Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30].S.[OH-].[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:30][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])=[CH:9][C:8]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc(C(=O)CC(C(=O)c2ccccc2)c2ccccc2)c(OC)c1
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)c(OC)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
In a 1-l stainless steel autoclave were placed 56.2 g (0.150 mole) of 1,2-diphenyl-4-(2,4-dimethoxyphenyl)butane-1,4-dione, 100 ml of xylene, 33.3 g (0.075 mole) of phosphorus pentasulfide and 120 g of hydrogen sulfide. The contents of the autoclave were stirred at 160°-162° C. (1040-1080 psig) for three hours. The autoclave was then cooled, and the remaining hydrogen sulfide was vented into a trap of aqueous sodium hydroxide. The residue was stirred with 150 ml of absolute ethanol to destroy excess phosphorus pentasulfide. Chilling to -78° C. and filtration gave 27.6 g (49.4%) of crude product, m.p. 107°-110° C. Recrystallization from 30 ml of dioxane and 60 mll of ethanol gave 17.3 g (31%) of pure 2,3-diphenyl-5-(2,4-dimethoxyphenyl)thiophene, m.p. 112°-114° C.
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:18][O:19][C:20](=[O:22])[CH3:21])=O)=CC=1)([O-])=O.C(O)(=O)C.[H][H]>C(O)C.[C].[Pd]>[C:20]([OH:22])(=[O:19])[CH3:21].[C:20]([O:19][CH2:18][C@@H:13]1[CH2:14][C@@H:15]([OH:17])[CH2:16][NH:12]1)(=[O:22])[CH3:21]
Reactant: [H][H]
Reactant: CC(=O)OC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)OC[C@@H]1C[C@@H](O)CN1

Procedure:
To a solution of (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-acetoxymethyl-4-hydroxypyrrolidine (1.55 g) in ethanol (23 ml), 10% palladium-carbon (233 mg) and acetic acid (330 mg) were added. The mixture was stirred at room temperature for 2 hours under an atmospheric pressure of hydrogen. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated to remove the solvent. The residue was combined with water, washed with dichloromethane and concentrated to give (2S,4R)-2-acetoxymethyl-4-hydroxypyrrolidine acetate.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9](O)[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+:2]=[N-:3].C(N(S(F)(F)[F:27])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[N:1]([CH2:4][C@@H:5]1[C@H:9]([F:27])[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Process A: (3R,4R)-3-Azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine (1.20 g) was dissolved in dichloromethane (40 mL). While this solution was chilled in a salt/ice bath, diethylaminosulfur trifluoride (1.20 mL) was added dropwise and the mixture was stirred at room temperature for 3 hours. The reaction vessel was again chilled in a salt/ice bath, followed by dropwise addition of a second portion of diethylaminosulfur trifluoride (0.57 mL) and stirring at room temperature for 2 hours. While the reaction mixture was kept chilled in the ice bath, a saturated aqueous solution of sodium bicarbonate (40 mL) was added dropwise and the dichloromethane layer was separated. The dichloromethane layer was then washed with a saturated aqueous solution of sodium bicarbonate (2×20 mL) and then water (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3R,4S)-3-azidomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine as a pale brown oil (726 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.[C:12]([NH:15][CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)(=[O:14])[CH3:13].Cl>C(Cl)CCl>[C:12]([NH:15][CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:8](=[O:9])[CH2:7][CH2:6][C:5]([OH:10])=[O:11])[CH:22]=2)[CH2:17]1)(=[O:14])[CH3:13]
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)NC1Cc2ccccc2C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)NC1Cc2ccc(C(=O)CCC(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
137.3 g (1.03 mol) of anhydrous aluminium chloride and 34.2 g (0.34 mol) of succinic anhydride are suspended in 500 ml of ethylene chloride and 54.5 g (0.311 mol) of 2-acetamido-indane are introduced at room temperature, with vigorous stirring. The mixture is stirred at room temperature for a further 2 hours, ice and 150 ml of concentrated hydrochloric acid are added, and the ethylene chloride is removed by steam distillation. On cooling, 4-(2-acetamido-indan-5-yl)-4-oxobutyric acid crystallises out from the aqueous solution. The acid is purified by being dissolved in 2N sodium hydroxide solution, the solution is filtered and the acid is reprecipitated by means of hydrochloric acid.
Reaction SMILES: [C:1]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:27](OC(=O)C)(=[O:29])[CH3:28].Cl>O1CCCC1>[C:1]1([CH:11]([C:27](=[O:29])[CH3:28])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cc1cccc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)c1cccc2ccccc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(naphthalen-1-yl)acetate (1 g, 4.7 mmol) in tetrahydrofuran (20 mL) at −78° C. was added LiHMDS (1M THF, 9.4 mL, 9.4 mmol) and the reaction mixture stirred at −78° C. for 1 hour. Acetic anhydride was then added (0.54 mL, 5.64 mmol) dropwise and the reaction allowed to warm to room temperature and stirred for 30 minutes. Aqueous HCl solution (1N, 25 mL) was added to the reaction mixture and then extracted with ethyl acetate, dried over sodium sulfate and concentrated to give compound ethyl 2-(naphthalen-1-yl)-3-oxobutanoate as a light yellow oil, that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:12][CH2:11][C@:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[C@H:5]([CH2:6][C:7]3[C:23]([CH3:24])=[C:22]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:26])[NH:21][C:8]=3[CH2:9]2)[CH2:4]1)[CH3:2].B(Br)(Br)Br>>[CH2:1]([N:3]1[CH2:12][CH2:11][C@:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[C@H:5]([CH2:6][C:7]3[C:23]([CH3:24])=[C:22]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:26])[NH:21][C:8]=3[CH2:9]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@@]2(c3cccc(OC)c3)Cc3[nH]c(C(=O)Nc4ccccc4)c(C)c3C[C@@H]2C1
Agent: BrB(Br)Br
Product: CCN1CC[C@@]2(c3cccc(O)c3)Cc3[nH]c(C(=O)Nc4ccccc4)c(C)c3C[C@@H]2C1
Yield: 22.1 %

Procedure:
0.28 g of (±)-trans-6-ethyl-8a-(3-methoxyphenyl)-3-methyl-2-phenylaminocarbonyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline were treated with 0.35 (1.9 mmol) of boron tribromide as described in example 2. The residue was purified by flash chromatography (EtOAc/MeOH/conc. NH4OH 80:20:2) yielding 0.06 g of the title compound. M.p.=271°-272° C.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[O:24][CH3:25].[OH-].[Na+].C(Cl)Cl>CO>[C:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][CH:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[C:5]([O:24][CH3:25])[CH:6]=2)[CH2:16][CH2:15]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)O
Yield: 95 %

Procedure:
4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoic acid methyl ester from Step 2 was saponified to the carboxylic acid with aqueous NaOH in MeOH using the procedure of Step 3 in Example 11. 4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoic acid was obtained as a foam by evaporation of a DCM solution under reduced pressure (95% yield).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:10]2=[C:11]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:13][N:9]2[CH2:8][CH2:7][NH:6]1)=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)CC)C>ClCCCl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:11]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:10]3[N:5]([C:3](=[O:4])[CH2:2][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[NH:6][CH2:7][CH2:8][N:9]3[N:13]=2)=[CH:15][CH:16]=1
Reactant: C1COCCN1
Reactant: O=C(CCl)N1NCCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(CN1CCOCC1)N1NCCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A mixture of 2-chloroacetyl-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (80 mg, 0.215 mmol), morpholine (37 mg, 0.430 mmol), and triethylamine (22 mg, 0.215 mmol) in 1,2-dichloroethane (2 ml) was stirred for 24 hours at ambient temperature. After dilution of dichloromethane, the mixture was washed with an aqueous saturated sodium bicarbonate solution, and brine. The organic phase was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent:ethyl acetate ethyl acetate/methanol; 20/1), and the obtained oil was crystallized from diisopropyl ether to give 7-(4-fluorophenyl)-2-morpholinoacetyl-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (50 mg).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-(4-methoxy-phenyl)-cyclohexanone (as prepared in Example 7, Step B) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[Br:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32]>>[Br:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2)=[O:32]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc(Br)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc(Br)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-bromo-benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=[O:7])=[CH:4][CH:3]=1.Br[C:16]1[S:17][CH:18]=[CH:19][N:20]=1.Cl.O1CCOCC1>C(O)(C)C>[S:17]1[CH:18]=[CH:19][N:20]=[C:16]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:13][CH:14]=1
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Nc2nccs2)cc1
Temperature: 100 °C
Yield: 56.9 %

Procedure:
To a suspension of tert-butyl 4-aminobenzoate (1.93 g, 10 mmol) and 2-bromothiazole (1.2 g, 7.3 mmol) in isopropanol (60 mL) was added 4 N HCl solution in 1,4-dioxane (0.5 mL, 2 mmol). The mixture was refluxed at 100° C. for 50 h, and then allowed to cool to room temperature. The mixture was concentrated to one third of the initial volume. The resulting precipitate was isolated by filtration to yield the first crop of the title compound as a brown solid (915 mg). The mother liquor was dried in vacuo. The obtained residue was dissolved in ethyl acetate (50 mL), washed with water (2×15 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was triturated with isopropanol (8 mL) to yield the second crop of the title compound (341 mg) (total 1.25 g, 78% yield). HPLC/MS (Method D): retention time=0.57 min, [M+H]+=221.3.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([C:12]#[N:13])=[C:7]([O:14][CH2:15][CH3:16])[N:6]=1)=O.[NH3:17]>CO>[NH2:11][C:9]1[C:8]([C:12]#[N:13])=[C:7]([O:14][CH2:15][CH3:16])[N:6]=[C:5]([C:3]([NH2:17])=[O:2])[CH:10]=1
Reactant: CCOc1nc(C(=O)OC)cc(N)c1C#N
Reactant: N
Solvent: CO
Product: CCOc1nc(C(N)=O)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 231 mg (1.00 mmol) of 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid methyl ester from Example 104A was added 5 mL of 7 M NH3 in methanol. The reaction was stirred at ambient temperature for 5 h, and concentrated in vacuo to 214 mg (100%) of the titled compound as a solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4](P(O)(O)=O)/[C:5](/C)=[C:6](\C)/[C:7]([O-:9])=[O:8].CC[O:18][CH:19](OCC)[C:20]1[CH:25]=[CH:24][C:23](C=O)=[CH:22][CH:21]=1.[OH-].[K+]>C1COCC1.C(O)C.C(OCC)(=O)C.O>[CH:19]([C:20]1[CH:25]=[CH:24][C:23]([CH:3]=[CH:4][CH:5]=[CH:6][C:7]([OH:9])=[O:8])=[CH:22][CH:21]=1)=[O:18]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: C/C(C(=O)[O-])=C(/C)C(C)P(=O)(O)O
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=Cc1ccc(C=CC=CC(=O)O)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice cooled solution of sodium hydride (2.26 g, 67.2 mmol as a 60% mineral oil suspension) in dry THF (100 ml) was added dropwise a solution of trimethyl4-phosphonocrotonate (10.5 g, 50.4 mmol) in dry THF (200 ml), and the solution was stirred under an inert atmosphere at 0° C. for 3 hours. Terephthaldialdehyde mono diethyl acetal (7.00 g, 33.6 mmol) was dissolved in dry THF (200 ml) and slowly added to the above solution. Stirring was continued for 2 hours at 0° C. Water (400 ml) was slowly added, and followed by ethyl acetate (500 ml) and the layers were mixed. The organic layer was collected and dried with anhydrous sodium sulphate. Solvent was removed by rotary evaporation to leave 10.0 g of a crude orange product that was dissolved in ethanol (20 ml) and added a solution of 20% potassium hydroxide (100 ml). The mixture was stirred at room temperature for 5 hours, and then partitioned between ethyl acetate (500 ml) and water (500 ml). The organic layer was washed with water (200 ml), and the combined water phases back extracted once with ethyl acetate (300 ml). The water phase was acidified with glacial acetic acid to pH 3.5, and extracted with ethyl acetate (2×500 ml). The organic layer was dried with sodium sulphate, and taken to dryness to leave the title material as an orange powder. Yield: 6.78 g (100%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=1[O:13][CH3:14])=[O:3].[CH3:15][CH:16]([OH:21])[CH2:17][CH:18]([OH:20])[CH3:19]>>[CH3:14][O:13][C:6]1[CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:20][CH:18]([CH2:17][CH:16]([OH:21])[CH3:15])[CH3:19])=[O:3]
Reactant: CC(O)CC(C)O
Reactant: COc1cc(C=O)ccc1OC(=O)Cl
Product: COc1cc(C=O)ccc1OC(=O)OC(C)CC(C)O

Procedure:
The reaction of 2-methoxy-4-formylphenyl chloroformate with 2,4-pentanediol is conducted on a 0.02 mole scale employing the same conditions as described in Example I. A 2.9 g yield of the pure product is obtained as an oil.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].Br[CH2:10]/[CH:11]=[C:12](/[C:23]1[N:28]=[C:27]([O:29][CH3:30])[C:26]([Cl:31])=[CH:25][CH:24]=1)\[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1.O>O1CCCC1>[C:19]([C:16]1[CH:15]=[CH:14][C:13](/[C:12](/[C:23]2[CH:24]=[CH:25][C:26]([Cl:31])=[C:27]([O:29][CH3:30])[N:28]=2)=[CH:11]\[CH2:10][N:5]2[CH2:6][CH2:7][O:3][C:4]2=[O:8])=[CH:18][CH:17]=1)([CH3:20])([CH3:21])[CH3:22]
Reactant: O=C1NCCO1
Reactant: COc1nc(/C(=C/CBr)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(/C(=C/CN2CCOC2=O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A suspension of sodium hydride (purity: 60%, 60 mg) in tetrahydrofuran (1.0 mL) was added to a solution of 2-oxazolidinone (153 mg) in tetrahydrofuran (1.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 6-[(1E)-3-Bromo-1-(4-tert-butylphenyl)prop-1-en-1-yl]-3-chloro-2-methoxypyridine obtained in Reference Example 4-5 (303 mg) was added thereto, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:2) to give 3-[(2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-yl]-1,3-oxazolidin-2-one as a light brown powder (298 mg, 98%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:21]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([Cl:32])=[O:31])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[ClH:32].[CH2:21]([O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:31])=[CH:33][CH:34]=1)[CH2:22][CH2:23][CH3:24]
Reactant: NCCCSc1ccncc1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1ccc(C(=O)NCCCSc2ccncc2)cc1
Yield: 69.6 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.78 ml (19.9 mmol) of triethylamine in 40 ml of methylene chloride was added 0.94 ml (4.96 mmol) of 4-n-butoxybenzoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.10 g of the desired compound (free base). (76.9%,.colorless-powder), mp: 98.0°-99.0° C.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:26])[N:12]([CH2:14][CH2:15][NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CN(C=O)C.O>[C:1]1([CH:7]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:26])[N:12]([CH2:14][CH2:15][NH:16][C:17]([C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[O:24][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:25])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(NCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc(C(=O)NCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Reaction time: 14 h

Procedure:
To a suspension of N-{2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}-3-hydroxybenzamide (60.0 mg) and K2CO3 (58.6 mg) in DMF (1.8 mL) was added dropwise ethyl bromoacetate (18.8 μL) at ambient temperature and the mixture was stirred at the same temperature for 14 hours. The resulting mixture was diluted with water (5.0 mL) and the aqueous solution was extracted with EtOAc (10.0 mL). The organic layer was washed successively with 1M HCl aqueous solution, saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=98:2) to give ethyl {3-[({2-[5-(diphenylmethyl)-2-oxo-1(2H) -pyridinyl]ethyl}amino)carbonyl]phenoxy}acetate (70 mg) as a colorless syrup.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[N:7]=1.[NH2:16][C:17]1[S:18][C:19]([C:25]2[C:30]([F:31])=[CH:29][C:28]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:27][C:26]=2[F:36])=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23]>>[F:36][C:26]1[CH:27]=[C:28]([C:32]([OH:35])([CH3:34])[CH3:33])[CH:29]=[C:30]([F:31])[C:25]=1[C:19]1[S:18][C:17]([NH:16][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[N:7]=2)=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Clc1ccc2nc(-c3ccco3)cn2n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4nc(-c5ccco5)cn4n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1, Step 5 using 6-chloro-2-(2-furyl)imidazo[1,2-b]pyridazine (61.9 mg, 0.282 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide as starting materials.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[CH2:11]([C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C:18]1[CH:19]=[C:20]([NH:24][C:25]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:26])[CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C=Nc1cccc(Cc2ccccc2)c1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Product: NC(=O)CC[C@H](NC(=O)Nc1cccc(Cc2ccccc2)c1)C(=O)O
Yield: 72.8 %

Procedure:
Preparation from L-(+)-glutamine (0.487 g, 3.33 mmol) and 3-benzylphenyl isocyanate (0.719 g, 3.33 mmol) (final pH value after 24 h stirring: 5-6) gave N2-[(3-benzylphenylamino)carbonyl]-L-glutamine (0.862 g, 73%, white solid).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][CH2:12][N:13](CC)[CH2:14][CH3:15].N(CC)CC>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([CH2:14][CH3:15])[CH2:12][CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To a mixture of 4-iodo-benzoyl chloride (75 g) in 500 mL CH2Cl2 was added a mixture of Et3N (50 mL) and Et2NH (100 mL) at 0° C. After the addition, the resulting reaction mixture was warmed up to room temperature in 1 hr and was then washed with saturated ammonium chloride. The organic extract was dried (Na2SO4), filtered and concentrated. Residue was recrystallized from hot hexanes to give 80 g of INTERMEDIATE 1.