Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C(O)=O)(=O)=[O:21])CC3)=NC=2)=CC=1.C([C@@H]1COC(=O)N1[C:44](=[O:73])[C@H:45]([CH2:49][S:50]([N:53]1[CH2:58][CH2:57][N:56]([C:59]2[N:64]=[CH:63][C:62]([C:65]3[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=3)=[CH:61][N:60]=2)[CH2:55][CH2:54]1)(=[O:52])=[O:51])[CH:46]([CH3:48])[CH3:47])C1C=CC=CC=1>>[Cl:72][C:67]1[CH:66]=[C:65]([C:62]2[CH:63]=[N:64][C:59]([N:56]3[CH2:57][CH2:58][N:53]([S:50]([CH2:49][C@H:45]([CH:46]([CH3:48])[CH3:47])[C:44]([OH:73])=[O:21])(=[O:52])=[O:51])[CH2:54][CH2:55]3)=[N:60][CH:61]=2)[CH:70]=[CH:69][C:68]=1[Cl:71]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(Cl)c(Cl)c3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(Cl)c(Cl)c3)cn2)CC1)C(=O)O
Yield: 73 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(R)-benzyl-3-(2-(R)-{4-[5-(3,4-dichlorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyryl)oxazolidin-2-one(0.51 g), to give the title compound as a pale yellow solid (0.27 g, 73%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[NH:6][C:7]1[N:8]=[C:9]([NH:17][C:18](=[O:20])[CH3:19])[NH:10][C:11](=O)[C:12]=1[N+:13]([O-:15])=[O:14])#[N:2].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:35])=O>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C>[Cl:35][C:11]1[C:12]([N+:13]([O-:15])=[O:14])=[C:7]([NH:6][C:5]2[CH:21]=[CH:22][CH:23]=[C:3]([C:1]#[N:2])[CH:4]=2)[N:8]=[C:9]([NH:17][C:18](=[O:20])[CH3:19])[N:10]=1
Reactant: CC(=O)Nc1nc(Nc2cccc(C#N)c2)c([N+](=O)[O-])c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CC(=O)Nc1nc(Cl)c([N+](=O)[O-])c(Nc2cccc(C#N)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
N1-[4-(3-Cyanoanilino)-5-nitro-6-oxo-1,6-dihydro-2-pyrimidinyl]acetamide (2.5 g) was suspended in 50 ml of acetonitrile, then 2.64 g of tetraethylammonium chloride, 1 ml of N,N-dimethylaniline and 4.5 ml of phosphorus oxy-chloride were added and the mixture was heated under reflux for 5 hours. The reaction solution was returned to room temperature and added to ice-water and the mixture was stirred for 30 minutes. The resulting crystals were collected by filtration washed with water and dried to give 2.5 g of N1-[4-chloro-6-(3-cyanoanilino)-5-nitro-2-pyrimidinyl]acetamide. The yield was 93%.
Reaction SMILES: Br.C(OC([N:12]1[CH2:24][CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:14]=2[CH2:13]1)=O)C1C=CC=CC=1.C(OCC)C>C(O)(=O)C>[C:28]1([S:25]([N:15]2[C:14]3[CH2:13][NH:12][CH2:24][CH2:23][C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:27])=[O:26])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c(n(S(=O)(=O)c3ccccc3)c3ccccc23)C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)n1c2c(c3ccccc31)CCNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
33% hydrogen bromide in glacial acetic acid (20.7 ml) was added to a suspension of the product from stage 2 (4.14 g, 9.27 mmol) in glacial acetic acid (20.7 ml) and the mixture was stirred at room temperature for 1 h. The mixture was poured into diethyl ether (500 ml). The hydrobromide which had precipitated out was filtered off with suction, washed with diethyl ether and dried over potassium hydroxide in a desiccator. Saturated potassium carbonate solution (100 ml) was added to the salt (3.60 g) and the resulting mixture was extracted with methylene chloride (3×25 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:17]([O:24][C:10]1[C:11]([I:12])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:7]=[C:8]([NH2:16])[N:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCc2ccccc2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, benzyl alcohol and DBU in THF. ES-MS m/e (%): 394 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19]>C(Cl)Cl>[C:18]([O:21][CH2:22][C:23]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[C:4]#[N:5])=[O:24])(=[O:20])[CH3:19]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cccc(N)c1C#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(NC(=O)COC(C)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-methoxybenzonitrile (3.7 g) in methylene chloride (50 ml) is added pyridine (2.4 ml), and thereto is added dropwise acetoxyacetyl chloride (2.7 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are washed with water and ether and then are recrystallized from ethanol to give the title compound (5.4 g) having the following physical properties.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine. P-157
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([N:7]([CH3:11])[C:8](=[O:10])[CH3:9])[N:6]=1.[Na].[CH3:13][OH:14]>>[CH3:13][O:14][C:2]1[S:3][CH:4]=[C:5]([N:7]([CH3:11])[C:8](=[O:10])[CH3:9])[N:6]=1
Reactant: CO
Reactant: CC(=O)N(C)c1csc(Br)n1
Agent: [Na]
Product: COc1nc(N(C)C(C)=O)cs1

Procedure:
2-Bromo-4-(N-methylacetamido)thiazole is treated with sodium in absolute methanol following the procedure described in Example 1 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]([CH2:21][CH2:22][NH2:23])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[CH3:31][O:32][C:33](Cl)=[O:34]>CN(C=O)C>[CH3:31][O:32][C:33](=[O:34])[NH:23][CH2:22][CH2:21][C:11]1[CH:12]=[C:13]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[C:3]2[C:2]([NH2:1])=[C:6]([C:7](=[O:8])[NH2:9])[S:5][C:4]=2[CH:10]=1
Reactant: NCCc1cc(OCC2CCCC2)c2c(N)c(C(N)=O)sc2c1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NCCc1cc(OCC2CCCC2)c2c(N)c(C(N)=O)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To a stirred solution of 3-amino-6-(2-amino-ethyl)-4-cyclopentylmethoxy-benzo[b]thiophene-2-carboxylic acid amide (11) (HCl salt form, 0.050 g, 0.14 mmol) and triethylamine (0.07 mL, 0.5 mmol) in DMF (1 mL) at 0° C. was added methyl-chloroformate (0.02 mL, 0.3 mmol). The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with MeOH and the solvent was removed under reduced pressure. The residue was purified by flash silica gel chromatography to afford the title compound (0.025 g, 47%).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(Cl)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (300 mg, 0.79 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (151 mg, 0.79 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (228 mg, 1.19 mmol) and 1-hydroxybenzotriazole hydrate (122 mg, 0.79 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (163 mg, 37%).
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5](=[C:7]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[C:8]1=O)[O-])C.[NH:15]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)[NH2:16].Cl>C(O)C.O>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[N:15]1[C:8]2[C@@H:9]3[CH2:10][C@@H:11]3[CH2:12][C:7]=2[C:5]([C:4]([OH:3])=[O:14])=[N:16]1
Reactant: CCOC(=O)C([O-])=C1C[C@H]2C[C@H]2C1=O
Reactant: NNc1cnccn1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To a stirred suspension of 2-ethoxy-2-oxo-1-((1R,5R)-2-oxobicyclo[3.1.0]hexan-3-ylidene)ethanolate (300 mg, 1.28 mmol) in ethanol (5 mL) was added 2-hydrazinylpyrazine (141 mg, 1.28 mmol) followed by 6 N HCl (0.5 mL, 3.0 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with H2O and extracted with DCM. The combined organic phases were washed with H2O, dried over MgSO4, and concentrated. Purification by silica gel flash chromatography gave the title compound (150 mg). LCMS m/z=271.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (td, J=4.7 and 3.4 Hz, 1H), 1.22-1.28 (m, 1H), 1.39 (t, J=7.1 Hz, 3H), 2.26-2.30 (m, 1H), 2.77-2.82 (m, 1H), 2.87 (d, J=16.6 Hz, 1H), 2.98 (dd, J=16.6 and 6.3 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 8.40 (dd, J=2.6 and 1.5 Hz, 1H), 8.51 (d, J=2.5 Hz, 1H), 9.39 (d, J=1.3 Hz, 1H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].C([C:19](CC)(P(=O)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>O1CCCC1>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([CH:5]2[CH2:6][CH2:7][C:2](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:3][CH2:4]2)=[CH:9][CH:10]=1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: CCOC(=O)C(CC)(CC)P(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCC(c2ccc(O)cc2)CC1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
10 g of 4-(4-hydroxyphenyl)cyclohexanone (52.56 mmol, 1 eq.) are placed in 150 mL of tetrahydrofuran in a 250 mL round-bottomed flask under nitrogen. The solution is cooled to 4° C. on an ice bath and 2.523 g of 60% sodium hydride (63.08 mmol, 1.2 eq.) are added portionwise. 14.141 g of ethyl diethylphosphoacetate (63.08 mmol, 1.2 eq.) are placed in 150 mL of tetrahydrofuran in another 250 mL round-bottomed flask under nitrogen. This second solution is cooled on an ice bath and 2.523 g of 60% sodium hydride (63.08 mmol, 1.2 eq.) are added portionwise. The ice baths are removed and the media are stirred at room temperature for 30 minutes. The 4-(4-hydroxyphenyl)-cyclohexanone solution is added to the ethyl diethylphosphoacetate solution. The reaction medium is stirred for 1 hour 30 minutes. Saturated aqueous ammonium chloride solution is added and the reaction medium is extracted three times with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated to give 13.5 g of ethyl [4-(4-hydroxyphenyl)cyclohexylidene]acetate. M+H+=261.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][N:9]([CH2:18][C:19]([O:21]CC)=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:26](CCN)CC)C.C(N(C(C)C)CC)(C)C>CCOCC>[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][N:9]([CH2:18][C:19]([NH2:26])=[O:21])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)Cn1cc(-c2ccccc2)c(-c2ccccc2)n1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)Cn1cc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 18 h

Procedure:
A mixture of 10 g (0.033 mol) of ethyl 3,4-diphenyl-1H-pyrazole-1-acetate, 6.9 mL (0.049 mol) of diethylaminoethylamine and 39 mL of diisopropylethylamine was stirred on a steam bath under nitrogen for 18 hours. The reaction was stripped, the residue taken up in about 300 mL of ether and washed twice with water. The ether layer was extracted twice with a total of 150 mL of cold water containing 20 mL of 10% HCl. The combined water extracts were washed once with ether, colled, made basic with solid sodium carbonate, extracted several times with methylene dichloride, dried over sodium sulphate, treated with decolorizing carbon, filtered and stripped. The oily red residue was crystallized from ether to yield 6.86 g of N-[2-diethylamino)ethyl]-3,4-diphenyl-1H-pyrazole-1-acetamide, mp 80°-83° C.
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([OH:12])[C:6]1=[S:13])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:16][N:17]([CH:19]=[O:20])C>>[O:20]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:16]=2[N:17]=[C:19]1[O:12][C:7]1[C:6](=[S:13])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]=[C:9]([CH3:11])[CH:8]=1
Reactant: CN(C)C=O
Reactant: CCCCn1cc(C)cc(O)c1=S
Agent: [H-]
Agent: [Na+]
Product: CCCCn1cc(C)cc(Oc2nc3ccccc3o2)c1=S
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a solution of 1-butyl-3-hydroxy-5-methylpyridine-2-thione (2-035-05) (300 mg) in DMF (6.0 mL) was added sodium hydride (60% wt, 79 mg) at room temperature. After the reaction mixture was stirred for 20 min, to the reaction mixture was added 2-chlorobanzoxazole (432 mg), and the reaction mixture was stirred at room temperature for 2 h. After the reaction was quenched with water, the solvent was removed. To the residue were added aqueous saturated ammonium chloride solution and ethyl acetate, and the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (toluene/acetone=4/1) to give 3-(benzoxazol-2-yloxy)-1-butyl-4-methylpyridine-2-thione (2-035) 372 mg, 73%) as a yellow crystal. The obtained crystal was purified by recrystallization from methylene chloride and diethyl ether.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([C:29](=O)[CH2:30][CH2:31][CH2:32][CH3:33])[C:23](=NOC)[C:24]#[N:25])=[C:17]([F:35])[CH:16]=1)(=[O:8])=[O:7])(C)(C)C.Cl.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][C:39]=1[NH:47][NH2:48]>>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][C:39]=1[N:47]1[C:23]([C:24]#[N:25])=[C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:16][C:17]=2[F:35])[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:48]1
Reactant: NNc1cc([N+](=O)[O-])ccc1Br
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F)C(C#N)=NOC
Agent: Cl
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(C#N)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F

Procedure:
The title compound is prepared by reaction of 3-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2-methoxyimino-4-oxooctanenitrile (from Example 8, Step J) with 2-bromo-5-nitrophenylhydrazine hydrochloride [prepared from 2-bromo-5-nitroaniline according to H. Stroh and G. Westphal, Chem. Ber., 96, 184 (1963)], following the procedure of Example 1, Step G.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23](Cl)=[O:24]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:23](=[O:24])[C:22]2[C:26]([O:30][CH3:31])=[CH:27][CH:28]=[CH:29][C:21]=2[O:20][CH3:19])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(N)cc1
Solvent: c1ccncc1
Product: COc1cccc(OC)c1C(=O)Nc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 70.9 %

Procedure:
N-(tert-butoxycarbonyl)-2-(4-nitrophenoxy)ethylamine (5.91 g) was dissolved into methanol (200 ml) and subjected to hydrogeration reaction at ambient pressure by adding 10% palladium carbon catalyst (0.5 g). After completion of hydrogeration reaction, excess catalyst was removed by filtration. Filtrate was concentrated under vacuum to obtain N-(tert-butoxycarbonyl)-2-(4-aminophenoxy)ethylamine (5.07 g) as color-less oily substance. (1-3) N-(tert-butoxycarbonyl)-2-(4-aminophenoxy)ethylamine (1.00 g) was dissolved into pyridine (5 ml) and 2,6-dimethoxybenzoic acid chloride (0.87 g) was added into the solution. After being stirred for one hour, the reaction mixture was concentrated under vacuum and residue was dissolved into chloroform (30 ml). The solution was washed with 1N sodium hydroxide aqueous solution (30 ml) followed by saturated sodium chloride (30 ml). Solvent was distilled out and residue was purified by silica-gel column chromatography (ethyl acetate:hexane=1:1) to obtain 4′-[2-(tert-butoxycarbonylamino)ethoxy]-2,6-dimethoxybenzanilide (1.17 g) as white powder.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1>CO>[N+:30]([C:29]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:23]([CH2:3][CH2:2][C:1]#[N:4])[C:20]1[CH:19]=[CH:18][CH:17]=[CH:22][CH:21]=1)([O-:32])=[O:31]
Reactant: C=CC#N
Reactant: O=[N+]([O-])c1ccccc1Nc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Product: N#CCCN(c1ccccc1)c1ccccc1[N+](=O)[O-]

Procedure:
Acrylonitrile (210 ml) and 40% benzyltrimethylammoniumhydroxide in methanol (1.5 ml) were added to 2-nitrodiphenylamine (100 g), and the mixture was refluxed with heat for one hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to thereby obtain 47.7 g of the titled compound as a red solid.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3](=[O:25])[CH2:4][C@@H:5]([NH:14]C(=O)OCC1C=CC=CC=1)[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>Br.C(O)(=O)C>[NH2:14][C@@H:5]([CH2:6][S:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:4][C:3]([N:2]([CH3:1])[CH3:26])=[O:25]
Reactant: CN(C)C(=O)C[C@H](CSc1ccccc1)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CN(C)C(=O)C[C@@H](N)CSc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
A suspension of (R)-benzyl 4-(dimethylamino)-4-oxo-1-(phenylthio)butan-2-ylcarbamate (INTERMEDIATE 15, 40 g, 0.10 mol) in 40% HBr in acetic acid (100 ml) was stirred at room temperature for 16 hours and the reaction mixture became homogeneous during this time. The mixture was concentrated to dryness, diluted with water (200 ml) and AcOH (200 ml) and washed with diethyl ether (3×50 ml). The aqueous phase was brought to approximately pH 8-9 with solid Na2CO3 and was extracted with CH2Cl2 (5×) The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to give the title product (15 g, 59%) that was used in the preparation of INTERMEDIATE 17 without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:34]([CH3:36])[CH3:35])[C:6]2[O:10][C:9]([C:11]3[CH:32]=[CH:31][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:33]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:34]([CH3:36])[CH3:35])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:23][CH2:22][NH:21][CH2:20]4)=[O:16])=[CH:31][CH:32]=3)=[N:8][C:7]=2[CH:33]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)OC(C)(C)C)C4)cc3)oc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCNC4)cc3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of tert-butyl 3-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)pyrrolidine-1-carboxylate (910 mg) in dichloromethane (75 ml) was added 20 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2 h, and then concentrated in vacuo. The residue was basified by the addition of 75 ml of saturated aqueous sodium bicarbonate and diluted with 75 ml of ethyl acetate. The solids were filtered from both layers and dried in vacuo to provide the title compound (655 mg, 90%). Mass spectrum (ESI) 389.9 (M+1).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6](=[O:24])[C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])=[C:11]([F:22])[C:10](Cl)=[N:9][CH:8]=1.CO>C1COCC1>[CH3:4][O:5][C:6](=[O:24])[C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])=[C:11]([F:22])[C:10]([O:2][CH3:1])=[N:9][CH:8]=1
Reactant: COC(=O)c1cnc(Cl)c(F)c1Nc1ccc(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cnc(OC)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Sodium methoxide (2.20 g, 40.8 mmol) was slowly added to a stirred solution of 4-(4-bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid methyl ester in 4:1 MeOH:THF (20 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred for 17 hours and then warmed to 40° C. and stirred for 5 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The desired product, contaminated with some starting material, was carried forward without purification.