Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:19]([O:21][C:22]([C:24]1[C:25]([Cl:30])=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23])[CH3:20]>ClCCl>[CH2:19]([O:21][C:22]([C:24]1[C:25]([Cl:30])=[N+:26]([O-:9])[CH:27]=[CH:28][CH:29]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccc[n+]([O-])c1Cl
Reaction time: 36 h
Yield: 33 %

Procedure:
A solution of m-chloroperbenzoic acid (mCPBA), prepared by suspending 41.4 g (0.021 mol) of 50% mCPBA in 100 ml of dichloromethane, adding a drying agent (sodium sulfate), and removing the solids by filtration, was added dropwise to a solution of 22.2 g (0.12 mol) of 2-chloro-3-pyridinecarboxylic acid ethyl ester (Aldrich, 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233 USA) in 100 ml of dichloromethane. After stirring the mixture for 36 hours, the precipitate was removed by filtration and the filtrate was evaporated. The residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium bisulfite solution (1×100 ml) and sodium bicarbonate solution (2×100 ml), dried (Na2SO4), and evaporated. The residue was purified by flash chromatography with an ethyl acetate-hexane eluant (5:95 to 100:0) to afford 8.1 g (33%) of the title compound as an oil. 1H NMR (CDCl3): δ 1.35 (3H, t, J=7), 4.36 (2H, q, J=7), 7.23-7.29 (1H, m), 7.61 (1H, d, J=7), 8.41 (1H, d, J=7).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:13]([Mg]Cl)([CH3:15])[CH3:14].C(Br)C=C.C([Cu])#N>C1COCC1>[CH2:8]([O:7][C:5](=[O:6])[C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([CH2:15][CH:13]=[CH2:14])[CH:3]=1)[CH3:9]
Reactant: CC(C)[Mg]Cl
Reactant: CCOC(=O)c1cccc(I)c1
Agent: N#C[Cu]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1cccc(C(=O)OCC)c1
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A −45° C. solution of ethyl 3-iodobenzoate (2.434 g, 8.8 mmol) in 40 mL THF was treated with i-PrMgCl (4.8 mL, 9.6 mmol, 2 M/ether). After 1 h, allyl bromide (1.6 mL, 18.9 mmol) was added followed by CuCN (79 mg, 0.88 mmol). The reaction was stirred for 1 h and then was quenched by addition of 50 mL saturated NH4Cl solution. Water (30 mL) was added and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined ethyl acetate solution was dried (MgSO4), filtered and evaporated. Purification by flash chromatography on silica gel (5% ethyl acetate/hexanes→10%) gave compound 7 (1.145 g, 68%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][O:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18]>C(COC)OC.O>[CH2:18]([N:10]1[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:13]=[CH:12][O:11]1)[CH:17]=[CH2:16]
Reactant: CC(C)(C)OC(=O)Nc1ccon1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=CCN1OC=CC1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.6 %

Procedure:
3-(t-Butoxycarbonylamino)isoxazole (12 g, 65.2 mM) was dissolved in dimethoxyethane (150 ml) and cooled to 0° C. under nitrogen. To the stirred solution was added sodium hydride (60% in oil, 2.87 g, 71.7 mM), and the mixture stirred 20 minutes. Allyl bromide (8.7 g, 71.7 mM) was added dropwise, and the mixture stirred at ambient temperature for 18 hours, then diluted with water (300 ml), and extracted into diethyl ether (3×100 ml). The extracts were washed with brine (100 ml), dried (magnesium sulfate), and chromatographed on silica (50 g) eluting with dichloromethane . Relevant fractions were combined to give the desired product as an oil (14.68 g). MS (ESP): 225 (MH+) for C11H16N2O3
Reaction SMILES: [NH3:1].[CH2:2]([N:4]([CH2:22][CH3:23])[C:5](=[O:21])[C:6]1([S:13][C:14](=[O:20])[N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:11]=[CH:10][CH:9]=[N:8][CH:7]1F)[CH3:3]>CO>[CH2:2]([N:4]([CH2:22][CH3:23])[C:5](=[O:21])[C:6]1([S:13][C:14](=[O:20])[N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:11]=[CH:10][CH:9]=[N:8][CH:7]1[NH2:1])[CH3:3]
Reactant: CCN(CC)C(=O)SC1(C(=O)N(CC)CC)C=CC=NC1F
Reactant: N
Solvent: CO
Product: CCN(CC)C(=O)SC1(C(=O)N(CC)CC)C=CC=NC1N
Temperature: 100 °C
Yield: 47 %

Procedure:
43 g of ammonia are injected into an autoclave with a solution of 40.2 g (122 mmol) of N,N-diethyl-3-(diethylcarbamoylthio)-2-fluoronicotinamide in 350 g of methanol, and the mixture is heated at 100° C. for 10 hours. It is then concentrated in vacuo and chromatographed on silica gel using ethyl acetate. Subsequent recrystallization from Et2O/hexane gives 18.7 g (47%) of yellowish crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][C:14](N3CCCCC3)=[O:15])[CH:8]=[CH:9][C:2]1=2.[OH-:22].[Na+]>C(O)C.O>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]([OH:15])=[O:22])[CH:8]=[CH:9][C:2]1=2
Reactant: [OH-]
Reactant: O=C(COCCc1ccc2sccc2c1)N1CCCCC1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)COCCc1ccc2sccc2c1
Yield: 74.6 %

Procedure:
In a mixture of 58 mL of ethanol and 6 mL of water is dissolved 6.40 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-1-piperidino-1-ethanone, to which is added 1.27 g of sodium hydroxide. The mixture is heated under reflux for 4 hours. After cooling the mixture, the deposited matter is collected by filtration. The deposited matter is added to a mixture of ethyl acetate and water, pH is adjusted to 1.5 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 3.72 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-acetic acid as a colorless crystalline product.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=1.[CH2:14]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[I-].[Na+].[H-].[Na+]>O.CN(C=O)C>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:3]2[N:2]=[N:1][C:5]([C:6]3[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=3)=[N:4]2)=[CH:28][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(-c2nn[nH]n2)c(N)n1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(-c2nnn(Cc3ccc(OCc4ccccc4)cc3)n2)c(N)n1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
3-(2H-tetrazol-5-yl)-pyridin-2,6-diamine (60 mg) described in Manufacturing Example 7-3, 4-benzyloxybenzyl chloride (79 mg), sodium iodide (51 mg), NaH (14 mg, 60% in oil), and DMF (0.69 mL) were stirred for 10 minutes at 60° C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was concentrated and purified by NH silica gel column chromatography (hexane:ethyl acetate=2:1, then ethyl acetate). Ethyl acetate-hexane was added to the residue thus obtained, and the solids were filtered off to obtain the titled compound (26 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:18]([OH:20])=[O:19])[CH2:16][CH2:15][C:14](=[O:17])[O:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I.O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:18]([O:20][CH3:23])=[O:19])[CH2:16][CH2:15][C:14](=[O:17])[O:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)(C(=O)O)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(NC(=O)OCc2ccccc2)CCC(=O)O1
Reaction time: 4 h

Procedure:
In 100 ml of N,N-dimethylformamide was dissolved 27.93 g of 2-benzyloxycarbonylamino-5-oxo-2-tetrahydrofurancarboxylic acid obtained by the method described in Journal of Organic Chemistry, 6 878 (1941). To the solution was added 4.0 g of sodium hydride (60% oil), to which was further added 28.4 of methyl iodide, and the reaction was allowed to proceed at room temperature for 4 hours. The reaction mixture was supplemented with 14.2 g of methyl iodide, which was stirred for further 3 hours. The reaction solution was poured into water, which was subjected to extraction with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate and a saturated saline solution, successively, followed by drying (MgSO4). The solvent was evaporated off, and the crystals which separated out were collected by filtration, followed by washing with ether to give 27.25 g of methyl 2-benzyloxycarbonylamino-5-oxo-2-tetrahydrofurancarboxylate as colorless crystals, m.p. 134-134.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N+:6]([O-:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N+]([O-])=O.P(Cl)(Cl)([Cl:15])=O.[OH-].[Na+]>ClCCl>[Cl:15][C:3]1[CH:4]=[C:5]([CH3:9])[N+:6]([O-:8])=[CH:7][C:2]=1[Br:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(Cl)c(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-bromo-4-nitro-2-picoline-N-oxide (30.0 g) in dichloromethane (250 ml) was cooled at 10°, and a solution of phosphoryl chloride (35.5 ml) in dichloromethane (200 ml) added over 15 minutes. The mixture was heated under reflux for 5 hours, allowed to cool to ambient temperature, and allowed to stand for 16 hours. After pouring onto ice (300 ml) and stirring for 15 minutes, the mixture was basified to pH 10 using concentrated aqueous sodium hydroxide. The organic phase was separated off, and the aqueous phase further extracted with chloroform (2×100 ml). The combined organic phases were dried (K2CO3) and stripped to a solid, which was triturated with petroleum ether (40-60), filtered, washed and dried to yield 4-chloro-5-bromo-2-picoline-N-oxide, 24.08 g, m.p. 121°-4° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)[C:15]#[CH:16].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[SH:13][C:10]([CH3:11])([CH3:12])[CH2:9][NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:19][C:18]([S:17][CH2:14][C:15]#[CH:16])([CH3:22])[CH3:21]
Reactant: CC(C)(S)CNc1ccccc1N
Reactant: C#CCSC(C)(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C#CCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Temperature: 21 °C
Reaction time: 17 h
Yield: 74.8 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (5.59 g, 2.85×10-2 mol) and 2-(2-propynylthio)-2-methylpropanal 6.07 g, 4.28×10-2 mol, 150 M %) were mixed, then 125 ml methanol and 5.27 ml (5.7×10-2 mol, 200 M %) acetic acid were added and solids were allowed to dissolve. Sodium cyanoborohydride (5.39 g, 8.56×10-2 mol, 300 M %) was added to the reaction solution in three equal portions. The reaction was stirred at 21° C. for 17 hr, then quenched with 100 ml 0.5M HCl, stirred for 15 min, and then extracted with 2×150 ml ether. The ether layers were combined, washed with 60 ml saturated NaCl solution and dried over Na2SO4. The solvent was removed on the rotary evaporator and the residue was purified by filtration through flash silica in a 600 ml sintered glass funnel 3/4 full of silica, eluting with 500 ml portions of 2 × hexane and 2× 90% hexane/ether to produce 6.88 g (75% yield) 2-(2-mercapto-2-methyl-propylamino)-1-[2-(2-propynylthio)-2methylpropylamino]-benzene.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]1[N:20]([CH3:21])[N:19]=[N:18][N:17]=1)=[C:7]2[C:11]([OH:13])=[O:12].[S:22]([C:26]1[N:27]([CH2:31][C:32](Cl)=[O:33])[CH:28]=[CH:29][N:30]=1)([CH3:25])(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>O.[Na].CC(C)=O>[C:11]([C:7]1[N:8]2[CH:3]([S:4][CH2:5][C:6]=1[CH2:14][S:15][C:16]1[N:20]([CH3:21])[N:19]=[N:18][N:17]=1)[CH:2]([NH:1][C:32](=[O:33])[CH2:31][N:27]1[CH:28]=[CH:29][N:30]=[C:26]1[S:22]([CH3:25])(=[O:24])=[O:23])[C:9]2=[O:10])([OH:13])=[O:12]
Reactant: CS(=O)(=O)c1nccn1CC(=O)Cl
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cn3ccnc3S(C)(=O)=O)C2SC1
Temperature: 4 °C
Yield: 3.8 %

Procedure:
Acetone (200 cc.) is added to a solution of 7-amino-2-carboxy-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (18.4 g.) in water (110 cc.) and sodium bacarbonate (9.41 g). The mixture is cooled to about 4° C., and (2-mesyl-imidazol-1-yl)-acetyl chloride (12.4 g.) in acetone (50 cc.) is added dropwise while keeping the pH at 7 by adding a saturated aqueous solution of sodium bicarbonate. After having allowed reaction to take place for 1 hour, the acetone is removed under reduced pressure (20 mm.Hg). The pH is brought to 2.5 by adding 6 N hydrochloric acid; a solid precipitates. Ethyl acetate (100 cc.) is added, the mixture is stirred, and then the solid is filtered off and washed with ethyl acetate (500 cc.). The combined organic filtrates are dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm.Hg). A residue (8.7 g.) is obtained and is taken up in a saturated aqueous solution of sodium bicarbonate (100 cc.). The aqueous phase is washed with ethyl acetate (100 cc.) and then acidified to pH 5 by adding 6 N hydrochloric acid; a slight amount of insoluble matter is filtered off and then the filtrate is acidified to pH 2.5: a product precipitates. Extraction is effected using ethyl acetate (800 cc.), and the organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm.Hg). The residue is stirred with acetonitrile (40 cc.) and the solid formed is collected to yield 2-carboxy-7-[(2-mesyl-imidazol-1-yl)-acetamido] -3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene (1.08 g.), m.p. approx. 230° C., [α]D20 = -42°± 1 (c= 0.87, dimethylformamide).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br>CCOCC>[Br:18][CH2:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)=[O:11]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CBr)c1cccc(C(F)(F)F)c1

Procedure:
To a solution of 24.8 g. (0.127 mol.) of m-trifluoromethylacetophenone in 20 ml. of anhydrous ether is added with cooling and stirring 0.15 g. of anhydrous aluminum chloride and 20.2 g. (0.127 mol.) of bromine. The reaction mixture is concentrated and the residue is distilled to give α-bromo-m-trifluoromethylacetophenone, b.p. 135°-140° (20 mm.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:17][OH:18])[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O.O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH:17]=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CO)cc(OCc2ccccc2)c1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(C=O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
To a solution of (3-(benzyloxy)-5-methoxyphenyl)methanol (6.50 g) in DMSO (100 mL) was added 2-iodoxybenzoic acid (9.00 g), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.50 g) as an oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][NH:18]2)=[CH:14][CH:13]=1.[OH-].[Na+]>O>[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH:8]=[O:9])=[CH:17][NH:18]2)=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc2c(C=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phosphorus oxychoride (3.2 ml, 34.3 mmol) was added dropwise to dimethyl formamide (26 ml) over ten minutes at ~5° C. To this solution was added a dimethyl formamide (32 ml) solution of 6-methylindole (3.307 g, 25.2 mmol) over 10 minutes. The mixture was slowly warmed to ambient temperature, then heated to 50° C. for four hours. The mixture was cooled to ambient temperature, then poured onto ice (500 g). The aqueous solution was left to stand for 16 hours. Sodium hydroxide (6.0 g) was dissolved in water (22 ml) and added dropwise to the brown solution. The resultant yellow precipitate was boiled and filtered hot. It was left to cool to room temperature, then to 5° C. The precipitate was filtered off and washed with water (800 ml), dried at the pump, then further dried in vacuo at 50° C. for 16 hours to yield a yellow solid.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[H-].[Na+].[CH3:11][C:12]1[CH:16]=[CH:15][O:14][C:13]=1[C:17]([C:19](=[C:22](SC)[S:23][CH3:24])[C:20]#[N:21])=O>CN(C=O)C>[NH2:7][C:6]1[N:8]=[C:17]([C:13]2[O:14][CH:15]=[CH:16][C:12]=2[CH3:11])[C:19]([C:20]#[N:21])=[C:22]([S:23][CH3:24])[N:5]=1
Reactant: N=C(N)N
Reactant: CSC(SC)=C(C#N)C(=O)c1occc1C
Agent: O=C(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(-c2occc2C)c1C#N
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
6.32 g (39.5 mmol) guanidine carbonate was added portionwise to a stirred suspension of 0.7 g (17.5 mmol, 60% dispersion in mineral oil) sodium hydride in 70 ml DMF under argon at room temperature and stirring continued at 40° C. for 30 minutes. A solution of 7.4 g (29.2 mmol) 2-(3-methyl-furan-2-carbonyl)-3,3-bis-methylsulfanyl-acrylonitrile in 15 ml DMF was then added dropwise and the reaction mixture heated at 100° C. for 30 minutes. The reaction mixture was then poured onto 2 l ice-water, and the precipitate collected by filtration and dried in vacuo to afford 6.12 g (85%) 2-amino-4-(3-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a yellow solid. ES-MS m/e (%): 247 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][S:11][C:12]2[N:13]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:14]([C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)([CH3:19])[CH3:18])=[CH:15][N:16]=2)=[CH:6][C:3]=1[C:4]#[N:5].[N-:36]=[N+:37]=[N-:38].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][S:11][C:12]2[N:13]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[C:14]([C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)([CH3:18])[CH3:19])=[CH:15][N:16]=2)=[CH:6][C:3]=1[C:4]1[NH:38][N:37]=[N:36][N:5]=1
Reactant: COc1ccc(C(C)(C)c2cnc(SCc3ccc(Cl)c(C#N)c3)n2-c2ccc(F)cc2)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(C)c2cnc(SCc3ccc(Cl)c(-c4nnn[nH]4)c3)n2-c2ccc(F)cc2)cc1Cl
Temperature: 110 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A mixture of 2-chloro-5-((5-(2-(3-chloro-4-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)benzonitrile (104 mg, 0.20 mmol), sodium azide (130 mg, 2.0 mmol, 10.0 eq) and NH4Cl (110 mg, 2.0 mmol) in DMF (2 mL, anhyd) was stirred at 110° C. for 16 h. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The combined extracts were washed with water and brine, then dried over MgSO4 and concentrated. Purification by column chromatography (silica, 0 to 20% MeOH/DCM) provided the title compound (85 mg, 76%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.59 (d, J=1.7 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.18-7.14 (m, 2H), 6.95-6.89 (m, 3H), 6.78-6.74 (m, 2H), 6.37-6.31 (m, 2H), 4.17 (s, 2H), 3.81 (s, 3H), 1.39 (s, 6H); MS (EI) m/z 569 (MH+).
Reaction SMILES: C([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=O.C1(P(=CC=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1(C)C=CC=CC=1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][CH:3]=1
Reactant: O=Cc1ccc2ccccc2n1
Agent: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2ncccc2c1

Procedure:
0.2 g (1.27 mmol) of 2-formylquinoline is dissolved in 10 ml of anhydrous toluene, in a dry round-bottomed flask equipped with a magnetic stirrer and a nitrogen inlet. 0.46 g (1.52 mmol) of (triphenylphosphoranylidene)acetaldehyde is added to this solution. The mixture is brought back to the reflux temperature of toluene for 90 minutes, and the solution is then slowly brought back to ambient temperature and hydrolyzed with 10 ml of water. After separation of the two phases, the aqueous phase is extracted with ethyl acetate (4×50 ml).
Reaction SMILES: O.[C:2]([OH:8])([C:4]([F:7])([F:6])[F:5])=[O:3].[CH2:9]([O:16][CH:17]1[C:22](OC)([O:23]C)[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[OH:8][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH2:9]([O:16][CH:17]1[C:22](=[O:23])[CH2:21][CH2:20][NH:19][CH2:18]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1CCNCC1OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A water/TFA mixed solution (1/1, 35 mL) was added to tert-butyl 3-(benzyloxy)-4,4-dimethoxypiperidine-1-carboxylate obtained in Example (90a) (4.99 g, 14.2 mmol), and the mixture was stirred at 60° C. for one hour. The reaction solution was concentrated to obtain crude 3-(benzyloxy)piperidin-4-one TFA salt as a brown oily substance. A 2 N aqueous sodium hydroxide solution (20 mL) was added to the crude 3-(benzyloxy)piperidin-4-one TFA salt, and a solution of di-tert-butyl dicarbonate (4.36 g, 20 mmol) in THF (10 mL) was added at room temperature. Following stirring for one hour, the reaction solution was diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 5/1, 2/1) to obtain 3.81 g of the title compound as a light brown oily substance (88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2([OH:22])[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1.[OH-].[Na+:24].C1COCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:7]([C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)=[O:22])[C:11]=1[C:9]([O-:10])=[O:8].[Na+:24]
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(Cl)cccc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)nc(C(=O)c2cccc(Cl)c2C(=O)[O-])n1

Procedure:
1.24 g of 7-chloro-3-hydroxy-3-(4,6-dimethoxy-2-pyrimidinyl)phthalide, 154 mg NaOH, 25 ml THF and 25 ml water are mixed until a yellow homogenous solution is achieved. The solvents are stripped on a rotovaporator and then on a Kugelrohr at 100° C. to produce the title compound as a yellow solid, m.p. 276°-278° C.
Reaction SMILES: Cl.[F:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:15]1[N:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][N:16]=1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:12]([O:11][C:9]([C:3]1([F:2])[CH2:4][CH2:5][N:6]([C:15]2[N:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][N:16]=2)[CH2:7][CH2:8]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)C1(F)CCNCC1
Reactant: OB(O)c1cnc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(F)CCN(c2ncc(B(O)O)cn2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 96.2 %

Procedure:
A mixture of ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (2 g, 9.4491 mmol), (2-chloropyrimidin-5-yl)boronic acid (1.5426 g, 9.4493 mmol) and sodium carbonate decahydrate (2.53 g, 23.6 mmol) in ethanol (15 mL) was stirred at 60° C. for 12 h. The reaction mixture was filtered through celite, the solvent was evaporated and the residue was dried under vacuum to give the title compound (2.7 g, 97%) as a pale yellow gum, which was used without further purification. LCMS (pH 10) MH+ 298, RT 1.19 minutes.