Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.[CH3:18][O:19][C:20]([C:22]1[O:38][C:25]2=[N:26][CH:27]=[CH:28][C:29]([O:30][C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)=[C:24]2[CH:23]=1)=[O:21]>C(#N)C>[CH3:18][O:19][C:20]([C:22]1[O:38][C:25]2=[N:26][CH:27]=[CH:28][C:29]([O:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)=[O:17])=[CH:33][CH:32]=3)=[C:24]2[CH:23]=1)=[O:21]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COC(=O)c1cc2c(Oc3ccc(N)cc3)ccnc2o1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2o1

Procedure:
After adding toluene (1 ml), acetonitrile (0.5 ml) and 4-fluorophenyl isocyanate (0.02 ml) to 4-(4-aminophenoxy)furo[2,3-b]pyridine-2-carboxylic acid methyl ester (28 mg), the mixture was heated to reflux for 30 minutes. After cooling, the precipitated crystals were filtered off and washed with toluene to obtain the title compound (24 mg) as light yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>CO.O>[OH:20][N:19]=[C:1]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCOC(=O)COc1ccc(C(=O)CC)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)COc1ccc(C(CC)=NO)cc1
Yield: 76.7 %

Procedure:
To a solution of the product of step 1 (49 g, 0.2076 moles) in methanol (343 ml), hydroxylamine hydrochloride (28.6 g, 0.4152 moles) and a solution of sodium acetate (34 g, 0.4152 moles) in water (147 ml) were added and the reaction mixture was refluxed for 1 hour. The solvents were evaporated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure to yield 40 gm (76%) of product as solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]([CH3:17])[CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:13][CH2:12][C:11]=2[N:24]=1.O.C([O-])([O-])=O.[K+].[K+]>OS(O)(=O)=O>[CH3:5][O:6][C:7]1[C:8]([N+:1]([O-:4])=[O:2])=[CH:9][C:10]2[CH:16]([CH3:17])[CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[CH2:13][CH2:12][C:11]=2[N:24]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(n1)CCN(C(=O)C(F)(F)F)CC2C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COc1nc2c(cc1[N+](=O)[O-])C(C)CN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Yield: 77 %

Procedure:
Nitric Acid (200 μl) was added dropwise to a stirred solution of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (174 mg, 604 μmol) in H2SO4 (1.5 ml). The reaction mixture was added into cold water after 3 d of stirring at room temperature. K2CO3 was added to neutralize the mixture to pH=8. After extraction with EtOAc, the organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 155 mg (77%) of 2-methoxy-5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 334. After treatment of 2-methoxy-5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (30.0 mg, 90.0 μmol) with K2CO3 (30 mg), methanol (1 ml) and H2O (0.2 ml) at 60° C. for 10 minutes, the reaction was quenched with sat. aq. NH4Cl and extracted with DCM. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 21 mg (99%) of 2-methoxy-5-methyl-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 8.10 (s, 1H), 4.09 (s, 3H), 3.25 (m, 2H), 3.10 (m, 3H), 2.93 (dd, 1H), 2.72 (dd, 1H), 1.39 (d, 3H) ppm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH:15](O)[CH2:14]2)[CH2:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(N(S(F)(F)[F:40])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH:15]([F:40])[CH2:14]2)[CH2:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CC(O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CC(F)C1
Reaction time: 12 h
Yield: 53.6 %

Procedure:
A 1.79 g (4.96 mmol) portion of 1-benzyl-4-[3-(tert-butoxycarbonylamino)-1-hydroxycyclobutan-3-yl]-2-pyrrolidone (Isomer B2) was dissolved in a mixed solvent consisting of 50 ml of toluene and 20 ml of dichloromethane to which, while cooling in an ice bath with stirring, was then added 1.31 ml (9.92 mmol) of diethylaminosulfur trifluoride, subsequently carrying out 12 hours of stirring at 50° C. While cooling in an ice bath with stirring, the reaction solution was alkalified by slowly adding saturated sodium bicarbonate aqueous solution and then mixed with chloroform to carry out separation of layers, and the resulting organic layer was washed with saturated brine. The aqueous layer was again extracted with chloroform, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure and the resulting residue was purified by a silica gel column chromatography to give 964 mg (53.6%) of the title compound. 1H-NMR data of the thus obtained compound coincided with the aforementioned data of its enantiomer Isomer B1.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5].ClCC(=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[NH2:5][C:4]1[C:3]2[C:6]([O:10][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)=[CH:7][CH:8]=[CH:9][C:2]=2[N:1]=[C:25]2[CH2:24][O:23][C:21](=[O:22])[C:20]=12
Reactant: N#Cc1c(N)cccc1OC1CCCCC1
Reactant: CCOC(=O)CC(=O)CCl
Product: Nc1c2c(nc3cccc(OC4CCCCC4)c13)COC2=O

Procedure:
Prepared as in Example 2a from 2-amino-6-(cyclohexyloxy)benzonitrile (Example 36b) and ethyl 4-chloro-3-oxobutanoate as an orange solid (29%). 1H NR (400 MHz, DMSO-d6) δ 1.30-1.72 (m, 8H), 2.04-2.08 (m, 2H), 4.70 (m, 1H), 5.26 (s, 2H), 7.09 (d, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.64 (m, 2H), 8.14 (brs, 1H). MS 299 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8]O)C.[CH2:10]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][CH:23]2[C:28]([N:30]([C:37]1[CH:38]=[N:39][C:40]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:42]=1)[CH2:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)=[O:29])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][CH:23]2[C:28]([N:30]([CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH3:1])[CH:36]=1)[C:37]1[CH:38]=[N:39][C:40]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:42]=1)=[O:29])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCOCCOCCO
Product: COCCOCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment of diethylene glycol monoethyl ether (1.5 mL) and 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.72 g) in the same manner as in Example 394, 5-benzyloxy-N-({1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.89 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:15]1[CH2:20][CH2:19][CH:18]=[CH:17][CH2:16]1.Cl>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:15]2[CH2:20][CH2:19][CH:18]=[CH:17][CH2:16]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: C1=CCNCC1
Agent: Cl
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)N2CC=CCC2)ccc1Cl
Temperature: 25 °C

Procedure:
2-Chloro-5-chlorosulfonylbenzoic acid (25.5 g.) is added in small portions over a 5 minute period with cooling to a solution of 1,2,5,6-tetrahydropyridine (25.0 g.) in 200 ml. of water. After stirring at room temperature for a half hour, the reaction mixture is acidified with concentrated hydrochloric acid. The crystalline precipitate is filtered off and dissolved in 75 ml. of methylene chloride and 10 ml. of ether. After concentration to 50 ml., hexane is added to turbidity, affording crystals, m.p. 180°-182° C.
Reaction SMILES: [OH:1][P:2]([CH2:14][C:15]([OH:17])=O)([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:3].S(Cl)(Cl)=O.Cl.[C:23]1([C:29]2[CH2:33][CH:32]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[NH:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ClC(OC(=O)C(C)(C)C)C(OCC)=O>C(N(CC)CC)C.ClCCl.CN(C)C=O>[OH:1][P:2]([CH2:14][C:15]([N:31]1[CH:32]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:33][C:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:30]1)=[O:17])([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:3]
Reactant: O=C(O)CP(=O)(O)CCCCc1ccccc1
Reactant: O=C(OCc1ccccc1)C1CC(c2ccccc2)=NN1
Agent: CCOC(=O)C(Cl)OC(=O)C(C)(C)C
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CC(c2ccccc2)=NN1C(=O)CP(=O)(O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10 g. of [hydroxy(4-phenylbutyl)phosphinyl]acetic acid, from part (b), in 40 ml. of dry dichloromethane containing 0.2 ml. of dimethylformamide is heated to reflux temperature. Thionyl chloride (5.1 g.) is added dropwise while maintaining the temperature at reflux. After an additional 30 minutes heating, the solution is cooled to 5° and a solution of 11.6 g. of (+)-4,5-dihydro-3-phenyl-1H-pyrazole-5-carboxylic acid, phenylmethyl ester, hydrochloride (1:1), from part (a), in 50 ml. of dichloromethane is added at once, followed by dropwise addition of 11.9 g. of triethylamine while the temperature is maintained at 5°-10° with cooling. After stirring overnight at ambient temperature, the mixture is washed three times with aqueous hydrochloric acid (1.5 N) and three times with water. The organic solution is dried (MgSO4) and concentrated in vacuo to give (+)-4,5-dihydro-1-[[hydroxy(4-phenylbutyl)phosphinyl]acetyl]-3-phenyl-1H-pyrazole-5-carboxylic acid, phenylmethyl ester which can be crystallized from acetone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:10](O)=[O:11]>C1(C)C=CC=CC=1>[CH:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:11]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=CO
Solvent: Cc1ccccc1
Product: O=CN1CCc2ccccc21
Yield: 89.1 %

Procedure:
A solution of indoline (5.0 g) and 98% formic acid (3.0 g) in toluene (17 mL) was heated at reflux for 6 hours with a Dean-Stark trap, cooled, washed with water and concentrated. The resulting dark brown solid was dissolved in methanol, concentrated to a fraction of its original volume, treated with 1:1 diethyl ether/hexane, and concentrated dryness to provide 5.5 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[CH:15]=[O:16])=[CH:4][C:3]=1[CH2:19][O:20]C1CCCCO1.[B:27]1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:28]1.C([O-])(=O)C.[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]3[B:27]([OH:28])[O:20][CH2:19][C:3]=3[CH:4]=2)=[C:8]([CH:15]=[O:16])[CH:9]=1)#[N:12]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: N#Cc1ccc(Oc2ccc(Br)c(COC3CCCCO3)c2)c(C=O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(C=O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
A mixture of 4-[4-bromo-3-(2-tetrahydropyranyloxymethyl)phenoxy]-3-formylbenzonitrile (28.0 g, 67.3 mmol), bis(pinacolato)diboron (18.8 g, 74.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.37 g, 2.5 mol %), and potassium acetate (19.8 g, 202 mmol) in 1,4-dioxane (270 mL) was stirred under nitrogen atmosphere at 80° C. overnight. The mixture was filtered through a Celite pad, and the solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (250 mL) and was added 6 M HCl (30 mL), and the mixture was stirred at room temperature for 2 h. The mixture was poured into ethyl acetate/water. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (5:5 to 3:7 hexane/ethyl acetate) followed by recrystallization from ethyl acetate/hexane to give 5-(4-cyano-2-formylphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (6.61 g, 35%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[C:15]1([C:21]2[CH:29]=[C:28]3[C:24]([CH2:25][C:26](=[O:30])[NH:27]3)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1CCCCC1.C(O)C>[CH3:14][C:7]1[NH:8][C:9]([CH:12]=[C:25]2[C:24]3[C:28](=[CH:29][C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:22][CH:23]=3)[NH:27][C:26]2=[O:30])=[C:10]([CH3:11])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)c(C)c1CCC(=O)O
Yield: 71.4 %

Procedure:
3-(2-carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.6 mg), 105 mg 6-phenyl-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 138 mg (71%) of the title compound as a brown solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=2)[CH2:16][C:15]1([CH3:26])[CH3:25].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CNC>CN(C=O)C>[C:23]([C:20]1[CH:21]=[C:22]2[C:17]([CH2:16][C:15]([CH3:26])([CH3:25])[C@H:14]2[NH:13][C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:12])=[CH:18][CH:19]=1)#[N:24]
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H]1N
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2ccccc2[nH]1
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 72.9 %

Procedure:
A mixture of 1H-indole-2-carboxylic acid (44.0 mg, 0.273 mmol), (R)-3-amino-2,2-dimethyl-2,3-dihydro-1H-indene-5-carbonitrile (34.0 mg, 0.182 mmol), BOP reagent (157 mg, 0.355 mmol), N-methylmorpholine (0.12 mL, 1.09 mmol) in DMF (0.5 mL) was stirred at 50° C. for 50 min. Dimethylamine (2.0 M in THF, 0.2 mL) was added to the mixture and the resulting mixture was stirred at 50° C. for 30 min. The desired title product (43.7 mg, 73% yield) was isolated as a white solid by prep. LCMS (M+H)+=330.33; HPLC. 1H NMR (500 MHz, DMSO-d6) δ: 11.6 (s, 1H), 8.53 (d, J=9.35 Hz, 1H), 7.70 (d, J=70 Hz, 1H), 7.60 (d, J=7.70 Hz, 1H), 7.62 (s, 1H) 7.46 (d, J=7.70 Hz, 1H), 7.44 (d, J=9.35 Hz, 1H), 7.29 (s, 1H), 7.18 (t, J=7.70 Hz, 1H), 7.03 (t, J=7.70 Hz, 1H), 5.38 (d, J=9.35 Hz, 1H), 2.86 (dd, J=22.5, 16.5 Hz, 2H), 1.21 (s, 3H), 0.94 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ: 161.1, 148.2, 144.1, 136.2, 131.4, 131.0, 127.9, 126.7, 125.7, 123.0, 121.2, 119.4, 118.8, 111.9, 108.8, 103.2, 61.0, 39.4, 39.2, 39.1, 38.9, 27.1, 22.2.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([C@@H:10]([NH:14]C(=O)OC(C)(C)C)[C@H:11]([OH:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[F:9]>C(OCC)(=O)C.CO>[ClH:1].[NH2:14][C@H:10]([C:5]1[CH:6]=[CH:7][C:8]([F:9])=[C:3]([F:2])[CH:4]=1)[C@H:11]([OH:13])[CH3:12]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H](O)[C@H](N)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4 N hydrogen chloride in ethyl acetate (10 mL) was added to a solution of tert-butyl [(1R,2R)-1-(3,4-difluorophenyl)-2-hydroxypropyl]carbamate (960 mg) in methanol (10 mL) at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain (1R,2R)-1-amino-1-(3,4-difluorophenyl)propan-2-ol hydrochloride (747 mg). DIEA (1.59 mL), WSC (880 mg), and HOBT (620 mg) were added to a solution of (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]valeric acid trifluoroacetate (1.00 g) and (1R,2R)-1-amino-1-(3,4-difluorophenyl)propan-2-ol hydrochloride (612 mg) in DMF (20 mL) at room temperature, and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water, water, a saturated ammonium chloride solution, and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting solid was washed with heptane to obtain (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid [(1R,2R)-1-(3,4-difluorophenyl)-2-hydroxypropyl]amide (977 mg). (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid [(1R,2R)-1-(3,4-difluorophenyl)-2-hydroxypropyl]amide (977 mg) was dissolved in DMF (25 mL). 60% sodium hydride (95 mg) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate-methanol system), solidified with ethyl acetate and heptane, and separated by filtration to obtain 740 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24]Br>C(O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][CH2:2][C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: Clc1ccc(CBr)cc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(NC(=O)CCc1ccc(Cl)c(Cl)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethyl acetamidomalonate (48.2 g) was dissolved in ethanol (250 ml) containing sodium ethoxide (10.2 g) and stirred at room temperature for 0.5 hours before adding 3,4-dichlorobenzyl bromide and heating at reflux for 3.5 hours. After cooling, the title compound was collected by filtration and dried under reduced pressure (36.73 g).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[C:27]([F:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=2[F:30])([C:20]#[N:21])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:29][C:25]1[CH:26]=[C:27]([F:28])[C:22]([C:11]2([C:20]#[N:21])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:23]([F:30])[CH:24]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1c(F)cc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1c(F)cc(Cl)cc1F
Yield: 91 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 108b (0.9 g, 1.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.9 g, 91%).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20].[F:21][C:22]([F:30])([S:28][CH3:29])[C:23](OCC)=[O:24].Cl>CCOCC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:23](=[O:24])[C:22]([F:30])([F:21])[S:28][CH3:29]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CCOC(=O)C(F)(F)SC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CSC(F)(F)C(=O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
A hexane solution (13.7 ml, 21.6 mmol) of 1.58 M n-butyllithium was added dropwise to a solution of 1-bromo-2,4-difluorobenzene (4.2 g, 21.8 mmol) in absolute ether (60 ml) at −70° C., and the mixture was stirred for 15 minutes at the same temperature. A solution of ethyl 2,2-difluoro-2-(methylthio)acetate (3.7 g, 21.6 mmol) in absolute ether (20 ml) was added to this solution at −70° C. After the resultant mixture was stirred for 1 hour at the same temperature, the temperature of the reaction mixture was raised to 0° C. for 1 hour. The reaction mixture was poured into diluted hydrochloric acid-containing ice to conduct extraction with ether. After the resultant ether solution was washed with water and dried, the solvent was distilled off. The resultant residue was purified by distillation under reduced pressure to obtain 1-(2,4-difluorophenyl)-2,2-difluoro-2-(methylthio)-1-ethanone (4.1 g, yield: 90.0%) as a colorless oil.
Reaction SMILES: [NH3:1].[CH3:2][C:3]1([CH3:28])[CH:12]2[O:13][CH:11]2[C:10]2[CH:9]=[C:8]([CH2:14][C:15]([NH:17][CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[O:16])[CH:7]=[CH:6][C:5]=2[O:4]1.ClCCl.CO>C(O)C.O>[NH2:1][CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:14][C:15]([NH:17][CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[O:16])[CH:9]=2)[O:4][C:3]([CH3:28])([CH3:2])[CH:12]1[OH:13]
Reactant: N
Reactant: CC1(C)Oc2ccc(CC(=O)NC3CCCc4ccccc43)cc2C2OC21
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC1(C)Oc2ccc(CC(=O)NC3CCCc4ccccc43)cc2C(N)C1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
88 ml of a 25%-strength aqueous ammonia solution was added to a solution of 16 g of the 2-(2,2-dimethyl-1a,7b-dihydro-2H-oxireno[c]chromen-6-yl)-N-1,2,3,4-tetrahydronaphth-1-yl acetamide obtained above in 88 ml ethanol, and the mixture was stirred for 18 hours at room temperature. Then 200 ml dichloromethane and 50 ml methanol were added thereto, and the mixture was stirred for a further 15 minutes. Then 200 ml water was added and the mixture was again stirred for 15 minutes. The organic phase was separated and largely evaporated at reduced pressure. The remaining residue was stirred with 30 ml of ethyl acetate, filtered and dried on a rotary evaporator at 70° C. and 20 bar. 3.1 g 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-N-1,2,3,4-tetrahydronaphth-1-yl acetamide was obtained as grey solid, which was used without further purification for the subsequent reaction.