Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH2:13][OH:14])[C:10]2[C:5](=[CH:6][C:7]([O:11][CH3:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25].O>C(#N)C.CO>[Cl:22][CH2:23][C:24]([NH:1][C:2]1([CH2:13][OH:14])[C:10]2[C:5](=[CH:6][C:7]([O:11][CH3:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)=[O:25]
Reactant: COc1ccc2c(c1)CCC2(N)CO
Reactant: O=C(Cl)CCl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc2c(c1)CCC2(CO)NC(=O)CCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 60.0 mmol of (1-amino-5-methoxyindan-1-yl)methanol in 120 ml of acetonitrile and 40 ml of methanol is cooled to −10° C. and 69 mmol of triethylamine and, dropwise over the course of 1 hour, 80.5 mmol of chloroacetyl chloride are successively added. The reaction mixture is warmed to room temperature and stirred for 3 hours. The reaction mixture is poured into water and extracted with tert-butyl methyl ether. The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. The title compound is obtained as a beige solid which is employed without further purification for the next stage. Rf=0.15 (ethyl acetate-heptane 1:1); Rt=3.01 (gradient I).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH2:10][C:9]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:8][N:7]=1.C(N(CC)CC)C.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:13]2[CH2:14][CH2:15][C:9]3([O:8][N:7]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][N:3]=4)[CH2:10]3)[CH2:11][CH2:12]2)=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: c1csc(C2=NOC3(CCNCC3)C2)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)N2CCC3(CC2)CC(c2nccs2)=NO3)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 52 %

Procedure:
Compound O (0.150 g, 0.578 mmol) was dissolved in toluene (15 ml) and mixed successively with triethylamine (0.12 ml, 0.867 mmol) and 4-tert-butylphenyl isocyanate (0.102 ml, 0.578 mmol). The reaction mixture was heated to boiling point and boiled under reflux for 3 h. After cooling to RT, the mixture was stirred for 36 h. The reaction mixture was extracted with EtOAc (3×20 ml). The combined organic phases were washed with sat. Na2HCO3 solution (10 ml), dried over Na2SO4 and concentrated to dryness under vacuum. After purification of the residue by column chromatography (hexane:EtOAc 1:1), the desired product was obtained in a yield of 52% (0.120 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:3]1=[O:14].[BH4-].[Na+]>C(O)C>[C:10]([O:9][C:7]([NH:4][CH2:5][CH2:6][C:2]([CH3:15])([CH3:1])[CH2:3][OH:14])=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CO)CCNC(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 92.9 %

Procedure:
A solution of 3,3-dimethyl-1-(t-butoxycarbonyl)pyrrolidin-2-one (3.35 g, 15.7 mmol) in absolute ethanol under a nitrogen atmosphere was treated with sodium borohydride (1.79 g, 47.1 mmol). The resulting mixture was stirred at ambient tempeature for about 24 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with sodium bicarbonate. The aqueous fraction was back extracted twice with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was further purified by chromatography to yield 3.17 grams (93%) of the title intermediate as a clear oil. mp 75.5-76.5° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([C:15]([O:17]CC)=[O:16])=[C:8]2[NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=[O:4].[OH-].[Na+]>>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([C:15]([OH:17])=[O:16])=[C:8]2[NH:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)=[O:4]
Reactant: CCOC(=O)c1cnc2ccc(C(=O)NC)cc2c1Nc1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)c1ccc2ncc(C(=O)O)c(Nc3ccc(C)cc3)c2c1

Procedure:
Ethyl 6-(methylcarbamoyl)-4-[(4-methylphenyl)amino]quinoline-3-carboxylate was hydrolysed under basic conditions using NaOH (aq.). The final product was purified by column chromatography.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N-:20]=[N+]=[N-].[Na+]>>[CH:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12](=[O:14])[NH:20][C:13]=2[CH:1]=[CH:2][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1[nH]c2ccccc2c2ccccc12

Procedure:
In Scheme I, a 9-fluorenone (A) is treated with sulfuric acid and aqueous sodium azide in a ring-expansion, or Schmidt, reaction to produce 6(5H)-phenanthridinone (B). Nitration of (B) produces 2-nitro-6(5H)-phenanthridinone (C) as a major product, which is then reduced by Fe, NH4CI and DMF, or catalytic dehdrogcnation, to produce 2-amino-6(5H)-phenanthridinone (D). In general, a compound falling within Formula II is prepared by modifying the parent molecule 6(5H)-Phenanthridinone. See, e g., U.S. Pat. Nos. 3,291,801 and 3,932,643; Taylor et al., J. Am. Chem. Soc. 78:5104-5108 (1956). The 2-nitro (Compound C)- and 2-amino (Compound D)-6(5H)-phenanthridinones are synthesized by a slight modification of procedures described in Andrievskii, et al., Chem. Heterocycl. Compds (English Transl.) 21:8, 924-931 (1985), and Migachev, et al. Chem. Heterocycl. Compds (English Transl.) 17:3, 394-397 (1981).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:16][C@H:7]([O:8]CC2C=CC=CC=2)[C@H:6]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@@H:5]([OH:28])[C@@H:4]1[OH:29].[CH2:30]([OH:39])[C@H:31]1[O:36][C:34](=[O:35])[C@H:33]([OH:37])[C@@H:32]1[OH:38]>O1CCOCC1>[CH2:21]([C@@:7]1([O:16][C@H:3]([CH2:2][NH:1][C:34]([C@@H:33]([C@@H:32]([C@@H:31]([CH2:30][OH:39])[OH:36])[OH:38])[OH:37])=[O:35])[C@@H:4]([OH:29])[C@H:5]([OH:28])[C@H:6]1[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[OH:8])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NC[C@H]1O[C@H](OCc2ccccc2)[C@H](NC(=O)OCc2ccccc2)[C@@H](O)[C@@H]1O
Solvent: C1COCCO1
Product: O=C(N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CNC(=O)[C@H](O)[C@H](O)[C@H](O)CO)O[C@@]1(O)Cc1ccccc1)OCc1ccccc1

Procedure:
Benzyl 6-amino-2-benzyloxycarbonylamino-2,6-didesoxy-α-D-glucopyranoside (see Ex. 9.C.) and D-ribonic acid g-lactone were reacted as described in Ex. 14.A. and gave D-ribonic acid (benzyl 2-benzyloxycarbonylamino-2,6-didesoxy-α-D-gluco-pyranosid-6-yl)-amide, [α]+81.5° (c 0.2; dioxan), MS: m/z 551.4 ([M+H]+).
Reaction SMILES: C(OC1C=C(C=C([N+]([O-])=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.[CH2:27]([S:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([N+:47]([O-])=O)[C:40]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]([OH:37])=[O:36])[CH2:28][CH2:29][CH3:30]>>[NH2:47][C:39]1[C:40]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[C:32]([S:31][CH2:27][CH2:28][CH2:29][CH3:30])[CH:33]=[C:34]([CH:38]=1)[C:35]([OH:37])=[O:36]
Reactant: CCCCSc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Agent: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Product: CCCCSc1cc(C(=O)O)cc(N)c1-c1ccccc1

Procedure:
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenylbenzoic acid with 3-n-butylthio-5-nitro-4-phenylbenzoic acid, and following the procedure described, 5-amino-3-n-butylthio-4-phenylbenzoic acid is obtained with a melting point of 143°-144° C.
Reaction SMILES: ClC1C(Cl)=CC=CC=1N[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18](=[O:31])[N:19]([C@H:22]3[CH2:24][C@@H:23]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:21])[C@@H:14]2[CH2:13]1)=O.Cl.[C:33]1([C@H:39]2C[C@@H]2N2C(=O)[C@@H]3CNCCN3C2=O)[CH:38]=CC=C[CH:34]=1.C(Cl)(=O)C(C)(C)C>C(Cl)Cl>[CH3:34][C:33]([CH3:39])([CH3:38])[CH2:10][N:12]1[CH2:17][CH2:16][N:15]2[C:18](=[O:31])[N:19]([C@H:22]3[CH2:24][C@@H:23]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:21])[C@@H:14]2[CH2:13]1
Reactant: O=C(Nc1cccc(Cl)c1Cl)N1CCN2C(=O)N([C@H]3C[C@@H]3c3ccccc3)C(=O)[C@@H]2C1
Reactant: O=C1[C@@H]2CNCCN2C(=O)N1[C@H]1C[C@@H]1c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)CN1CCN2C(=O)N([C@H]3C[C@@H]3c3ccccc3)C(=O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of Example 4, D2 (1 eq) and TEA (1.1 eq) in DCM (0.08M) was added pivaloyl chloride (2.1 eq) and the reaction mixture was stirred at 25° C. for 2 h. The crude product was purified by preparative RP-HPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents, affording the title compound. 1H NMR (400 MHz, DMSO-d6, 300K) 7.48-7.18 (5H, m), 4.75-4.63 (1H, m), 4.42-4.33 (1H, m), 4.05-3.93 (2H, m), 3.15-2.80 (3H, m), 2.72-2.63 (1H, m), 2.50-2.38 (1H, m), 1.58-1.51 (1H, m), 1.48-1.38 (1H, m), 1.35 (9H, s). MS (ES) C20H25N3O3 requires: 354 found: 355 (M+H)+.
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.[Br:10][C:11]1[C:12](Cl)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]>CC#N.CCOCC>[Br:10][C:11]1[C:12]([N:3]2[CH2:4][CH2:6][C:20]([O:22][CH3:23])([CH3:19])[CH2:9][CH2:7]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOCC
Product: COC1(C)CCN(c2c(Br)c(C)nc(C)c2C(=O)C(=O)OC(C)C)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 121.7 %

Procedure:
To a solution of 4-methoxy-4-methylpiperidine, HCl (1.0 g, 6.04 mmol) and DIEA (4.2 mL, 24.5 mmol) in anhydrous CH3CN (30 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (3.4 g, 6.04 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-35% EtOAc/hexanes) using an Isolera chromatography station gave isopropyl 2-(5-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate 1.57 g (61%). 1H NMR (500 MHz, DMSO-d6) δ 5.08-5.03 (m, 1H), 3.44-3.40 (m, 4H), 3.11 (s, 3H), 2.60 (s, 3H), 2.29 (s, 3H), 1.67 (d, J=13.2 Hz, 2H), 1.43 (br. s., 2H), 1.29 (d, J=6.2 Hz, 6H), 1.11 (s, 3H). UPLC (M+H)=429.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15][N:14]2[C:29](=[O:43])[CH:30]([NH:35][C:36]([O:38][C:39]([CH3:42])(C)[CH3:40])=[O:37])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4].O=C1CCC(=O)N1OC(=O)OC1C[CH:58]2[CH:56]([CH2:57]2)C1>Cl.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15][N:14]2[C:29](=[O:43])[CH:30]([NH:35][C:36]([O:38][CH:39]2[CH2:40][CH:58]3[CH:56]([CH2:57]3)[CH2:42]2)=[O:37])[C:31]([CH3:33])([CH3:32])[CH3:34])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4]
Reactant: CCC1CC1(NC(=O)C1CC(OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)OC
Reactant: O=C(OC1CC2CC2C1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCC1CC1(NC(=O)C1CC(OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)C(NC(=O)OC1CC2CC2C1)C(C)(C)C)C(=O)OC
Reaction time: 2 h
Yield: 92 %

Procedure:
1-{[4-(4-Bromobenzenesulfonyloxy)-1-(2-tert-butoxycarbonylamino-3,3-dimethylbutyryl)-pyrrolidine-2-carbonyl]amino}-2-ethylcyclopropanecarboxylic acid methyl ester was dissolved in 4N HCl in dioxane (300 mL) at room temperature and stirred for 2 h. It was then concentrated under vacuum, and co-evaporated with dichloromethane (2×200 mL) to dryness. The residue was dissolved in EtOAc (600 mL) and sat'd aq. NaHCO3 (1 L). It was stirred vigorously. After 10 min, carbonic acid bicyclo[3.1.0]hex-3-yl ester 2,5-dioxo-pyrrolidin-1-yl ester (41.4 g, 173.1 mmol) was added in one portion. After the resulting mixture was stirred for another 30 min, the organic layer was collect and washed with brine (500 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel with ethyl acetate/hexane to afford 94.4 g (92% yield) of 1-{[1-[2-(bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-(4-bromobenzenesulfonyloxy)-pyrrolidine-2-carbonyl]-amino}-2-ethylcyclopropanecarboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].[CH2:16]([O:23][C:24]([NH:26][C@@H:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34]OS(C)(=O)=O)[CH2:29][C@H:28]1[C:40]([O:42][CH3:43])=[O:41])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.FC1C(F)=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>>[CH2:16]([O:23][C:24]([NH:26][C@@H:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:7]2[C:8]3[C:3](=[C:2]([F:1])[CH:11]=[C:10]([F:12])[CH:9]=3)[CH:4]=[CH:5][C:6]2=[O:13])[CH2:29][C@H:28]1[C:40]([O:42][CH3:43])=[O:41])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=c1ccc2c(F)cc(F)cc2[nH]1
Reactant: COC(=O)[C@@H]1CN(CCOS(C)(=O)=O)CC[C@H]1NC(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)c(F)c32)CC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC(=O)OCc1ccccc1

Procedure:
5,7-Difluoroquinolin-2(1H)-one (Intermediate 25) (350 mg, 1.93 mmol) was deprotonated with sodium hydride (85 mg, 60% in oil, 2.13 mmol) and alkylated with methyl (3R,4R)-4-{[(benzyloxy)carbonyl]amino}-1-{2-[(methylsulfonyl)oxy]ethyl}piperidine-3-carboxylate (Intermediate 40) (1.93 mmol) as described for Intermediate 20 to give the product as a colorless hard foam, 538 mg (56%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[C:12](/[CH3:24])=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1.[OH-].[K+]>C(O)C>[CH3:1][C:2]1([CH3:25])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[C:12](/[CH3:24])=[CH:13]/[C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCO3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 60 °C
Yield: 99.6 %

Procedure:
Under a nitrogen atmosphere, a suspension of 10.9 g (32.4 mmol) of methyl 4-[(E)-2-(4,4-dimethyl-6-chromanyl)-2-methylvinyl]benzoate in 100 ml of ethanol was treated by dropwise addition of 100 ml of 6N potassium hydroxide, with stirring at 60° C. After 1 hour a clear solution resulted. The ethanol was removed by evaporation under reduced pressure, and 100 ml of water was added. The resulting mixture was acidified with 125 ml of concentrated hydrochloric acid, and the acidified mixture was extracted with dichloromethane. The combined extracts were dried (MgSO4) and evaporated in vacuo to give 10.4 g (99% yield) of a solid. Recrystallization of 8.4 g of this solid yielded 5.6 g of the title compound, mp 179°-181° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Product: O=C(Nc1nc(-c2ccccc2)c(-c2ccccc2)s1)c1cc(Br)ccc1O

Procedure:
Using 5-bromosalicylic acid and 2-amino-4,5-diphenylthiazole as the raw materials, the same operation as the example 195(3) gave the title compound. (2-Amino-4,5-diphenylthiazole: refer to Nihon Kagaku Zasshi, 1962, 83, 209.)
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)=[O:5].C([O-])([O-])=O.[Na+].[Na+].Br[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH:50]([F:52])[F:51])[N:44]=1>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH:50]([F:52])[F:51])[N:44]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)=[O:5]
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2Cl)n(-c2ccccc2)n1
Reactant: FC(F)Oc1cccc(Br)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3cccc(OC(F)F)n3)ccc2Cl)n(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 64.7 %

Procedure:
To a degassed solution of ethyl 5-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate (Preparation 5, 229 mg, 0.44 mmol) in dioxane (4 mL) and water (0.5 mL) heated to 50° C. was added Na2CO3 (228 mg, 1.32 mmol), Cataxium A (16 mg, 0.044 mmol), a solution of 2-bromo-6-(difluoromethoxy)pyridine (Preparation 58, 100 mg, 0.44 mmol) in dioxane (1 mL) and Pd(OAc)2 (5 mg, 0.022 mmol). The reaction was heated at 80° C. for 3 hours. Further Cataxium A (16 mg, 0.044 mmol) and Pd(OAc)2 (5 mg, 0.022 mmol) were added and the reaction continued at 90° C. for 3 hours. The reaction was cooled and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 10-40% EtOAc in heptanes to afford the title compound (146 mg, 60%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[CH:5]([CH2:7][OH:8])[NH2:6].[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:12]=1[C:13](Cl)=[O:14]>N1C=CC=CC=1>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][C:13](=[O:14])[C:12]1[C:11]([F:10])=[CH:19][CH:18]=[CH:17][C:16]=1[F:20]
Reactant: COC(=O)C(N)CO
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H](CO)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.8 %

Procedure:
To a mixture of 39.0 g (251 mmol.) of D,L-serine methyl ester hydrochloride and 800 ml of pyridine, there was added dropwise 37 ml (324 mmol.) of 2,6-difluorobenzoylchloride with stirring at room temperature for 5 hours. Then the reaction mixture was further stirred at the same temperature for 2 hours. After the reaction was completed, the resultant mixture was concentrated under reduced pressure. To the residue, there was added 500 ml of chloroform. The mixture was washed with water, extracted with chloroform, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 25.88 g of N-(2,6-difluorobenzoyl)serine methyl ester as a colorless oily substance (nD22.9 1.5038).
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[C:14]([N:21]1[CH2:25][CH2:24][C@@H:23](O)[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])O.[Na+]>ClCCl>[F:11][C@H:23]1[CH2:24][CH2:25][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
Slowly add [bis(2-methoxyethyl)amino]sulfur trifluoride (2.40 mL, 13.03 mmol) to a solution of N-Boc-(R)-(−)-3-pyrrolidinol (2.00 g, 10.86 mmol) in anhydrous dichloromethane (10 mL), at −78° C. and under nitrogen. Allow the reaction mixture to warm to room temperature and stir overnight. Carefully add an aqueous solution of sodium hydrogen carbonate (saturated, 20 mL) and extract with dichloromethane. Concentrate the combined organic extracts under vacuum then purify using automated flash chromatography (ISCO® System, 120 g Redisep® SiO2 column; 0-40% ethyl acetate in cyclohexane gradient elution over 30 minutes at 85 mL/min) to give the title compound as a pale yellow liquid (1.67 g): MS (m/e): 212 (M+23).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[O:25])[CH:19]=2)=[C:13]([CH3:26])[CH:12]=1)(=[O:3])[CH3:2].[BH4-].[Na+].CC(C)=O>CO>[C:1]([O:4][C@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][OH:25])[CH:19]=2)=[C:13]([CH3:26])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CCC[C@@H]1Oc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: CC(=O)O[C@H]1CCC[C@@H]1Oc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
(1R,2R)/(1S,2S)-2-((3′-Formyl-2,6-dimethylbiphenyl-4-yl)oxy)cyclopentyl acetate 17c (71 mg, 0.20 mmol) was dissolved in 10 mL of methanol, followed by addition of sodium borohydride (15 mg, 0.40 mmol). The reaction solution was stirred for 2 hours. The resulting solution was mixed with 6 mL of acetone and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (1R,2R)/(1S,2S)-2-((3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-yl)oxy)cyclopentyl acetate 17d (61 mg, yield 85.2%) as a colorless slime.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:17][O:16]2)[CH:12]=[CH:13][CH:14]=1.[CH3:18][NH2:19]>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:16])[CH2:17][NH:19][CH3:18])[CH:12]=[CH:13][CH:14]=1
Reactant: CN
Reactant: COCCOCCOc1cccc(C2CO2)c1
Solvent: CO
Product: CNCC(O)c1cccc(OCCOCCOC)c1

Procedure:
A solution of 1.78 g of 2-{3-[2-(2-methoxyethoxy)ethoxy]phenyl}oxirane in 30 ml of 2.0 M methylamine in methanol is stirred at room temperature overnight, then concentrated under reduced pressure. Flash chromatography of the residue on silica using 5-7% methanolic ammonia in CH2Cl2 affords 809 mg of the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[N:9][CH:10]=1.[CH2:26]([O:28][C:29](=[O:42])[CH2:30][C:31]1[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:33][NH:34][CH:35]=1)[CH3:27].O>CN(C)C=O>[CH3:19][C:18]1[O:17][C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:15][C:14]=1[CH2:13][CH2:12][O:11][C:8]1[N:9]=[CH:10][C:5]([CH2:4][N:34]2[CH:35]=[C:31]([CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:42])[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:33]2)=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCl)cn1
Reactant: CCOC(=O)Cc1c[nH]nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (575 mg) and ethyl(3-phenyl-1H-pyrazol-4-yl)acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [1-[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (575 mg, yield: 63%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).