Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][CH2:4][NH:5][CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[BH4-].[Na+]>C(O)C>[OH:1][CH:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][CH2:4][NH:5][CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCCCCC(=O)CCNC(CCCCCCC(=O)OCC)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)CCNC(CCCCCCC(=O)OCC)C(=O)OCC

Procedure:
The above aminodiester was alternatively prepared in the following manner. Diethyl 2-aminononanedioate (10.40 g) and oct-1-en-3-one (5.04 g) were mixed slowly at 0° C. with stirring, and set aside at room temperature for 3 hours, giving diethyl 2-(3-oxooctylamino)nonanedioate as a colourless oil, δ2.3(4H, multiplet, -CH2 -CO2Et and NCH2CH2CO-), 3.16(1H, triplet, EtO2C-CHR-N), 4.11(2H, quartet, --O--CH2 --CH3), 4.17(2H, quartet, -O-CH2 -CH3). A stirred solution of this ketone (13.5 g) in absolute ethanol (140 ml) was treated dropwise at 0° C. with sodium borohydride (665 mg) in absolute ethanol (70 ml), then kept for 31/2 hours at room temperature and concentrated at 40° C. in vacuo. The residue, dissolved in water, was brought to pH 5 with N-hydrochloric acid and extracted thoroughly with chloroform, the extract was washed with water, dried, and evaporated, giving diethyl 2-(3-hydroxy-octylamino)nonanedioate as a colourless oil. Without further purification, the latter was dissolved in dihydropyran (14.0 ml), treated with ether (10 ml) followed by p-toluenesulphonic acid (6.72 g) in portions, and set aside at room temperature for 18 hours. The reaction solution was diluted with ether, washed with aqueous sodium carbonate then water, dried, and evaporated, and the residue was purified by column chromatography on silica in 1:4 hexane/ether, giving diethyl 2-(3-(tetrahydropyran-2-yloxy)octylamino)nonanedioate identical (n.m.r., i.r. mixed t.l.c.) with that prepared previously.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17]O)=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[C:5]1([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][Cl:3])=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(C#Cc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(C#Cc2ccccc2)cc1

Procedure:
Thionyl chloride, 7 ml., is added dropwise to a stirred solution of 6.0 g. (0.0288 mole) of 4-(phenylethynyl) benzyl alcohol in 100 ml. of dry chloroform at room temperature and the mixture is stirred for 6 hours. Solvent is evaporated under reduced pressure and at a temperature below 50°. The residue is freed from traces of thionyl chloride by dissolution in dry benzene and evaporation under reduced pressure. This process is repeated and the residual solid product is purified by sublimation in vacuo; m.p. 61.5°-63.5°C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[C:23](Cl)(=[O:26])[CH2:24][CH3:25].O>O1CCCC1>[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][CH:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH3:7])[CH:10]=2)[CH2:18]1)(=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)Cl
Reactant: COc1ccc(C2CCCNC2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)N1CCCC(c2ccc(OC)c(OC)c2)C1
Reaction time: 2 h

Procedure:
260 mg of sodium carbonate were added under a nitrogen atmosphere to a mixture of 500 mg of 3-(3',4'-dimethoxyphenyl)-piperidine in 5 ml of tetrahydrofuran and while cooling the mixture on an ice bath, 0.21 ml of propionyl chloride was added dropwise over 5 minutes. After the temperature rose to room temperature, the mixture was stirred for 11/2 hours and was then poured into 10 volumes of ice and water. The mixture was extracted with methylene chloride and the extracts were washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The 460 mg of residue was chromatography over silica gel and was eluted with a 6-3-1 cyclohexane-chloroform-triethylamine mixture. The product was crystallized to get 270 mg of amorphous N-propionyl-3-(3',4'-dimethoxyphenyl)-piperidine.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].CN>ClCCl.[Cl-].[Na+].O>[CH3:23][N:15]([CH2:14][CH2:13][CH:12]=[O:11])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CN(CCC=O)C(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 100.7 %

Procedure:
Dimethylsulfoxide (6.22 ml, 87.6 mmol) was dissolved in dry dichloromethane (100 ml) under nitrogen and the solution was cooled to −78° C. with stirring. Oxalyl chloride (3.95 ml, 45.4 mmol) was then added dropwise and the solution was stirred at −78° C. for a further 30 minutes when effervescence had ceased. A solution of 1,1-dimethylethyl (3-hydroxypropyl)methylcarbamate (6.62 g, 35.0 mmol) in dichloromethane (100 ml) was then added dropwise at −78° C. The resultant solution was stirred at −78° C. for 45 minutes, then a solution of methylamine (24.4 ml, 175 mmol) in dichloromethane (50 ml) was added. The resultant solution was allowed to warm to room temperature and stirred for a further 18 h. The reaction mixture was then poured into brine and extracted with dichloromethane three times. The combined organic fractions were then washed with brine, dried (MgSO4) and evaporated. The residue was triturated with diethyl ether and filtered. The solvent was evaporated to give the title compound (6.60 g, 100%) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10].Cl[CH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10])[O:8][CH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([N:30]([CH3:31])[CH3:32])=[O:29])=[CH:26][CH:25]=1
Reactant: CN(C)C(=O)c1ccc(CCl)cc1
Reactant: O=C(c1ccc(O)cc1F)N1CCC[C@H]1CN1CCCC1
Product: CN(C)C(=O)c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C using (2-Fluoro-4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-chloromethyl-N,N-dimethyl-benzamide [CAS 121083-51-0]. MS (ES+) 454.2
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]2[O:31][C:32]([CH3:35])=[N:33][N:34]=2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]3[O:31][C:32]([CH3:35])=[N:33][N:34]=3)=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Cc1nnc(-c2ccc(Cl)nc2C)o1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nnc(-c2ccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)nc2C)o1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 6-chloro-2-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine (101 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@:5]([CH3:19])([C:14]2[N:15]=[N:16][NH:17][N:18]=2)[CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]([F:36])(S(F)(=O)=O)C(O)=O.C(=O)([O-])O.[Na+]>C(#N)C>[F:27][CH:28]([F:36])[N:16]1[N:17]=[N:18][C:14]([C@:5]2([CH3:19])[CH2:4][O:3][C:2]([CH3:20])([CH3:1])[N:6]2[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])=[N:15]1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(C)c1nn[nH]n1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(C)c1nnn(C(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen gas flow, to a mixture of 9.89 g of tert-butyl (4R)-2,2,4-trimethyl-4-(2H-tetrazol-5-yl)-1,3-oxazolidine-3-carboxylate, 11 g of potassium carbonate, and 200 ml of acetonitrile was added dropwise 7.5 ml of 2,2-difluoro-2-(fluorosulfonyl)acetic acid under ice-cooling, followed by warming to room temperature and stirring for 1 hour. The reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 7.59 g of tert-butyl (4R)-4-[2-(difluoromethyl)-2H-tetrazol-5-yl]-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>>[CH2:16]([N:18]([CH2:19][CH3:20])[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:15])[CH3:17]
Reactant: CCNCC
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: CCN(CC)C(=O)c1cnoc1-c1ccc(C)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and diethylamine (4.4 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method A to give a solid (7.0 mg). MS (pos) m/z 259.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]#[N:16].[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C.O>[Br:1][C:2]1[C:3]([NH:9][C:15]([C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)=[NH:16])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: N#Cc1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: N=C(Nc1ncc(Br)nc1Br)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A stirred solution of 3,5-dibromo-pyrazin-2-ylamine (500 mg, 1.98 mmol), thiophene-2-carbonitrile (260 uL, 2.04 mmol) and AlCl3 (232 mg, 1.74 mmol) in dichloroethane (5 ml) was heated at 115° C. overnight. The mixture was allowed to cool to room temperature and diluted with water (5 mL). After 30 minutes, the resulting precipitate was collected and purified by column chromatography (SiO2, THF) to afford 488 mg (68%) of N-(3,5-dibromo-pyrazin-2-yl)-thiophene-2-carboxamidine as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.22 (t, J=3.9 Hz, 1H), 7.83 (dd, J=4.8 Hz, 1H), 7.99 (d, J=4.1 Hz, 1H), 8.49 (s, 1H), 8.88 (br. s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:22][C:23]([CH3:25])=[CH2:24]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH:9]([CH3:10])[CH3:11])[C:3]=1[O:12][CH2:24][C:23]([CH3:25])=[CH2:22]
Reactant: C=C(C)CCl
Reactant: CC(C)c1cc(Br)cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)COc1c(Br)cc(Br)cc1C(C)C

Procedure:
Following general procedure B and using 2,4-dibromo-6-isopropyl-phenol (Compound 4, 76.56 g, 0.25 mol), potassium carbonate (41.46 g, 0.3 mol), sodium iodide (3.75 g, 0.025 mol) and 3-chloro-2-methylpropene (74 mL, 0.375 mol) in 1L of acetone, the title compound was obtained as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.52 (d, 1H, J=2.2 Hz), 7.30 (d, 1H, J=2.2 Hz), 5.17 (s, 1H), 5.01 (s, 1H), 4.29 (s, 2H), 3.29 (heptet, 1H, J=6.9 Hz), 1.91 (s, 3H), 1.23 (d, 6H, J=6.7 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.CC1N(C(N(C)C)=O)C1>[Cu](I)I>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:20]2[C:21]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:3][CH:4]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccc(Br)cc1
Agent: I[Cu]I
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC1CN1C(=O)N(C)C
Product: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 180 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
First, 56 g (240 mmol) of p-dibromobenzene, 31 g (180 mmol) of carbazole, 4.6 g (24 mmol) of copper iodide, 66 g (480 mmol) of potassium carbonate, and 2.1 g (8 mmol) of 18-crown-6-ether were put in a 300-mL three-neck flask, and nitrogen was substituted for air in the flask. Then, 8 mL of N,N-dimethylpropyleneurea (abbreviation: DMPU) was added therein, and the mixture was stirred at 180° C. for 6 hours. After the reaction mixture was cooled to room temperature, a precipitate was removed by suction filtration. The filtrate was washed with dilute hydrochloric acid, a saturated sodium hydrogen-carbonate aqueous solution, and a saturated saline solution in this order and dried with magnesium sulfate. After being dried, the solution was filtered naturally and concentrated, and an obtained oily substance was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) and recrystallized with chloroform and hexane; thus, 21 g of a light brown plate-shaped crystal of 9-(4-bromophenyl)carbazole that was an object was obtained (yield: 35%).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>>[Br:8][C:6]1[CH:7]=[C:2]([NH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 120 °C

Procedure:
In a 300 mL sealed tube was placed 3,5-dibromo-1-methylpyridin-2(1H)-one (4.0 g, 15.0 mmol), methyl 6-aminonicotinate (2.3 g, 15.0 mmol), cesium carbonate (10.7 g, 33 mmol), and Xantphos (740 mg, 8.5 mol %). The flask was evacuated and filled with nitrogen 3×. Dioxane (100 ml) was added and the mixture degassed for 25 min with bubbling nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (690 mg, 5 mol %) was then added, the vessel sealed and the reaction heated to 120° C. overnight. The reaction was cooled and diluted with Ethyl acetate (500 mL) and saturated aqueous NaHCO3 (150 mL), the layers were separated and extracted ethyl acetate 2×. The organics were washed with brine 3×, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography: ISCO 80 g silica, ethyl acetate/hexanes, to give 186a.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:18]([N:25]=[C:26]=[S:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([NH:25][C:26]([NH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:26](=[S:27])[NH:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1)=[S:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: S=C=NCc1ccccc1
Reactant: Nc1ccc(NC(=O)c2ccc(N)cc2)cc1
Solvent: CC(C)=O
Product: O=C(Nc1ccc(NC(=S)NCc2ccccc2)cc1)c1ccc(NC(=S)NCc2ccccc2)cc1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
4,4'-Diaminobenzanilide (0.568 g, 2.5 mM) was dissolved in 20 ml of acetone, and 2 equivalents of benzylisothiocyanate (0.746 g, 5 mM) was added. The mixture was stirred at 55° C. for 10 minutes. After cooling, the reaction mixture was filtered, and washed with acetone/n-hexane to obtain 0.57 g (43.4% yield) of a colorless crystal of compound A-16.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.Cl[CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[O:29]>>[C:19]([C:12]1[CH:11]=[C:10]2[C:15]([C:16]3[C:17](=[O:18])[C:5]4[CH:4]=[CH:3][C:2]([O:1][CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[O:29])=[CH:23][C:6]=4[C:7]([CH3:21])([CH3:22])[C:8]=3[NH:9]2)=[CH:14][CH:13]=1)#[N:20]
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: NC(=O)NCCCl
Product: CC1(C)c2cc(OCCNC(N)=O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 2-chloroethylurea.
Reaction SMILES: [CH3:1][NH2:2].Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Cl)[CH:5]=1>>[CH3:1][NH:2][CH2:10][C:6]1[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=1
Reactant: ClCc1cccnc1
Reactant: CN
Agent: Cl
Product: CNCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To 25 ml of a 20% aqueous solution of NAOH stirred under cooling with ice-water, a 40% aqueous solution of methylamine (13.6 g, 0.175 mole) was added dropwise over 5 minutes, followed by further dropwise addition of an aqueous solution (10 ml) of 8.2 g (0.05 mole) of 3-pyridylmethyl chloride hydrochloride over 10 minutes. The mixture was further stirred at room temperature for 2 hours and, then, extracted with CH2Cl2 (100 ml×3). The extract was dried over MgSO4 and distilled to remove the solvent. The residue was subjected to vacuum distillation to give 2.6 g of the title compound as a yellow oil.
Reaction SMILES: CN.Cl[C:4]1[C:13]([C:14]([C:16](=[CH:22][N:23]([CH3:25])C)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[CH:12][C:11]2[C:6](=[C:7]([F:28])[C:8]([F:27])=[C:9]([F:26])[CH:10]=2)[N:5]=1.C1CCN2C(=NCCC2)CC1>C(O)C>[CH2:20]([O:19][C:17]([C:16]1[C:14](=[O:15])[C:13]2[CH:12]=[C:11]3[CH:10]=[C:9]([F:26])[C:8]([F:27])=[C:7]([F:28])[C:6]3=[N:5][C:4]=2[N:23]([CH3:25])[CH:22]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Agent: CN
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A solution, at about 5° C., of 10 g of methylamine in 50 cm3 of ethanol is added in the course of 10 minutes, at between 5° and 10° C., to a stirred suspension of 19.3 g of ethyl 2-(2-chloro-6,7,8-trifluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate in 150 cm3 of ethanol kept at a temperature close to 5° C., the mixture is stirred for 1 hour at between 5° and 10° C. and the temperature is allowed to rise to about 20° C. 7.6 g of DBU are added to the solution obtained and the mixture is heated at about 30° C. for 1 hour. After cooling to a temperature close to 20° C., the product is drained and washed with twice 100 cm3 of ethanol and twice 100 cm3 of diisopropyl ether. 13.4 g of 3 -ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 320° C., which is used for the subsequent steps without further purification.
Reaction SMILES: O1CCCC1.[F:6][C:7]([F:27])([F:26])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:25])[CH2:16][C@@H:17](OS(C)(=O)=O)[CH2:18][CH3:19])=[CH:10][CH:9]=1.O1CCCC1.C([Mg]Cl)(C)(C)C>O>[CH2:18]([C@H:17]1[N:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([F:27])([F:26])[F:6])=[CH:9][CH:10]=2)[C:15](=[O:25])[CH2:16]1)[CH3:19]
Reactant: CC[C@@H](CC(=O)Nc1ccc(C(F)(F)F)cc1)OS(C)(=O)=O
Agent: CC(C)(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a tetrahydrofuran solution (1 mL) containing 200 mg (0.589 mmol) of (S)-N-[4-(trifluoromethyl)phenyl]-3-methanesulfonyloxypentanoic acid amide produced in Example 3, 368.4 mg (0.589 mmol) of tert-butylmagnesium chloride tetrahydrofuran solution (1.6 mmol/g) was added dropwise at room temperature for 5 minutes. After stirring at room temperature for further 2 hours, water (5 mL) was added and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine and the product was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone as a brown solid (136.4 mg). The reaction yield of the product was determined by the method described in Example 7 to be 61%.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:36])[N:10]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]([CH2:32][C:33]([OH:35])=[O:34])[CH:25]=1)[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([O:44][C:45]([C@@H:47]1[C@@H:52]([OH:53])[C@H:51]([OH:54])[C@@H:50]([OH:55])[C@H:49](O)[O:48]1)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[N+]1([O-])CCOCC1>CC#N>[CH2:37]([O:44][C:45]([C@@H:47]1[C@@H:52]([OH:53])[C@H:51]([OH:54])[C@@H:50]([OH:55])[C@H:49]([O:34][C:33](=[O:35])[CH2:32][C:26]2[CH:25]=[C:24]([C:15]3[CH:16]=[CH:17][C:18]([C:20]([F:22])([F:23])[F:21])=[CH:19][C:14]=3[CH2:13][N:10]([CH2:11][CH3:12])[C:9]([NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:36])[C:29]([O:30][CH3:31])=[CH:28][CH:27]=2)[O:48]1)=[O:46])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)NCc1ccccc1
Reactant: O=C(OCc1ccccc1)[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[N+]1([O-])CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O[C@@H]2O[C@H](C(=O)OCc3ccccc3)[C@@H](O)[C@H](O)[C@H]2O)ccc1OC)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
[2′-(3-Benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (0.110 g, 0.2 mmol), (2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-carboxylic acid benzyl ester (0.060 g, 0.2 mmol), HATU (0.026 g, 0.2 mmol), and N-methylmorpholine-N-oxide (0.05 mL, 0.4 mmol) were combined in MeCN (2 mL) and stirred for 2 days at room temperature. The mixture was concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[C:13](Cl)(=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([O:14][C:13]([NH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc(C(=O)O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.2 %

Procedure:
Aqueous NaOH (2N, 1.93 g, 48.3 mmol) was added to a solution of 4-aminobenzoic acid (3.0 g, 21.90 mmol) in H2O at 0° C. A clear solution appeared within 5 min. Then, benzyl carbonochloridate (4.45 g, 26.28 mmol) was added dropwise to the mixture and it was heated to room temperature and stirred for 2 h. The reaction mixture was diluted with water and separated with ether. The aqueous layer was cooled to 0° C. temperature and acidified with 6M HCl. The solid was collected by filtration, washed with water and dried. The crude solid was recrystallized from ethyl acetate-hexane to furnish 4-(benzyloxycarbonylamino)benzoic acid 10 (5.0 g, 84%) as a white solid.