Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[C:5]=1[CH2:15]Br.[CH3:18][NH2:19]>C1COCC1>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]2[C:5]=1[CH2:15][N:19]([CH3:18])[C:3]2=[O:2]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(OC)c1CBr
Reactant: CN
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c2c1CN(C)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
At room temperature, a solution of 2-Bromomethyl-3-methoxy-6-nitro-benzoic acid methyl ester (crude 7.0 g, 18.2 mmol) in 46 mL of THF is treated with 2M solution of methylamine in THF (27.3 mL, 54.6 mmol), and the mixture is stirred for 4 hours at the room temperature. The reaction mixture is quenched with a saturated ammonium chloride solution and partitioned between ethyl acetate. The organic layer is washed with brine and then dried over Na2SO4 following concentrated to give 4-Methoxy-2-methyl-7-nitro-2,3-dihydro-isoindol-1-one (3.1 g) as orange solid in 77% yields (2 steps). 1H-NMR (400 MHz, δ, ppm) CDCl3: 3.19 (s, 3H), 3.99 (s, 3H), 4.32 (s, 2H), 7.0 (d, 1H), 7.89 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N+]([O-])=O)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)C.[Cl-].[NH4+].C(=O)([O-])[O-].[K+].[K+]>[Fe].O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)Nc2ccc(F)c(Cl)c2)cc1
Temperature: 70 °C
Yield: 117.1 %

Procedure:
0.7 g of the product of Step 1 was added into 80 ml of ethanol:water (v/v=31), then 1.0 g iron powder and 0.4 g ammonium chloride. After addition, the reaction mixture was heated to 70° C. and reacted for 30 min. The completion of reaction was indicated by TLC. The reaction mixture was filtered, and the filter cake was washed with hot ethanol repeatedly. Then the filtrate was concentrated under reduced pressure to give a white solid. Then 20 ml potassium carbonate solution (10%) was added into the solid. The mixture was stirred, left to stand, filtered, and dried to give a light yellow solid (0.7 g).
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:14]([CH3:16])[CH3:15]>>[CH2:18]([N:17]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CNCCCCCCNCC(C)C
Reactant: CCCCCCCCCC1CO1
Product: CCCCCCCCCC(O)CN(CCCCCCN(CC(C)C)CC(O)CCCCCCCCC)CC(C)C

Procedure:
Condensation of 1-undecene oxide and N,N'-di(isobutyl)hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[N-isobutyl-2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = (CH3)2CHCH2, X = (CH2)6, Z = H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=2[Cl:16])=[C:6]([NH:17][C@@H:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])[N:5]2[N:23]=[CH:24][C:25]([C:26]([O:28]C)=[O:27])=[C:4]2[N:3]=1.[OH-].[K+].O.Cl>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=2[Cl:16])=[C:6]([NH:17][C@@H:18]([CH:20]([CH3:21])[CH3:22])[CH3:19])[N:5]2[N:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[C:4]2[N:3]=1
Reactant: COC(=O)c1cnn2c(N[C@H](C)C(C)C)c(-c3ccc(C#N)cc3Cl)c(Cl)nc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[C@@H](C)Nc1c(-c2ccc(C#N)cc2Cl)c(Cl)nc2c(C(=O)O)cnn12
Reaction time: 12 h

Procedure:
0.35 g (0.001 mol) of atropisomer A of methyl 5-chloro-6-(2-chloro-4-cyanophenyl)-7-[(R)-3-methyl-2-butylamino]pyrazolo[1,5-a]pyrimidine-3-carboxylate were dissolved in 4.6 ml of dioxane. 0.37 g (0.009 mol) of potassium hydroxide in 4.6 ml of aqueous solution was added at room temperature, and the reaction mixture was then stirred for 12 hours. The mixture was then poured into water and acidified with hydrochloric acid. 0.15 g of product was filtered off. The product was chromatographed on silica gel using ethyl acetate:cyclohexane:acetic acid=40:10:1, which gave the atropisomer A of 5-chloro-6-(2-chloro-4-cyanophenyl)-7-[(R)-3-methyl-2-butyl-amino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1Cl)[C:7]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)=[O:8])([O-:3])=[O:2].[NH3:18]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH2:18])[C:7]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1nccs1
Reactant: N
Solvent: CCO
Product: Nc1ccc(C(=O)c2nccs2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A suspension of 63 g. (0.24 mol) of 2-(3-nitro-4-chlorobenzoyl)thiazole in 3 liters of a saturated solution of ammonia in ethanol was autoclaved at 100° C. for 24 hrs. The mixture was concentrated in vacuo and the resulting residue dissolved in 1.5 liters of warm 5N hydrochloric acid. The solution was cooled to room temperature and neutralized with concentrated ammonium hydroxide to yield 2-(3-nitro-4-aminobenzoyl)thiazole as yellow-orange prisms, mp. 179°-181° C. (methanol).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](B(O)O)=[CH:10][C:9]=2[CH:16]=1)[CH:2]([CH3:4])[CH3:3].Br[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[CH:10][C:9]=2[CH:16]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)Cc1ccc2oc(B(O)O)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)Cc1ccc2oc(-c3ccc(C=O)cc3)cc2c1
Yield: 64.2 %

Procedure:
A mixture of 5-isobutylbenzofuran-2-ylboronic acid (70 mg, 0.33 mmol), 4-bromobenzaldehyde (61 mg, 0.33 mmol), triethylamine (1.7 mL, 12.6 mmol) and bis(triphenylphosphine)palladium(II) chloride (12 mg, 0.017 mmol) in ethanol (10 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was treated with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo (the aqueous work-up is optional). Purification by silica gel chromatography on ISCO system gave the title compound (59 mg, 65% yield): >99% purity by LCMS, ESI-MS: 279.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:3]([NH:16]C(=O)OC(C)(C)C)[C:4](=[O:15])[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH:7]=[CH:8]1.Cl>O1CCOCC1>[NH2:16][CH:3]1[C:2]([CH3:24])([CH3:1])[CH:8]=[CH:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]1=[O:15]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N(c2ccccc2)CC=CC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)C=CCN(c2ccccc2)C(=O)C1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a round bottom flask was added (Z)-tert-butyl 4,4-dimethyl-2-oxo-1-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (7 mg, 0.02 mmol) and 4 N HCl in dioxane (1 mL). The reaction was stirred at rt for 1 hr. The solvent was removed to give (Z)-3-amino-4,4-dimethyl-1-phenyl-3,4-dihydro-1H-azepin-2(7H)-one (4 mg, 0.02 mmol, 82% yield) as mono hydrochloride salt. Anal. Calcd. for C14H18N2O m/z 230.2. found: 231.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH2:10][C@@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:22])[CH2:10][C@@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][N:32]1[CH2:31][CH2:30][CH:29]([O:28][C:27]2[CH:35]=[CH:36][C:24]([F:23])=[CH:25][CH:26]=2)[CH2:34][CH2:33]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(OC2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CI)CC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Triphenylphosphine bound to cross-linked polystyrene resin (2.16 g, mol/g, 6.47 mmol) is suspended in dry DCM (50 ml) at ambient temperature under a nitrogen atmosphere. Iodine (1.64 g, 6.47 mmol) is added and the reaction mixture stirred for 15 minutes. Imidazole (0.50 g, 7.35 mmol) is then added and the reaction mixture is stirred for a further 15 minutes. A solution of (R)-3-.tert.-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (prepared as described by D. Gani et al J. Chem. Soc. Perkin Trans. 1, 2513–2525, 1997 (0.909 g, 2.94 mmol) in dry DCM (10 ml) is added and the reaction mixture is stirred at reflux for 1 hour. The polymer is removed by filtration, and the filtrate is first washed with aqueous 5% sodium thiosulphate solution and then water. The organic phase is dried over MgSO4 and evaporated to yield (R)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester as a crude oil. A solution of (R)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester (1.017 g, 2.43 mmol) and 4-(4-fluoro-phenoxy)-piperidine (0.569 g, 2.916 mmol) in DMF (25 ml) is treated with triethylamine (0.406 ml, 2.916 mmol). The reaction mixture is stirred at ambient temperature for 60 hours, and then partitioned between ethylacetate and water. The ethylacetate phase is dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 2:1 hexane/ethylacetate) to afford (R)-3-tert-butoxycarbonylamino-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid benzyl ester. [MH]+ 487.1.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=[C:5]([CH3:14])[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:3]1=[O:25].[Br:26]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Br:26][C:10]1[S:11][CH:12]=[CH:13][C:9]=1[C:6]1[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:25])[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)[C:5]=1[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccsc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(-c2ccsc2Br)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
To a solution of 3,6-dimethyl-5-(thiophen-3-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference example 199) (30.7 mg) in acetic acid (1.5 ml) was added N-bromosuccinimide (20.2 mg) and the resulting mixture was stirred at room temperature for three hours. To the reaction mixture were added an aqueous saturated sodium hydrogen carbonate solution (10 ml) and an aqueous saturated sodium thiosulfate solution (10 ml), and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-(2-bromothiophen-3-yl)-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (17.4 mg).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[C:37](=[N:39]O)[NH2:38]>>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[C:37]1[N:39]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:38]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1c(F)cccc1F
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3c(F)cccc3F)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 38 mg (0.22 mmol, 1.1 eq.) of 2,6-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 42 mg (39% of theory)
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][C:4](OCC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.Cl>O1CCCC1>[CH3:14][C:2]([OH:1])([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][CH2:4][OH:5]
Reactant: CCCCCC(C)(O)CC(=O)OCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCC(C)(O)CCO
Reaction time: 0.58 h
Yield: 93.9 %

Procedure:
A solution of the compound 37 (13.86 g) in tetrahydrofuran (100 mL) was added dropwise to a suspension of lithium aluminum hydride (3.9 g) in tetrahydrofuran (100 mL) at 0° C. After 35 minutes, to the reaction solution was added ethyl acetate at 0° C. until foam was lost and 5N hydrochloric acid (20 mL) was added dropwise thereto. The solution temperature was risen to room temperature and the solution was stirred overnight. The reaction solution was dried over anhydrous magnesium sulfate, filtrated through Celite (Brand name) and concentrated. The obtained residue was purified by flush column chromatography (n-hexane:ethyl acetate=1:1), to give the title compound (10.31 g) having the following physical data.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:39])[NH:6][C@@H:7]1[CH2:38][C:10]2[N:11]([CH2:20][C:21]3[C:22]([N:27]4C(=O)C5C(=CC=CC=5)C4=O)=[N:23][CH:24]=[CH:25][CH:26]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].O.NN>C1COCC1.C(O)C>[CH:1]([O:4][C:5](=[O:39])[NH:6][C@@H:7]1[CH2:38][C:10]2[N:11]([CH2:20][C:21]3[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3cccnc3N3C(=O)c4ccccc4C3=O)c3ccc(C#N)cc23)C1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3cccnc3N)c3ccc(C#N)cc23)C1
Reaction time: 0.25 h
Yield: 13.3 %

Procedure:
Combine crude (S)-{7-cyano-4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl}-carbamic acid isopropyl ester (2.12 mmol, 1100 mg crude material) in a mixture of THF (22 mL) and ethanol (4 mL) and stir for 15 min. Add hydrazine hydrate 0.5 mL, 10 mmol) and stir the mixture at room temperature for 18 h. Vacuum filter the crude reaction and wash the solid with THF (50 mL). Collect the filtrate and remove the solvent under vacuum. Purify the resulting residue by silica gel chromatography (50-100% ethyl acetate/CH2Cl2) to provide 110 mg (13%) of the title compound. MS (m/z): 390 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC(=O)[S:10][N:9]=2)=[CH:4][CH:3]=1.[F:14][C:15]([F:24])([F:23])[C:16]#[C:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClC1C=CC=C(Cl)C=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([C:15]([F:23])([F:24])[F:14])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1oc(-c2ccc(Cl)cc2)ns1
Reactant: CCOC(=O)C#CC(F)(F)F
Solvent: Clc1cccc(Cl)c1
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Temperature: 150 °C
Reaction time: 18 h

Procedure:
Into a 50-mL sealed tube, was placed 5-(4-chlorophenyl)-2H-1,3,4-oxathiazol-2-one (2.2 g, 10.30 mmol, 1.00 equiv), ethyl 4,4,4-trifluorobut-2-ynoate (2.5 g, 15.05 mmol, 1.46 equiv), 1,3-dichlorobenzene (20 mL). The resulting solution was stirred for 18 h at 150° C. in an oil bath. The reaction progress was monitored by LCMS/GCMS/TLC (ethyl acetate/petroleum ether=1:20). The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether. This resulted in 2.8 g (81%) of ethyl 3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazole-4-carboxylate as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C13H9ClF3NO2S, 336.0 (M+H). found 336.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].[CH3:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].CC1C=CC=CC=1C=O.CNC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:15]([N:16]([CH3:17])[CH3:18])[C:14]1[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=1[CH3:12]
Reactant: Cc1ccccc1C=[N+](C)C
Reactant: Clc1ccc2[nH]ccc2c1
Agent: CNC
Agent: Cc1ccccc1C=O
Agent: [Cl-]
Product: Cc1ccccc1C(c1c[nH]c2ccc(Cl)cc12)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-chloro-1H-indole and (2-methyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2-methyl-benzaldehyde and dimethylamine.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]2[C:7]([O:9][CH:10]=[C:11]([CH3:12])[CH:5]2[CH2:4][CH2:3]1)=[O:8]>C[C@@H]1[C@@H](C(O)=O)[C@@H]([C@H](C=O)C)CC1>[CH3:1][CH:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH:5]([CH:11]([CH3:12])[CH3:10])[CH2:4][CH2:3]1
Reactant: CC1=COC(=O)C2C(C)CCC12
Agent: C[C@@H](C=O)[C@H]1CC[C@H](C)[C@H]1C(=O)O
Product: CC(C)C1CCC(C)C1C(=O)O
Temperature: 76 °C
Reaction time: 7 h

Procedure:
This example shows the effect of treating crude catmint oil by steam distillation, followed by distillation with isopropanol on the rate of hydrogenation of nepetalactone (NPL) to DHN. Catmint oil (2400 grams; Lot 2003 from George Thacker Sons) and deionized water (1440 grams) were combined in a 4 liter heated resin kettle outfitted with a shell and tube condenser and a dry ice cold finger. This resin kettle was outfitted with a vacuum control. Vacuum was controlled at a pressure of 6.9 kPa while the kettle was heated using an electrical heating mantel. The temperature of the water and catmint oil was controlled at 39 to 45° C. Water and some of the catmint oil was stripped off, condensed using the shell and tube condenser and the cold finger and periodically drained from the condenser receiver. After about 7 hours, most of the water was distilled off and a total of approximately 400 mL of isopropanol was added to the catmint oil remaining in the resin kettle. The distillation was continued at about 6.9 kPa but the temperature of the catmint oil/isopropanol mixture was raised to 72 to 80° C. to facilitate the distillation. The distillation was carried out for an additional hour. For the last 10 to 15 minutes, the vacuum was adjusted to 752 Pa to help drive off any residual isopropanol. About 4.5 wt % of the initial charge of the oil was distilled off in this fashion. A total of 7 distillations were performed in this fashion and the distilled catmint oil obtained from the distillations was combined to give a total of about 14.7 Kg of distilled catmint oil. A small portion was used in a hydrogenation test performed as described in Comparative Example 1. Table 4 shows the rate of hydrogenating this treated oil as the NPL conversion as a function of hydrogenation time or time on stream (TOS). After 1.75 hours of hydrogenation, the conversion of the nepetalactone was 82.2%, which is substantially higher than the conversion at approximately the same time in Example 1. This was done with no apparent increase in nepetalic acid or yield loss to puleganic acid. The crude catmint oil had an initial sulfur content of 278 ppm; the content of the sulfur in the sample used for hydrogenation was 205 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([CH2:19]Br)=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1.[CH3:23][O-:24].[Na+]>CO>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([CH2:19][O:24][CH3:23])=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1Cl)c1oc2cc(Br)ccc2c1CBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Reaction time: 3 h
Yield: 23.8 %

Procedure:
To a solution of (6-bromo-3-bromomethyl-benzofuran-2-yl)-(2,4-dichloro-phenyl)-methanone (1.1 g, 2.3 mmol) in methanol (4 mL) was added 0.5 M sodium methoxide (252 mg, 4.7 mmol). The reaction was stirred at 50 C for 3 h. The solvent was removed at reduced pressure and the mixture was triturated with methanol, providing (227 mg, 23%) a cream colored solid. 1H-NMR (CDCl3) δ 7.87-7.37 (m, 6H), 5.00 (s, 2H), 3.47 (s, 3H)
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH3:16])[C:8]=2[N:9]=[C:10](Cl)[N:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:17]([NH2:20])[CH:18]=[CH2:19].C(=O)([O-])O.[Na+]>>[CH2:17]([NH:20][C:10]1[N:11]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:7]2[S:15][CH:14]=[C:13]([CH3:16])[C:8]=2[N:9]=1)[CH:18]=[CH2:19]
Reactant: C=CCN
Reactant: CCCCNc1nc(Cl)nc2c(C)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCCCC)c2scc(C)c2n1
Yield: 73.9 %

Procedure:
In a sealed tube were heated 307 mg (1.2 mmol) of 4-butylamino-2-chloro-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 245 mg (yield: 73.8%) of the title compound.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=1[Cl:16])(=O)C.Cl>CO>[Cl:16][C:8]1[CH:9]=[C:10]([C:13](=[O:15])[CH3:14])[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCc1ccc(C(C)=O)cc1Cl
Agent: Cl
Solvent: CO
Product: CC(=O)c1ccc(CCO)c(Cl)c1
Yield: 110 %

Procedure:
2-(4-Acetyl-2-chlorophenyl)ethyl acetate (4.87 g) was dissolved in methanol (80 ml), and thereto was added concentrated hydrochloric acid (20 ml), followed by refluxing. Four hours later the temperature of the reaction mixture was kept at room temperature, and methanol was removed in vacuo. Then the residue was diluted with ethyl acetate, washed with brine, dried and concentrated to give the object compound (4.42 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[CH:4][CH:3]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:22])=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 57 %

Procedure:
As described for example 10b, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (94 mg, 0.29 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of 4-aminotetrahydropyran, to the title compound (65 mg, 57%) which was obtained as a white solid. MS: m/e=400.3 [M+H]+.