Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>ClCCl>[CH3:8][C:6]1[C:7]([S:13]([Cl:12])(=[O:15])=[O:14])=[C:2]([CH3:1])[C:3]([CH3:11])=[C:4]([CH3:10])[C:5]=1[CH3:9]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cc(C)c(C)c(C)c1C
Solvent: ClCCl
Product: Cc1c(C)c(C)c(S(=O)(=O)Cl)c(C)c1C
Temperature: 0 °C

Procedure:
In 500 ml of dichloromethane was dissolved 17.8 g of pentamethylbenzene and the solution was cooled to -5°~-10° C. A solution of 24 ml of chlorosulfonic acid in 400 ml of dichloromethane was added dropwise, and the mixture was allowed to stand at room temperature. The reaction mixture was poured into ice-5% aqueous sodium hydrogen carbonate. The organic layer was washed with water and dried over magnesium sulfate. Removal of the solvent by distillation leaves crystals which were collected by filtration and recrystallized from n-hexane. Yield 27.7 g (93.5%), m.p. 80°-81° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[NH:11][C:12]([C:14]1[NH:18][C:17]2[C:19]([Cl:23])=[C:20]([Cl:22])[S:21][C:16]=2[CH:15]=1)=[O:13].C(N(CC)CC)C.[Cl:31][CH2:32][C:33](Cl)=[O:34].O>ClCCl>[Cl:22][C:20]1[S:21][C:16]2[CH:15]=[C:14]([C:12]([NH:11][C@@H:3]3[CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@H:2]3[NH:1][C:33](=[O:34])[CH2:32][Cl:31])=[O:13])[NH:18][C:17]=2[C:19]=1[Cl:23]
Reactant: O=C(Cl)CCl
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
N-[(1R,2R)-1-Amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Method 8, 602 mg, 1.6 mmol) was dissolved in dichloromethane (30 mL), to this was added triethylamine (0.25 mL, 1.8 mmol) and chloroacetyl chloride (0.14 mL, 1.8 mmol). The solution was stirred at ambient temperature for 16 hours, after which triethylamine (0.25 ml, 1.8 mmol) and chloroacetyl chloride (0.14 ml, 1.8 mmol) were added before stirring for 1 hour. To the resulting slurry, water (15 mL) was added before filtering to give the title product (532 mg, 73%) as a cream solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)[CH:28]=[O:29]>O>[CH2:12]([O:11][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:10][C:6]=1[C:7]([O:29][CH2:28][C:2]1[CH:10]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(I)ccc1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(OCc1ccccc1)c1cc(I)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 5-iodosalicylic acid (6.60 g), benzyl bromide (6.54 ml), potassium carbonate (13.8 g) and N,N-dimethylformamide (100 ml) was stirred at room temperature for 2 hrs. and poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed three times with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1, volume ratio), and crystallized from hexane-ethyl acetate to give benzyl 2-benzyloxy-5-iodobenzoate (7.75 g, yield 70%) as colorless plate crystals. melting point: 72–73° C.
Reaction SMILES: [CH3:1][CH:2](C(OCC)=O)C(OCC)=O.[NH2-].[Na+].Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1>C1COCC1>[CH2:1]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
Diethyl methylmalonate (52.2 g) was added dropwise to a suspension of sodamide (11.7 g) in dry THF (150 ml) with stirring at ambient temperature under nitrogen. The mixture was boiled under reflux for 1 hour and then a solution of 2-chloro-5-nitropyridine (47.7 g) in dry THF (150 ml) was added dropwise cautiously with stirring. After the addition the mixture was boiled under reflux for 3 hours, then cooled and evaporated to remove approximately 80% of the solvent. The residue was poured into water (1 l) and extracted with ether to give an oil which partially crystallised on standing. A mixture of the residue, concentrated sulphuric acid (50 ml) and water (25 ml) was boiled under reflux for 4 hours then cooled in ice and neutralised using concentrated aqueous sodium hydroxide solution. The mixture was left to stand at ambient temperature for 64 hours and then filtered to give a solid which was extracted continuously with dichloromethane in a soxhlet extractor. The dichloromethane was cooled, dried and evaporated. The residue was filtered and the filtrate was distilled under vacuum to give 2-ethyl-5-nitropyridine, b.p. 82°-92° C. at 1 mm Hg.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].O.[NH2:11][NH2:12]>C(O)(C)C>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[NH:12][N:11]=1
Reactant: NN
Reactant: CC(C)(C)C(=O)CC#N
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)c1cc(N)n[nH]1
Reaction time: 3 h
Yield: 96.4 %

Procedure:
Isopropanol 800 ml was added to pivaloylacetonitrile 600 g and heating and stirring were applied. Hydrazine hydrate 288 g was dropped thereto and heating and stirring were applied for 3 hours. After finishing the reaction, isopropanol 400 ml was distilled off under reduced pressure. Ethyl acetate 2000 ml and a saturated salt aqueous solution were added to a residue and stirring was applied. After leaving for standing for a while, an aqueous layer was removed and an ethyl acetate layer was washed twice with the saturated salt aqueous solution, followed by drying an ethyl acetate solution over magnesium sulfate anhydrous. This ethyl acetate solution was concentrated under reduced pressure and then n-hexane 2000 ml was added to a residue to precipitate crystal. This crystal was filtered off and dried, whereby 3-amino-5-t-butylpyrazole (Compound (A)) 643 g (96.2%) was obtained. The melting point was 74.0 to 75.0° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.[NH:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17][OH:18].[OH-].[Na+].O>ClCCl>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17][OH:18])(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCNCCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccc(O)cc1)N(CCO)CCO
Temperature: 5 °C

Procedure:
A solution of 46.9 g (0.20 mole) of 4-acetoxybenzenesulfonyl chloride (I) in 400 ml dichloromethane contained in a 500-ml round-buttomed flask was dried over magnesium sulfate, then filtered and placed in a 3-liter, 3-necked, round-buttomed flask equipped with a stirrer, an additional funnel, a condenser and a thermometer. After subsequent cooling to 5° C., 142.2 g (0.70 mole) of diethanolamine (II) were added slowly with stirring. The reaction mixture was allowed to reach room temperature and was then stirred for 2 hours, followed by the addition of a mixture of 30 ml sodium hydroxide (50%) and 20 ml water. The resulting two phase mixture was stirred at room temperature for an additional two hours. The aqueous layer was extracted with two 150-ml portions of dichloromethane, and the aqueous phase was cooled in an ice bath and acidified with concentrated HCl to a pH of 2.0. Sodium hydroxide was added to saturate the aqueous phase, which was then extracted with ten 300-ml portions of ethylacetate, followed by roto-evaporation of the combined ethyl acetate extracts to dryness. A white solid (III) was collected, washed with heptane and dried under vacuum. The yield was 24.7 g (42.3%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[F:19][C:20]([F:29])([F:28])[C:21]([O:23]C(C)(C)C)=O.[C:30]1([CH2:36][C:37](=[N:39]O)[NH2:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>O1CCCC1>[F:29][C:20]([F:19])([F:28])[C:21]1[O:23][N:38]=[C:37]([NH2:39])[C:36]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NC(Cc1ccccc1)=NO
Reactant: CC(C)(C)OC(=O)C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Nc1noc(C(F)(F)F)c1-c1ccccc1
Temperature: -75 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
Under a nitrogen atmosphere, dry tetrahydrofuran (90 ml) was added to diisopropylamine (14.5 ml, 0.105 mole, 5.23 mole) and then to the solution was added a 15% solution of butyllithium in n-hexane (64 ml, 0.100 mole, 5.0 eq.) with cooling below 0° C. After keeping the mixture at 0° C. for 30 minutes, it was cooled at -75° C. The mixture of t-butyl trifluoroacetate (10.21 g, 0.0600 mole, 3 eq.), phenylacetamide oxime (3.00 g, 0.0200 mole) and dry tetrahydrofuran (45 ml) was added dropwise, keeping the mixture below -72° C. After the mixture was stirred at -75° C. for 1 hour, it was allowed to warm to room temperature over 1 hour. To the mixture was added 10% hydrochloric acid (90 ml, 0.246 mole) and refluxed for 2.5 hours. The reaction mixure was distilled under reduced pressure to remove tetrahydrofuran and n-hexane. The resulting residue was adjusted above pH 13 with a 48% solution of sodium hydroxide and extracted with methylene chloride. After the extract was dried with anhydrous sodium sulfate, the solvent was distilled off. The resulting residue was purified by column chromatography on alumina and silica gel to give the title compound (0.60 g, 13.1%). This product was recrystallized from cyclohexane to give colorless needles, m.p. 92.0°-93.0° C. The structure of this compound was confirmed by IR, NMR and UV.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][CH3:14])=[CH:7]2)([OH:3])=[O:2].Br[CH2:16][C:17](C)=[CH2:18]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][CH2:14][C:17]([CH3:18])=[CH2:16])=[CH:7]2)([OH:3])=[O:2]
Reactant: CCc1cc2cc(C(=O)O)ccc2[nH]1
Reactant: C=C(C)CBr
Product: C=C(C)CCc1cc2cc(C(=O)O)ccc2[nH]1

Procedure:
Refer to 36a) using 3-bromo-2-methylpropene as the alkylating agent
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.C1CCCCC1.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1>O1CCCC1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:25]2([OH:28])[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)c1
Reactant: CN1CCC(=O)CC1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COc1cccc(C2(O)CCN(C)CC2)c1
Temperature: -50 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A suitable dry reaction vessel having a mechanical stirrer, low temperature thermometer and addition funnel was charged with 250 g (1.34 mol) of m-bromoanisole (Aldrich Chemical Company, Milwaukee, Wis.) in 675 ml of dry tetrahydrofuran and the solution was cooled under nitrogen to -50° C. to -55° C. in a dry ice/acetone bath. A solution of 1357 ml. of sec.-butyllithium in cyclohexane (1.71 mol) was added dropwise to the reaction mixture at such a rate so that the temperature did not rise above -50° C. The resulting white suspension was stirred at -50° C. for 1 hour followed by the addition of 174.2 g (1.54 mol) of 1-methyl-4-piperidone (Aldrich Chemical Company) in 440 ml of dry tetrahydrofuran so as to maintain the reaction temperature below -40° C. When the addition was complete the temperature was allowed to rise to approximately -20° C. over approximately 11/2 hours and then to room temperature over a 1 hour period. Residual sec.-butyllithium was quenched by the addition of 350 ml of saturated sodium chloride solution followed by the addition of 525 ml of water. The aqueous phase was separated and extracted twice with 350 ml portions of methylene chloride. The combined organic extracts were extracted in two portions, each with 1250 ml of 1N hydrochloric acid. The separated aqueous extracts were made basic (pH=10) with 28 percent ammonium hydroxide and extracted 3 times with 350 ml portions of methylene chloride. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was slurried in 1000 ml of hot hexane and the slurry was cooled and filtered. The isolated crystalline product was dried in a vacuum oven to provide 225.6 g of 98% pure product.
Reaction SMILES: [Cl-].[NH4+].O.[OH:4][CH2:5][CH2:6][N:7]([CH2:19][CH2:20][OH:21])[C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:9]=1[C:10]#[N:11]>[Fe].C(O)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:8]([N:7]([CH2:19][CH2:20][OH:21])[CH2:6][CH2:5][OH:4])=[C:9]([CH:12]=1)[C:10]#[N:11]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N(CCO)CCO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#Cc1cc(N)ccc1N(CCO)CCO
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
Subsequently, ammonium chloride (0.9 g) and iron powder (4.5 g) were added to a mixed solvent of water (10 ml) and ethanol (30 ml), and the mixture was heated to 65° C. Then, 2-bis(2-hydroxyethyl)amino-5-nitrobenzonitrile (11 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide ice solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of diisopropyl ether-n-hexane to give the title compound (8 g), melting point: 38° C.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].CC(OC(=O)[NH:13][C@H:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:26][CH:25]=3)[CH:22]=2)[N:17]([C:40](=[O:42])[CH3:41])[C@@H:16]([CH3:43])[CH2:15]1)C.[C:45]1(C)[CH:50]=CC=C[CH:46]=1.[ClH:52]>ClCCl>[ClH:52].[CH3:46][CH:45]([N:13]([C@H:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:26][CH:25]=3)[CH:22]=2)[N:17]([C:40](=[O:42])[CH3:41])[C@@H:16]([CH3:43])[CH2:15]1)[C:3](=[O:4])[OH:5])[CH3:50]
Reactant: Cc1ccccc1
Reactant: CC(=O)N1c2ccc(-c3ccc(CCNC(=O)OC(C)(C)C)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3ccc(CCNC(=O)OC(C)(C)C)cc3)cc2[C@H](N(C(=O)O)C(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Trifluoroacetic acid (TFA) (3 mL) was added to a solution of 1-methylethyl((2S,4R)-1-acetyl-6-{4-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]phenyl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Intermediate 87) (50 mg, 0.098 mmol) in dichloromethane (DCM) (3.00 mL) and the resulting mixture was stirred at room temperature under nitrogen for 3 h then concentrated in vacuo. The residue obtained was co-evaporated with toluene then purified using a SCX column (5 g, elution 5 column volume (CV) methanol, then 5 CV 2M NH3 in methanol). The ammonia fractions were collected and concentrated in vacuo to give a residue which was treated with HCl (1.0 M in Et2O, 2 mL, 2 mmol). The resulting mixture was concentrated in vacuo to give 1-methylethyl((2S,4R)-1-acetyl-6-{4-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]phenyl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate hydrochloride (50 mg, 0.098 mmol, 80%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([S:15][C:16]3[C:24]([Br:25])=[CH:23][C:19]4[O:20][CH2:21][O:22][C:18]=4[CH:17]=3)[N:10]([CH2:11][CH2:12][CH2:13][OH:14])[C:6]=2[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>O1CCOCC1>[CH3:33][S:34]([O:14][CH2:13][CH2:12][CH2:11][N:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=2[N:8]=[C:9]1[S:15][C:16]1[C:24]([Br:25])=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)(=[O:36])=[O:35]
Reactant: Nc1nccc2c1nc(Sc1cc3c(cc1Br)OCO3)n2CCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CS(=O)(=O)OCCCn1c(Sc2cc3c(cc2Br)OCO3)nc2c(N)nccc21
Temperature: 40 °C
Yield: 45707.7 %

Procedure:
Compound 0403-51 (264 mg, 0.624 mmol) was dissolved in hot anhydrous dioxane (8.6 mL). The solution was cooled to 40° C. and was treated with NEt3 (189 mg, 1.87 mmol) and MsCl (107 mg, 0.935 mmol) for 20 min. The mixture was concentrated and purified by column chromatography on silica gel (CH2Cl2/MeOH=50/1) to give the title compound 0404-51 as a white solid (143 g, 50%): LCMS: 501 [M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:20][O:21][CH2:22][CH2:23]Br.C(Cl)Cl>C1COCC1.O>[CH2:1]([C:3]1[N:4]([CH2:23][CH2:22][O:21][CH3:20])[N:5]=[C:6]([C:11]([NH2:13])=[O:12])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:2]
Reactant: COCCBr
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1CCOC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (2.5 kg, 13.6 Mol), sodium carbonate (1.8 Kg, 17.0 Mol) and 2-bromoethyl methyl ether (1.98 kg, 14.2 Mol) in THF (22.5 L) and water (2.5 L) was heated under reflux and stirred for 20 hours. The mixture was cooled to ambient temperature and CH2Cl2 (67.5 L) and water (22.5 L) were added. The resultant organic and aqueous layers were separated. The aqueous phase was extracted with CH2Cl2 (22.5 L) and the combined organic solution was distilled under atmospheric pressure and replaced with ethyl acetate (33 L) to a final volume of 17 L. The cooled mixture was granulated at ambient temperature for 2 hours, filtered and washed with ethyl acetate (2.5 L). This afforded 5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide as a white crystalline solid, 2.10 kg, 57%. m.p.=140° C. Found: C, 44.46; H, 5.79; N, 23.01. C9H14N4O4 requires C, 44.63; H, 5.79; N, 23.14%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30](Cl)=[N:29][CH:28]=1.C(N(CC)CC)C.N12CCN(CC1)CC2>CN(C=O)C.O>[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:23])[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=3)([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:4]=2)=[N:29][CH:28]=1
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)nc1
Reaction time: 0.17 h
Yield: 25 %

Procedure:
4-Chloro-3-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 130, step 7) was added to a solution of methyl-6-chloro-nicotinate (41 mg, [CAS Reg. No. 73781-91-6]) in DMF (0.6 mL) followed by the addition of triethylamine (0.021 mL). Stirring was continued for 10 minutes at r.t. Then 1,4-diazabicyclo[2.2.2]octane (1.9 mg) was added and the mixture was stirred over night at r.t. The reaction mixture was poured into water, extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate:heptane=3:7) to give the desired compound as a colorless gum (14 mg, 25%). MS (neg. ion, m/e)=499.1 [(M−H)−].
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[C:9]([Cl:18])[C:8]=2[Cl:19])[N:5]=[CH:4][C:3]=1[C:20]#[N:21].[C:22](OC(=O)C)(=[O:24])[CH3:23]>O>[C:22]([NH:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[C:9]([Cl:18])[C:8]=2[Cl:19])[N:5]=[CH:4][C:3]=1[C:20]#[N:21])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)c(Cl)c2Cl)c1N
Solvent: O
Product: CC(=O)Nc1c(C#N)cnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl

Procedure:
5-Amino-4-cyano-1-(2,3,6-trichloro-4-trifluoromethylphenyl)pyrazole (3.74 g) in acetic anhydride (20 ml) was heated at reflux for 6 hours. The reaction mixture was then evaporated under reduced pressure to remove unreacted acetic anhydride. The residual oil was dissolved in dichloromethane (50 ml) and filtered. The filtrate was evaporated to give a foam, which was then suspended in water (70 ml). The suspension was filtered and the filtrate deposited a solid on standing. The solid was collected by filtration and washed with water to give 5-acetamido-4-cyano-1-(2,3,6-trichloro-4-trifluoromethylphenyl)pyrazole (0.4 g), m.p. 177°-178° C., in the form of a fawn-coloured solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](OC)=[C:7](OC)[CH:8]=2)[C:3]=1[CH:16]=[O:17].CN(C)C=O.P(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:16]=[O:17]
Reactant: COc1cc2ccc(Br)c(C=O)c2cc1OC
Agent: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=CC1=C(Br)CCc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
2-Bromo-6,7-dimethoxy-1-napthaldehyde (10). Dimethylformamide (3.0 g, 41 mmol) was added dropwise to solution of phosphorus tribromide (3.3 mL, 35 mmol) in dry chloroform (50 mL) at 0° C. The mixture was stirred at 0° C. for 1 h to give pale yellow suspension. A solution of compound 8 (2.0 g, 9.7 mmol) in chloroform was added to the yellow suspension and the mixture was heated at reflux for 1 h. The reaction mixture was cooled to 0° C. and saturated aqueous NaHCO3 solution was added dropwise until no effervescence was obtained. The resulting mixture was extracted with dichloromethane, dried (Na2SO4) and evaporated to provide the respective 2-bromo-3,4-dihydro-1-napthaldehyde derivatives as yellow solids. Each of the 2-bromo-3,4-dihydro-1-napthaldehyde derivatives were chromatographed on silica gel using a 3:1 mixture of hexanes:ethyl acetate as the eluent to give the 2-bromo-3,4-dihydro-1-napthaldehydes in an 87% yield. The 2-bromo-3,4-dihydro-1-napthaldehyde (2.4 g, 8.1 mmol) and DDQ (2.2 g, 97 mmol) was refluxed in toluene (50 mL) for 15 h. After cooling to room temperature, the mixture was subjected to filtration through a celite bed and the filtrate was evaporated to dryness. The residue obtained was chromatographed on 75 g silica gel using a 3:1 mixture of hexanes:ethyl acetate as eluent to give the 2-bromo-1-napthaldehyde in a 95% yield; 1H NMR δ 4.00 (3H, s), 4.05 (3H, s), 7.07 (1H, s), 7.54 (1H, d, J=8.5), 7.79 (1H, d, J=8.5), 8.71 (1H, s), 10.74 (1H, s); 13C NMR δ 56.3, 56.6, 104.2, 107.0, 126.5, 128.8, 129.4, 129.8, 129.9, 134.3, 150.4, 153.1, 195.9; HRMS calcd for C,3H11O3Br: 293.9891; found: 293.9896.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[CH3:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][C:12](=O)[CH2:11]1>>[CH3:9][C@H:10]1[CH2:11][C:12]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:13][CH2:14][CH2:15]1.[CH3:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][C:12]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:11]1
Reactant: C#Cc1ccccn1
Reactant: C[C@@H]1CCCC(=O)C1
Product: C[C@@H]1CCC=C(C#Cc2ccccn2)C1
Product: C[C@H]1C=C(C#Cc2ccccn2)CCC1

Procedure:
Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), (3R)-(+)-3-methylcyclohexanone (6.0 mmol, 0.73 mL); yields 2-{[(5R)-5-methyl-1-cyclohexen-1-yl]ethynyl}pyridine and 2-{[(3R)-3-methyl-1-cyclohexen-1-yl]ethynyl}pyridine (1:1) as a transparent yellow oil (440 mg, 37% overall yield) as a mixture of regioisomers. 1H NMR (CDCl3, 300 MHz) Δ8.56 (m, 1H), 7.62 (m, 1H), 7.40 (m, 1H), 7.18 (m, 1H), 6.31 (m, 0.5H), 6.19 (m, 0.5H), 2.30 (m, 3H), 1.85 (m, 2.5H), 1.22 (m, 1H), 0.98 (m, 3.5H). MS (EI ionization) 197 (M+) two peaks resolved.