Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[CH:13]=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].Cl.CN(C)[CH:34]=[O:35]>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[C:13]([CH:34]=[O:35])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2ccc3ccc([N+](=O)[O-])cc32)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-n2cc(C=O)c3ccc([N+](=O)[O-])cc32)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(6-nitroindol-1-yl)benzoic acid ethyl ester (0.53 g) in N,N-dimethylformamide (6 mL) was added phosphoryl chloride (0.31 g) under ice cooling and this mixture was stirred at 70° C. overnight. After cooling to ambient temperature, to this reaction mixture was added 2 mol/L aqueous sodium hydroxide solution and this mixture was stirred at 30 minutes. This reaction mixture was poured into 1 mol/L hydrochloric acid, and the precipitated solid was collected by filtration, and washed with water and n-hexane, and dried under reduced pressure at 40° C. to give 4-(3-formyl-6-nitroindol-1-yl)benzoic acid ethyl ester (0.46 g). To a solution of this aldehyde (0.46 g) in tetrahydrofuran (10 mL) were added hydroxylamine hydrochloride (0.19 g) and pyridine (0.43 g) at room temperature, and this mixture was stirred at 80° C. for 8 hours. To this reaction mixture was added acetic anhydride (0.42 g) at 80° C., this mixture was stirred at same temperature overnight. After cooling to ambient temperature, to this reaction mixture was added 1 mol/L hydrochloric acid, and the precipitated solid was collected by filtration. This solid was washed with water, n-hexane and diethyl ether to give the title compound (0.13 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]#[N:26].O>CN(C)C=O>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([O:13][CH3:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: N#CCCCBr
Reactant: CNCCc1cc(OC)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CCN(C)CCCCN)cc(OC)c1
Reaction time: 12 h
Yield: 80 %

Procedure:
10.0 g of N-methyl-(2-(3,5-dimethoxyphenyl)ethyl)amine was dissolved in 130 ml of N,N-dimethylformamide, followed by the addition of 10.63 g of anhydrous potassium carbonate and 6.12 ml of 4-bromobutyronitrile. The reaction was carried out at a room temperature for 12 hours. Water was added to the reaction mixture. The obtained mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous solution of common salt successively, dried over anhydrous potassium carbonate and distilled to remove the solvent. 150 ml of ethanol, 11 ml of concentrated hydrochloric acid and 1 g of platinum oxide were added to the obtained residue to carry out hydrogenation at a room temperature under 3 kg/cm2 for 12 hours. The catalyst was filtered out and the filtrate was concentrated under a reduced pressure, followed by the addition of concentrated aqueous ammonia. The obtained mixture was extracted with chloroform. The chloroform phase was dried over anhydrous potassium carbonate. After the solvent had been distilled off, the residue was distilled under a reduced pressure to obtain 10.85 g of the title compound as a colorless oil (yield: 80%).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:12](=[O:13])[CH2:11][C:9](=[O:10])[N:8]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]1=[O:7].N1C=CC=CC=1.[C:26](Cl)(=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29]>ClCCl>[CH3:17][CH:16]([CH3:18])[CH2:15][CH2:14][N:8]1[C:9](=[O:10])[CH:11]([C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:12](=[O:13])[N:5]([CH2:4][CH2:3][CH:2]([CH3:19])[CH3:1])[C:6]1=[O:7]
Reactant: CC(C)CC(=O)Cl
Reactant: CC(C)CCN1C(=O)CC(=O)N(CCC(C)C)C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CCN1C(=O)C(C(=O)CC(C)C)C(=O)N(CCC(C)C)C1=O
Temperature: 0 °C
Yield: 78.9 %

Procedure:
To a solution of 1,3-bis(3-methylbutyl)barbituric acid 268 mg (1.00 mmol) in dry dichloromethane 3.0 mL under a nitrogen atmosphere, added was pyridine 0.81 mL (0.79 g, 10 mmol, 10 equivalents) and stirred at 0° C. Added was isovaleryl chloride 121 mg (1.00 mmol, 1.00 equivalent) in dichloromethane 1.5 mL to the solution slowly during a period of 20 minutes, then stirred at room temperature for 4 hours. Added was dichloromethane 40 mL and washed the organic layer with 2 M hydrochloric acid and saturated brine, and dried over sodium sulfate. Purified was the crude product 383 mg, after removal of the solvent under the reduced pressure, by column chromatography (silica gel, eluted with dichloromethane). It obtained 1,3-bis(3-methylbutyl)-5-(3-methyl-1-oxobutyl)barbituric acid 278 mg as white plates (79.0% yield).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]([CH3:13])[N:6]=1>CO>[OH:3][NH:2][C:11](=[NH:12])[C:9]1[CH:8]=[C:7]([CH3:13])[N:6]=[C:5]([CH3:4])[CH:10]=1
Reactant: NO
Reactant: Cc1cc(C#N)cc(C)n1
Agent: Cl
Solvent: CO
Product: Cc1cc(C(=N)NO)cc(C)n1
Temperature: 60 °C
Reaction time: 15 h
Yield: 82.1 %

Procedure:
To an ice-cooled solution of potassium tert.-butylate (1.25 g, 11.1 mmol) in methanol (20 mL), hydroxylamine hydrochloride (773 mg, 11.1 mmol) is added. The suspension is stirred for 30 min before 2,6-dimethyl-4-cyano-pyridine (490 mg, 3.71 mmol) is added. The mixture is stirred at 60° C. for 15 h before it is filtered. The filtrate is evaporated to dryness and the resulting solid is washed with water and then dried under HV to give N-hydroxy-2,6-dimethyl-isonicotinamidine (503 mg) as a white powder; LC-MS: tR=0.23 min; [M+1]+=166.01; 1H NMR (D6-DMSO): δ 2.43 (s, 6H), 5.88 (s, 2H), 7.30 (s, 2H), 9.90 (s, 1H).
Reaction SMILES: O[C:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:2](=[CH2:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:18]=[CH:17]2
Reactant: CCOC(=O)C(C)(O)c1ccc2cc(OC)ccc2c1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=C(C(=O)OCC)c1ccc2cc(OC)ccc2c1
Yield: 64 %

Procedure:
Ethyl 2-hydroxy-2-(6-methoxynaphth-2-yl)propionate (5,0 g, 18,2 mmol), Dowex HCR-W2 strong acid exchange resin (0,50 g) and acetic anhydride (4,09 g, 40,1 mmol) were added to acetic acid (100 g) and refluxed for 7 hours, cooled and the resin was removed by filtration. Ethyl 2-(6-methoxynaphth-2-yl)acrylate was produced in 64,6% yield and could be used without purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(O[CH:16]([C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[F:34])[C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]=1)=O)(C)(C)C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([SH:42])=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42][CH:16]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]=2)=[CH:38][CH:37]=1
Reactant: Cn1c(C(OC(=O)OC(C)(C)C)c2cc(F)ccc2F)nc2ccccc21
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cn1c(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
Trifluoroacetic acid (2.0 ml) was added to the 2-[(t-butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-methyl-1H-benzimidazole (204 mg, 0.545 mmol) obtained in Referential Example 13. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration under reduced pressure. The residue was dissolved in thionyl chloride (1.0 ml). One drop of dimethylformamide was added to the resulting solution. The resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue and the resulting mixture was concentrated further under reduced pressure. The residue was dissolved in dimethylformamide (5.0 ml). After addition of 4-chlorobenzenethiol (118 mg, 0.82 mmol) and potassium carbonate (451 mg, 3.27 mmol), the resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was then allowed to stand at room temperature and ethyl acetate (60 ml) was added thereto. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 5:1) to give the title compound (195 mg, 89%) as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]([C:12]2[CH:30]=[CH:29][C:15]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]3)=[CH:14][CH:13]=2)[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2.[NH3:31]>>[Cl:2][C:3]1[N:4]([C:12]2[CH:30]=[CH:29][C:15]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([C:26]([NH2:31])=[O:28])[CH2:24][CH2:25]3)=[CH:14][CH:13]=2)[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: N
Reactant: O=C(O)C1CCN(CCCOc2ccc(-n3nc4ccccc4c3Cl)cc2)CC1
Agent: Cl
Product: NC(=O)C1CCN(CCCOc2ccc(-n3nc4ccccc4c3Cl)cc2)CC1
Yield: 67.8 %

Procedure:
1-{3-[4-(3-Chloro-indazol-2-yl)-phenoxy]-propyl}-piperidine-4-carboxylic acid hydrochloride (0.1 g, 0.25 mmol) and ammonia (28% in H2O, 3.0 g, 49 mmol) using the procedure of step 3 of the Example 11 to provide the title compound (0.07 g, 70%). 1H NMR (400 MHz, CDCl3) δ 7.71(d, J=8.8 Hz, 1H), 7.59-7.56 (m, 3H), 7.37-7.33 (m, 1H), 7.17-7.14 (m, 2H), 7.04 (d, J=8.8 Hz, 2H), 5.46 (br, 1H), 5.33 (br, 1H), 4.10 (t, J=6 Hz, 2H), 3.01 (br d, J=12 Hz, 1H), 2.54 (t, J=6 Hz, 2H), 2.10-1.73 (m, 9H), LC/MS (APCI) m/z: 97%.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)CCC>CN(C)C=O.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:25]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[NH:4][N:3]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2cc(C#N)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 57.3 %

Procedure:
To a solution of 300 mg of tert-butyl 3-bromo-5-cyano-1H-1-indazolecarboxylate produced in Production Example I-14-b in 10 ml dimethylformamide were added 376 mg of tri-n-butyl (phenyl)tin and 54 mg of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 150° C. for 45 minutes. After removing the solvent by distillation, the residue was dissolved in 1.5 ml of ethyl acetate and the mixture was adsorbed by 1.5 g of silica gel. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=3:97 to 1:19) and the resulting amorphous powder was crystallized from diisopropyl ether, to give 117 mg of the title compound as pale yellow crystals.
Reaction SMILES: [Cl:1]Cl.[CH2:3]([O:5][C:6]([CH2:8][C:9]([CH3:17])([CH3:16])[CH:10](C(O)=O)[C:11]#[N:12])=[O:7])[CH3:4].C([O-])(=O)C.[Na+].Cl>O>[CH2:3]([O:5][C:6]([CH2:8][C:9]([CH3:17])([CH3:16])[CH:10]([Cl:1])[C:11]#[N:12])=[O:7])[CH3:4]
Reactant: ClCl
Reactant: CCOC(=O)CC(C)(C)C(C#N)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(C)(C)C(Cl)C#N
Temperature: 20 °C
Reaction time: 5 h
Yield: 68.7 %

Procedure:
17.8 g (0.25 mol) of chlorine were passed into a solution of 42.6 g (0.2 mol) of 3-carboxy-3-cyano-2,2-dimethyl-propane-1-carboxylic acid ethyl ester and 41 g of sodium acetate in 400 ml of water at 20° C. The mixture was subsequently stirred at 20° C. for 5 hours and then acidified with dilute HCl. The acid solution was worked up as described under Example 1. 28 g (69% of theory) of 3-chloro-3-cyano-2,2-dimethyl-propane-1-carboxylic acid ethyl ester were obtained in the form of a colorless oil of boiling point 80°-82° C./1 mm Hg.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][C:9](=[O:19])[C:8]=2[C:7]([O:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[H][H]>[Pd].C(O)C>[CH3:24][CH:23]([CH3:25])[CH2:22][CH2:21][O:20][C:7]1[C:8]2[C:9](=[O:19])[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[O:12][C:13]=2[C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: C=CCc1ccc(OCCC(C)C)c2c(=O)cc(C(=O)OCC)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(OCCC(C)C)c2c(=O)cc(C(=O)O)oc12
Reaction time: 2 h

Procedure:
A suspension of 12.05 parts of 8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester in 225 parts of ethanol was treated with 0.2 parts of 5% palladium/charcoal catalyst and hydrogenated at a pressure of 4 atmospheres. After 30 minutes the hydrogen uptake ceased and the reaction mixture was filtered. The volume of the filtrate was reduced and then water was added. On standing 10.2 parts of 5-(3-methyl-n-butoxy)-8-n-propyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester crystallised as yellow needles, melting point 64.5°-65° C. This material was stirred with a hot aqueous solution of sodium bicarbonate containing some ethanol for two hours. The resulting solution was cooled, washed with diethyl ether and acidified with dilute hydrochloric acid. The yellow precipitate was collected and crystallised from aqueous ethanol to give 7.2 parts of 5-(3-methyl-n-butoxy)-8-n-propyl-4-oxo-4H-1-benzopyran-2-carboxylic acid as yellow needles, melting point 166°-167° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([CH:22]=O)[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20](/[CH:22]=[N:25]/[OH:26])[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc(C=O)c2)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc(/C=N/O)c2)CC1

Procedure:
To the solution of tert-butyl 4-(3-bromo-5-formylphenoxy)piperidine-1-carboxylate (205 mg, 0.533 mmol) in ethanol (1.9 mL) and water (0.6 mL), hydroxylamine hydrochloride (40.8 mg, 0.587 mmol) and sodium acetate (61.3 mg, 0.747 mmol) were added sequentially, then the resulting solution was refluxed for 1 hour. The most organic solvent was removed in vacuo and the solution was diluted with water. The resultant precipitate was collected and dried under vacuum to give the desired product as white solid. LCMS (M+H)+: 399.1, 401.1.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:7]([OH:16])=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([CH:13]=1)[CH:11]=[O:12])([O-:5])=[O:4].[CH3:17]I.O>CN(C=O)C>[CH3:15][O:14][C:8]1[CH:9]=[C:10]([CH:13]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]=1[O:16][CH3:17])[CH:11]=[O:12]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (4.87 g, 121.7 mmole) in 18 mL dry DMF was cooled to 0° C. and then 5-nitrovanillin (20 g, 101.4 mmole) in 30 mL of DMF was added dropwise. After 30 minutes, methyl iodide (43.18 g, 304.2 mmole) was added dropwise at 0° C. When the addition was completed, the mixture was warmed to room temperature and stirred overnight. Water was added and the solution extracted with ethyl ether, the organic layer was washed with 10% NaOH solution, dried over MgSO4, filtered and evaporated in vacuo to an oil (8.7 g, 40.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([CH:30]4[CH2:32][CH2:31]4)[CH:27]=[CH:26][C:25]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:42])=[O:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:36])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:49]3[CH2:48][CH2:47][N:46]([CH2:45][CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:51][CH2:50]3)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([CH:30]4[CH2:32][CH2:31]4)[CH:27]=[CH:26][C:25]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1ccc(C2CC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccc(C2CC2)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(5-cyclopropyl-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% isopropanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C37H44N4O4SCl2 [(M+H)+] 711.2533, observed 711.2536.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[CH3:12][Mg]Br.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1.O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])([CH3:12])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)c1cc(C#N)ccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(C#N)ccn1
Temperature: -40 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of 2-acetylisonicotinonitrile (67.1 g, 0.457 mol) in tetrahydrofuran (2400 mL) was added dropwise a solution of methylmagnesium bromide (3.0 M, 167.6 mL, 0.503 mol) in toluene/tetrahydrofuran mixture (3:1) at −40° C. over a period of 2.5 h. The reaction mixture was stirred at −40° C. for another 2 h. A saturated aqueous solution of ammonium chloride (50 mL) was added. The resulting mixture was warmed to room temperature and another 400 mL of a saturated aqueous solution of ammonium chloride was added. The layers were separated and the aqueous layer was extracted with dichloromethane (400 mL×2). The combined organics were dried over sodium carbonate and sodium sulfate and concentrated. The residue was purified via flash chromatography (ethyl acetate/petroleum ether 1:20, 0.3% triethylamine) to afford 2-(2-hydroxypropan-2-yl)isonicotinonitrile (33.0 g, 44.3%).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([CH2:17][N:18]([CH:28]([CH3:30])[CH3:29])[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:21])=[O:20])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([CH3:16])([CH3:15])[CH:11]=[CH:10]2.O>O1CCCC1.Cl>[OH:4][C:5]1[CH:6]=[C:7]([CH2:17][N:18]([CH:28]([CH3:30])[CH3:29])[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:21])=[O:20])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([CH3:15])([CH3:16])[CH:11]=[CH:10]2
Reactant: COCOc1cc(CN(C(C)C)S(=O)(=O)c2ccccn2)cc2c1OC(C)(C)C=C2
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(Cc1cc(O)c2c(c1)C=CC(C)(C)O2)S(=O)(=O)c1ccccn1
Reaction time: 3 h

Procedure:
N-[(8-Methoxymethoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-2-sulfonamide (31 mg, 0.07 mmol) was dissolved in a cosolvent of tetrahydrofuran (1 mL) and 6 N aqueous HCl (1 mL), and the reaction stirred for 3 h. Ten milliliters of water was added to the reaction mixture, and then tetrahydrofuran was evaporated. The remaining aqueous phase was extracted by methylene chloride (10 mL×3), washed with brine, dried with anhydrous magnesium sulfate, and concentrated in vacuo. 6h (19 mg, 49%) was purified by silica gel chromatography with ethyl acetate/hexane (1/1). 1H NMR (CDCl3): δ 0.77 (d, J=6.45 Hz, 6H), 1.44 (s, 6H), 1.72-1.79 (m, 1H), 3.11 (d, J=7.62 Hz, 2H), 4.39 (s, 2H), 5.61 (d, J=9.67 Hz, 1H), 6.25 (d, J=9.96 Hz, 1H), 6.50 (d, J=1.76 Hz, 1H), 6.65 (d, J=1.76 Hz, 1H), 7.43-7.47 (m, 1H), 7.84-7.97 (m, 2H), 8.69 (d, J=4.40 Hz, 1H). HRMS (m/z): [M+Na]+ calcd 425.15055, found 425.15091. HPLC-1: flow rate 2 mL/min, tR=2.9 min, purity=100%; flow rate 1 mL/min, tR=5.6 min, purity=100%. HPLC-2: tR=5.172 min, purity=100%.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:7]([C:15]([O:17]CC)=O)=[N:6]1)[CH2:2][CH2:3][CH3:4].[NH3:20]>CO>[CH2:1]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:7]([C:15]([NH2:20])=[O:17])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C(=O)OCC)cc1CC(C)(C)O
Reactant: N
Solvent: CO
Product: CCCCn1nc(C(N)=O)cc1CC(C)(C)O
Temperature: 25 °C

Procedure:
Ethyl 1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxylate (26 g, 97 mmol) and ammonia (160 mL of a 7 N solution in methanol) were heated at 150° C. in a stainless steel reactor for 42 hours and allowed to cool to ambient temperature. The volatiles were removed under reduced pressure to provide 1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxamide as a black oil, which was treated with trifluoroacetic anhydride (40 mL, 289 mmol) and triethylamine (53 mL, 386 mmol) according to a modification of the method of Part C of Example 1253 to provide 2-(1-butyl-3-cyano-1H-pyrazol-5-yl)-1,1-dimethylethyl trifluoroacetate as a dark brown oil. The reaction with trifluoroacetic anhydride was stirred for three hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.N1C=CC=CC=1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>CCOCC>[N+:8]([C:6]1[CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=[C:2]([NH:1][C:22](=[O:23])[CH2:21][Cl:20])[CH:7]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: CCOc1cc([N+](=O)[O-])cc(N)n1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOc1cc([N+](=O)[O-])cc(NC(=O)CCl)n1
Reaction time: 0.33 h

Procedure:
A solution of 2-amino-4-nitro-6-ethoxypyridine (29.4 grams) in absolute ether (150 ml), and pyridine (25 grams) are charged into a glass reaction vessel equipped with stirrer, thermometer and addition funnel. The mixture is cooled to a temperature of about 0° C and chloroacetyl chloride (11.3 grams) dissolved in ether (50 ml) is then slowly added thereto with stirring over a period of about 20 minutes. Stirring and cooling are continued for an additional period of about 30 minutes. The resulting precipitate is then recovered from the reaction medium by filtration, is washed first with aqueous sodium carbonate and then with water, and is dried to yield the desired product N-(4-nitro-6-ethoxy-2-pyridyl)-α-chloroacetamide.