O)[nH]ccc2cc1O[C@H]1CC[C@H](N)CC1
Agent: Cl
Agent: N[C@H]1CC[C@@H](O)CC1
Product: Cc1cc2c(=O)[nH]ccc2cc1O[C@H]1CC[C@@H](N)CC1

Procedure:
From 2.55 g (16.8 mmol) of cis-4-aminocyclohexanol hydrochloride and 5.0 g (16.8 mmol) of 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one (25, step b) were prepared 0.98 g of 6-(cis-4-amino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1-one hydrochloride as described in example 25 (steps c and d). Rt=0.99 min (Method B). Detected mass: 273.18 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH:23]2CCCCO2)=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].BrCCOC>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCOC2CCCCO2)cc1
Agent: COCCBr
Product: COCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Prepared by the same method as described in example 48 except that (i) 2,6-difluoro-4-iodoaniline was used in place of 2-fluoro-4-iodoaniline, and (ii) (R)-tert-butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid was used in place of (R)-tert-butoxycarbonylamino-{4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-acetic acid. (R)-tert-Butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid was prepared as described in example 48 except that 1-bromo-2-methoxyethane was used in place of 2-(2-bromo-ethoxy)-tetrahydropyran.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([CH3:22])[C:10](=[O:21])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:11][C:10](=[O:21])[C:9]=1[CH3:22]
Reactant: CC(C(=O)CC(=O)c1ccccc1F)C(=O)c1ccccc1Cl
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2Cl)n(-c2ccccc2)c(-c2ccccc2F)cc1=O
Yield: 25.1 %

Procedure:
In 450 ml of xylene were suspended 15.3 g of 1-(2-chlorophenyl)-2-methyl-5-(2-fluoro-phenyl)-1,3,5-pentanetrione, 6.4 g of aniline, 6.6 g of para-toluenesulfonic acid and 85 g of Molecular Sieves 5A, followed by refluxing the resultant mixture for 8 hours. Xylene was distilled off from the reaction mixture and 300 ml of chloroform was added to the residue. The mixture obtained was filtered and the filtrate was washed first with 10% hydrochloric acid and then with a 10% aqueous solution of sodium hydroxide. After washing the chloroform phase further with water, the solution in chloroform was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate-n-hexane, 1:3) to afford crude crystals. The crystals were recrystallized from ethyl acetate, yielding 4.5 g of 2-(2-chlorophenyl)-6(2fluorophenyl)-3-methyl-1-phenyl-4(1H)-pyridinone having a melting point of 182°-183° C.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:23]([NH:25][C@H:26]([C:29]([NH:31][C@H:32]([C:41]([NH:43][C@@H:44]([C:46]([NH:48][C@H:49]([C:54]([O:56][CH3:57])=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH3:45])=[O:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)=[O:30])[CH2:27][OH:28])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=O)C1C=CC=CC=1.[ClH:58].O.[H][H]>CO.[Pd]>[ClH:58].[NH2:11][C@H:12]([C:23]([NH:25][C@H:26]([C:29]([NH:31][C@H:32]([C:41]([NH:43][C@@H:44]([C:46]([NH:48][C@H:49]([C:54]([O:56][CH3:57])=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH3:45])=[O:42])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=1)=[O:30])[CH2:27][OH:28])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
A solution of 1.58 g. of Nα -benzyloxycarbonyl-L-tryptophyl-L-seryl-L-tyrosyl-D-alanyl-L-leucine, methyl ester in 100 ml. of methanol with 1.6 ml. of 1.3 N hydrogen chloride in methanol is stirred with 150 mg. of palladium on carbon under one inch water pressure of hydrogen for two and a half hours. Thin layer chromatography of samples of the solution shows the disappearance of the starting material in about two hours. The catalyst is removed by filtration and the filtrate evaporated at 40° and reduced pressure. The residue is used without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.Cl.[CH2:33]([N:35]=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN>CN(C=O)C.O>[CH3:33][NH:35][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
(S)-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (50 mg, 0.119 mmol) was taken up in DMF (0.5 mL). To the mixture was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (34.1 mg, 0.178 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (27.2 mg, 0.178 mmol), 4-methylmorpholine (0.065 mL, 0.593 mmol) and methanamine hydrochloride (8.01 mg, 0.119 mmol). The reaction was stirred at room temperature overnight. To the stirred solution was added water (2 mL) and the precipitate was filtered, collected, and dried in vacuum to afford the title compound (23.8 mg, 46.2%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.49 (s, 1H), 8.14 (q, J=4.5 Hz, 1H), 7.58-7.80 (m, 3H), 6.82-7.04 (m, 3H), 4.51 (d, J=12.9 Hz, 1H), 3.84 (dd, J=11.2, 2.7 Hz, 1H), 3.30-3.51 (m, 3H), 3.23 (br. s., 4H), 2.74 (d, J=4.5 Hz, 3H), 2.61 (td, J=12.7, 2.7 Hz, 1H), 2.49 (br. s., 3H), 2.04 (d, J=12.6 Hz, 1H), 1.85 (d, J=12.1 Hz, 1H), 1.64 (d, J=12.6 Hz, 1H), 1.33-1.59 (m, 3H). [M+H] calc'd for C24H30N6O2, 435; found, 435.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:31])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si](C(C)(C)C)(C)C)=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:31])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:29])([CH3:30])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)benzamide (2E, 1.9 g, 1.0 equivalent) was dissolved in THF (0.4 M). Cooled mixture in ice bath, and followed by a slow addition of TBAF (1.0M THF solution, 6.5 equivalents). After addition, mixture was warmed to room temperature and then heated to 60° C. for 3 h. After stirring, water was added and followed by extraction with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography (SiO2, gradient of 1 to 5% MeOH/CH2Cl2) to give 2F (60%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 6H) 3.48 (s, 2H) 4.77 (br. s., 1H) 7.57 (d, J=8.59 Hz, 2H) 7.72 (d, J=8.34 Hz, 1H) 8.05-8.16 (m, 3H) 13.08 (s, 1H); ESI-MS: m/z 406.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=1[CH2:11][C:12]1[C:13](=[O:24])[NH:14][NH:15][C:16]=1[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]([O:32][CH2:33][C@H:34]1[O:39][C@H:38](Br)[C@H:37]([O:41][C:42]([CH3:44])=[O:43])[C@@H:36]([O:45][C:46]([CH3:48])=[O:47])[C@@H:35]1[O:49][C:50]([CH3:52])=[O:51])=[O:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=1[CH2:11][C:12]1[C:13]([O:24][C@@H:38]2[O:39][C@H:34]([CH2:33][O:32][C:30](=[O:31])[CH3:29])[C@@H:35]([O:49][C:50](=[O:51])[CH3:52])[C@H:36]([O:45][C:46](=[O:47])[CH3:48])[C@H:37]2[O:41][C:42](=[O:43])[CH3:44])=[N:14][NH:15][C:16]=1[C:17]([F:22])([F:23])[C:18]([F:19])([F:20])[F:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=c1[nH][nH]c(C(F)(F)C(F)(F)F)c1Cc1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)C(F)(F)F)c2Cc2ccccc2OCc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(2-benzyloxybenzyl)-5-pentafluoroethyl-1,2-dihydropyrazol-3-one (55 mg) and acetobromo-α-D-glucose (63 mg) in acetonitrile (2 mL) was added potassium carbonate (23 mg), and the mixture was stirred at room temperature for 3 days. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate/hexane=1/1-ethyl acetate) to give 4-(2-benzyloxybenzyl)-5-pentafluoroethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole. To a solution of 4-(2-benzyloxybenzyl)-5-pentafluoroethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added sodium methoxide (28% methanol solution, 50 μL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (33 mg).