Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][SH:2].[Na].F[C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].C(O)C.Cl>O>[CH3:1][S:2][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11]
Reactant: CS
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CSc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reaction time: 48 h

Procedure:
2.5 mL of 15% sodium methylmercaptan aqueous solution was added to the mixture of 11.0 g (5.40 mmol) of 5-fluoro-2-nitrobenzoic acid and 5 mL of ethanol and stirred for 2 days. Then, 10 mL of water was added and pH thereof was adjusted to become 1 by concentrated hydrochloric acid. After filtering out the precipitated compound, it was washed with water, ether and hexane and dried to obtain a crude material of 5-methylthio-2-nitrobenzoic acid. 3 mL of thionyl chloride was added to the obtained crude material and stirred for 5 hours. The thionyl chloride was removed to obtain the title compound.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([O:32][CH2:33][C:34](=[O:36])[CH3:35])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.O1CCCC1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]([OH:36])[CH3:35])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(=O)COc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)COc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 77.7 %

Procedure:
To a solution of 1-[([6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-pyrrol-2-yl)pyridin-3-yl]oxy}propan-2-one (0.050 g) in a mixed solvent of tetrahydrofuran (5 mL) and ethanol (1 mL) was added sodium borohydride (18 mg) under ice-cooling. The reaction solution was warmed to room temperature, and stirred at room temperature for 10 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-100:0, volume ratio), and recrystallized from hexane-ethyl acetate to give the title compound (0.039 g, yield 78%) as colorless crystals. MS: 511 (MH+). melting point 116-118° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1)#[CH:2].Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:35]=1)[C:23]([N:25]=[S:26]([CH3:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH3:34][S@:26](=[N:25][C:23]([C:22]1[CH:35]=[C:18]([C:2]#[C:1][C:3]2[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[CH:7][CH:8]=2)[CH:19]=[N:20][CH:21]=1)=[O:24])(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CS(=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1ccc(NC(=O)OC(C)(C)C)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)cc1
Yield: 44.1 %

Procedure:
In a manner similar to that described in Example 449, tert-butyl 4-ethynylphenylcarbamate (0.096 g, 0.443 mmol) and 5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (63 mg, 0.13 mmol, 45%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6].[CH3:12]OS(OC)(=O)=O>O>[CH3:12][O:6][C:5]1[C:4]([CH3:3])=[C:10]([OH:11])[CH:9]=[CH:8][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1c(O)cccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(O)c1C
Temperature: 95 °C
Reaction time: 2 h

Procedure:
3-Methoxy-2-methyl-phenol was prepared according to published procedure: J. Org. Chem. 55, 5, 1990, 1469. To a solution of 2.0 g (50 mmol) NaOH and 2-methylresorcinol (6.2 g, 50 mmol) in water (50 mL), dimethylsulfate (4.8 mL, 50 mmol) was added at 95° C. over 30 min, then reaction was stirred for 2 h at 95° C. After cooling to RT, the reaction mixture was poured into aqueous NaOH (8.0 g in 200 ml H2O). Extracted with Et2O (2×100 mL). The aqueous phase was acidified with 5 N aq. HCl, extracted with Et2O (2×100 mL), extracts were dried over Na2SO4 and evaporated. The residue was purified on SiO2 (200 g) column, hexane-EtOAc (0 to 20%). Yield 3.37 g (24.0 mmol, 49%), colorless oil.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[C:5]([O:9][C:10](=[O:20])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=1)([CH3:8])([CH3:7])[CH3:6].[Cl-].[NH4+]>N1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:5]([O:9][C:10](=[O:20])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:3]#[C:2][CH2:1][OH:4])[CH:14]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)COc1cccc(Br)c1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)COc1cccc(C#CCO)c1
Temperature: 77.5 °C
Yield: 64 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.66 g, 0.57 mmol) and propargyl alcohol (1.34 mL, 22.97 mmol) were added to a solution of (3-bromophenoxy) acetic acid tert-butyl ester (3.3 g, 11.49 mmol) in pyrrolidine (35 mL) under an argon atmosphere at room temperature. The mixture was heated at 75-80° C. for 2.5 hours. Excess saturated ammonium chloride was added and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over sodium sulfate, and concentrated to dryness. Purification by flash chromatography, eluting with hexane/ethyl acetate, gave [3-(3-hydroxyprop-1-ynyl)phenoxy]acetic acid tert-butyl ester as a pale yellow oil (1.93 g, 64%).
Reaction SMILES: CO.NN.[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[S:10](Cl)(=[O:12])=[O:11].[Br:14]Br>C(Cl)(Cl)Cl.O>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[S:10]([Br:14])(=[O:12])=[O:11]
Reactant: BrBr
Reactant: O=S(=O)(Cl)c1cccs1
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: O=S(=O)(Br)c1cccs1
Temperature: 7 °C
Yield: 67.5 %

Procedure:
In a 500 ml Erlenmeyer flask equipped with a magnetic stirrer and a thermometer were placed 200 ml of methanol and 6.80 g (0.20 mol) of 95% hydrazine. This solution wa cooled to 7° C. and 18.26 g (0.10 mol) of 2-thiophenesulfonyl chloride was added portion-wise in such a manner that the temperature did not exceed 15° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature. The methanol was removed in vacuo leaving a mixture of a heavy oil and a fluffy solid. The mixture was treated with water, and the solid dissolved and oil separated. The mixture of oil and water (which contained the hydrazine hydrochloride from the first reaction) was placed in a flask containing 300 ml of chloroform and a magnetic stirrer. Crushed ice was added and to the resulting slurry 64.0 g of bromine was added at such a rate that the reaction temperature remained below 10° C. After the addition was complete and the bromine color had dissipated, the layers were separated. The chloroform layer was dried over anhydrous magnesium sulfate, and the chloroform removed in vacuo leaving a yellow oil which crystallized on addition of hexane. The solid was filtered and dried to give 15.33 g of the title compound as slightly yellow crystals, mp 49°-51° C.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br>>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1)[CH2:26][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 53.2 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-bis(trifluoromethyl)benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (266 mg, yield: 53.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Br)[N:14]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([NH2:32])[N:24]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[N:24]=[C:25]([NH2:32])[C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[CH:12]=[N:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Reactant: O=[N+]([O-])c1ncc(Br)nc1-c1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(NCCNc2cnc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-5-bromo-2-nitropyrazine (20 mg, 0.057 mmol) in DMF (1 ml), (2-aminoethyl)(6-amino-5-nitro(2-pyridyl))amine (12.3 mg, 0.06 mmol) and diisopropylethyl amine (40 μl, 0.228 mmol) were added. The reaction mixture was stirred for 12 hours at 80° C. The crude mixture was concentrated in vacuo and subjected to column chromatography (5% methanol in methylene chloride) to afford the title compound as bright yellow solid.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].Br[CH2:26][CH2:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:30][C:29]([CH3:32])([CH3:31])[O:28][CH2:27][CH2:26][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OCCBr
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OCCN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Yield: 65 %

Procedure:
5 g (14.43 mmol) of 1,4,7-tris-(carboxymethyl)-1,4,7, 10-tetraazacyclododecane is stirred in 75 ml of dimethylformamide for 18 hours with 3.14 g (17.35 mmol) of (2-bromoethyl)-tert-butyl ether and 6.50 g of potassium carbonate at 95° C. It is concentrated by evaporation in a vacuum and the residue is dissolved in 100 ml of water, the pH is adjusted to 2 by adding 12 N hydrochloric acid and the solution is put on a column of 320 ml of cation exchanger IR-120 (H+ form). It is eluted with 2 l of water, which is discarded, then with 2 l of 0.5 N ammonia solution. This solution is concentrated by evaporation in a vacuum, the residue is dissolved in 100 ml of water. With stirring, enough cation exchanger IR-120 is added in portions up to pH 3.5. The solution is filtered and freeze-dried and 4.19 g of the title compound is obtained as white solid with a water content of 6.3%.
Reaction SMILES: [C:1]([C:5]1[C:18]2[C:19]3=[C:20]4[C:15](=[CH:16][CH:17]=2)[CH:14]=[CH:13][CH:12]=[C:11]4[CH:10]=[CH:9][C:8]3=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:28])C(=O)C1>COCCOC>[Br:28][C:6]1[CH:7]=[C:8]2[C:19]3=[C:20]4[C:15]([CH:14]=[CH:13][CH:12]=[C:11]4[CH:10]=[CH:9]2)=[CH:16][CH:17]=[C:18]3[C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccc2ccc3cccc4ccc1c2c34
Solvent: COCCOC
Product: CC(C)(C)c1c(Br)cc2ccc3cccc4ccc1c2c34
Temperature: 0 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Next, 25.0 g (0.10 mol) of tert-butylpyrene and 250 ml of DME (1,2-dimethoxyethane) were charged in a reaction vessel, and the mixture was cooled to 0° C. Next, NBS was added in an amount of 4 equivalents relative to tert-butylpyrene, and the resulting mixture was stirred overnight at room temperature, filtered, and recrystallized to produce 29.5 g of bromo-tert-butylpyrene crystals in a yield of 90%.
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[N:20]=[C:19]([CH3:21])[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:17]2)=[CH:12][CH:11]=1.CN(C)C=O>O>[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[N:20]=[C:19]([CH3:21])[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:17]2)=[CH:12][CH:11]=1)=[O:3]
Reactant: CCOC(=O)c1nn(-c2ccc(CBr)cc2)nc1C
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ccc(C=O)cc2)nc1C
Temperature: 18 °C

Procedure:
4.6 g of sodium are dissolved in 330 ml of absolute alcohol, with stirring and whilst passing a vigorous stream of nitrogen over the mixture. After cooling to 18° C., 23.2 g of 2-nitropropane are added dropwise in the course of 15 minutes and the reaction mixture is stirred for a further one hour at room temperature. 64.8 g of 2-(p-bromomethylphenyl)-4-methyl-5-carboethoxy-2H-1,2,3-triazole are then introduced, 330 ml of dimethylformamide are added and the reaction mixture is stirred for 22 hours at room temperature. The reaction mixture is then discharged into 2 liters of water and the product which has crystallised out is filtered off with suction, dried in vacuo at 50° to 60° C. and recrystallised from 1 liter of hexane with the aid of bleaching earth. This gives 25.8 g of 2-(p-formyl-phenyl)-4-methyl-5-carboethoxy-2H-1,2,3-triazole with a melting point of 97° to 99° C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Br:9]Br>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CC(=O)CBr
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 150 ml of anhydrous carbon tetrachloride solution containing 116 g of methyl acetoacetate was added dropwise 51 ml of bromine at below 5° C. After the addition was finished the reaction mixture was stirred overnight, then the reaction mixture was poured into ice-water, washed with a diluted sodium carbonate aqueous solution five times, then with a saturated sodium chloride aqueous solution, and dried with anhydrous calcium chloride. The solvent was removed by evaporation to yield 170 g of methyl 4-bromoacetoacetate.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][C:14]3([CH2:26][C:25](=[O:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22](/[CH:28]=[CH:29]/[C:30]([NH:32][O:33]C5CCCCO5)=[O:31])[CH:23]=4)[O:18]3)[CH2:13]2)=[CH:3]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][C:14]3([CH2:26][C:25](=[O:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22](/[CH:28]=[CH:29]/[C:30]([NH:32][OH:33])=[O:31])[CH:23]=4)[O:18]3)[CH2:13]2)=[CH:3]1
Reactant: Cn1cc(CN2CCCC3(CC(=O)c4cc(/C=C/C(=O)NOC5CCCCO5)ccc4O3)C2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(CN2CCCC3(CC(=O)c4cc(/C=C/C(=O)NO)ccc4O3)C2)c2ccccc21
Yield: 86.2 %

Procedure:
(E)-3-[1′-(1-Methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (300 mg, 0.56 mmol) in DCM (10 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving (E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide (215 mg, hydrochloride salt) as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH:6]=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15]>>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH:6]=[N:12][NH:13][C:14]([NH2:16])=[S:15]
Reactant: Cc1ccccc1C=CC=O
Reactant: NNC(N)=S
Product: Cc1ccccc1C=CC=NNC(N)=S
Yield: 42 %

Procedure:
The compound is prepared according to the method described in Example 1A from 2-methylcinnamaldehyde (0.27 mmol) and from thiosemicarbazide (0.27 mmol). Yield 42%.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29]O)=[N:27][CH:28]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[N:27][CH:28]=1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1ccc(Cl)cn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cn12
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (5-chloropyridin-2-yl)methanol (102 mg) and tributylphosphine (266 μl) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg) at 60° C., and the mixture was stirred at the same temperature for 3 h. The mixture was diluted with EtOAc, and washed with water and brine. The organic layer was concentrated, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (76.8 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]([Br:32])=[C:29]([OH:31])[CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39][CH2:40]C)(=O)[CH2:36]O>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]([Br:32])=[C:29]([O:31][CH2:36][CH2:35][O:39][CH3:40])[CH:30]=2)=[CH:33][CH:34]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CO
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3ccc(Br)c(O)c3)cc2)cccc1[N+](=O)[O-]
Product: COCCOc1cc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Br

Procedure:
The product from example 63F was processed as described in Example 62A substituting 2-methoxyethanol for ethyl glycolate to provide the title compound.
Reaction SMILES: [C:1]1([C:7]([NH2:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C:13]2[N:17](C)[C:16]([CH:19]=[O:20])=[CH:15]N=2)CC1>>[CH3:13][N:17]1[C:16]([CH:19]=[O:20])=[CH:15][N:9]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(C=O)cnc1C1CC1
Reactant: NC(=O)c1ccccc1
Product: Cn1c(C=O)cnc1-c1ccccc1

Procedure:
3-Methyl-2-phenyl-3H-imidazole-4-carbaldehyde was prepared from benzene carboxamide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[N:3]1.CO/[CH:14]=[C:15](/[C:17](/[O:20][Si](C)(C)C)=[CH:18]/[CH3:19])\[CH3:16].CC(C(CC(C(C)(C)C)=O)=O)(C)C.CC(C(CC(C(C)(C)C)=O)=O)(C)C.CC(C(CC(C(C)(C)C)=O)=O)(C)C.[Eu]>>[CH3:19][CH:18]1[C:17](=[O:20])[C:15]([CH3:16])=[CH:14][O:8][CH:7]1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: C/C=C(O[Si](C)(C)C)/C(C)=C/OC
Reactant: Cn1ncc([N+](=O)[O-])c1C=O
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: [Eu]
Product: CC1=COC(c2c([N+](=O)[O-])cnn2C)C(C)C1=O
Temperature: 80 °C

Procedure:
To a solution of 2-methyl-4-nitro-pyrazole-3-carbaldehyde (487 mg, 3.14 mmol) in CDCl3 (12 mL) was added [(Z)-1-[(E)-2-methoxy-1-methyl-vinyl]prop-1-enoxy]-trimethylsilane (944 mg, 4.71 mmol) and Resolve-Al™ EuFOD (127 mg, 0.31 mmol). The reaction mixture was heated at 80° C. in a sealed tube for 18 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 3,5-dimethyl-2-(2-methyl-4-nitro-pyrazol-3-yl)-2,3-dihydropyran-4-one as a mixture of diastereomers as a yellow oil (829 mg). A solution of this oil (829 mg, 3.14 mmol) and cerium(III) chloride heptahydrate (4.8 g, 12.56 mmol) in MeOH (10 mL) was stirred at room temperature for 15 min. After cooling to 0° C., sodium borohydride (143 mg, 3.8 mmol) was added portionwise and the mixture was stirred at 0° C. for 1 hr. The reaction was quenched with 1 M aqueous HCl (10 mL) and extracted with EtOAc (50 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in MeOH (40 mL) and treated with tosic acid monohydrate (87 mg). The mixture was heated at reflux for 18 hr and concentrated under reduced pressure. The residue was dissolved in DCM (30 mL) and the organic layer was washed with aqueous NaHCO3 (2×20 mL), washed with brine (20 mL), passed through a phase separation cartridge and concentrated under reduced pressure to give 5-(6-methoxy-3,5-dimethyl-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-pyrazole as a yellow oil (558 mg, 51% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.15-7.98 (m, 1H), 5.90 (d, J=3.6 Hz) and 5.78 (d, J=3.2 Hz) (1H), 5.72 (d, J=5.6 Hz) and 5.64 (d, J=10.8 Hz) (1H), 4.80 and 4.76 (2s, 1H), 4.16 and 4.06 (2s, 3H), 3.42 and 3.40 (2s, 3H), 2.65-2.58 (m, 1H), 1.77 and 1.65 (2s, 3H), 0.90 (d, J=7.2 Hz) and 0.83 (d, J=7.2 Hz) (3H).
Reaction SMILES: [C:1]([NH:9][NH:10][C@H:11]([C@@H:17]([CH3:20])[CH:18]=[CH2:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)C>[C:1]([NH:9][NH:10][C@H:11]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@H](C)[C@@H](NNC(=O)c1ccccc1)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](NNC(=O)c1ccccc1)[C@@H](C)CC
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.9 %

Procedure:
10% palladium activated carbon (20 mg) was added to an ethanol solution (5 mL) of (2R, 3S)-ethyl 2-(N′-benzoylhydrazino)-3-methyl-4-pentenoate (116 mg, 0.4 mmol), and the reaction mixture was stirred at a room temperature for 12 hours. The reaction mixture was filtered to obtain filtrate, and the palladium activated carbon was washed with ethanol (15 mL). The filtrate and the ethanol were distillated under a reduced pressure to remove the solvent, and the residue was purified and isolated by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain (2R, 3S)-ethyl 2-(N′-benzoylhydrazino)-3-methylpentanoate (80 mg, yield: 70%):
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([OH:13])[CH2:7]2)([O-:3])=[O:2].[C:14]([O-])([O-])=O.[K+].[K+]>>[CH3:14][O:13][CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:9]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(O)C2
Agent: [K+]
Product: COC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
5-nitro-indan-2-ol (1.55 g, 8.65 mmol) and K2CO3 (2.8 g, 20 mmol) was charged into a schlenk flask. The flask was evacuated and back filled with N2. DMF (10 mL) was added and stirred at r.t. for 30 min. MeI (excess, 10 mL) was added and the reaction mixture was stirred at 100° C. overnight. The reaction mixture was allowed to cool to room temperature. Water was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine and dried over Na2SO4. Purification of the concentrated crude product by column chromatography (EtOAc:Hexane=1:9) afforded the title product as a pale yellow oil (520 mg, 74% based on recovered starting material).