Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[CH:10]1([CH:16]=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CC1OCCC1>[CH:10]1([CH2:16][NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=CC1CCCCC1
Reactant: CCOC(CN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Product: CCOC(CNCC1CCCCC1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2,2-diethoxyethylamine (209 mL, 1.43 mol) and MeTHF (1050 L) was added cyclohexanecarbaldehyde (107 mL, 0.89 mol). The reaction mixture was stirred for 30 min at room temperature and cooled to 0° C. Sodium triacetoxyborohydride (378 g, 1.79 mol) was added over 40 min and the reaction mixture was stirred for 2 h and cooled to 0° C. 1 M NaOH (1 L) was added. The organic layer was washed with brine in water (1:1, 2×1 L) and the volume was reduced to ˜20%. MeTHF (1 L) was added and the volume reduced to ˜20%. The solution of the crude title intermediate was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24]S(C)(=O)=O)=[CH:16][CH:15]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH:35]=[CH:36][CH:37]=[N:38]3)=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:41]1([CH2:44]O)[CH2:43][CH2:42]1.[H-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:44][CH:41]3[CH2:43][CH2:42]3)=[CH:16][CH:15]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH:35]=[CH:36][CH:37]=[N:38]3)=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCC1CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOS(C)(=O)=O)cc2)[C@@H](OCc2ccc3cccnc3c2)C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC3CC3)cc2)[C@@H](OCc2ccc3cccnc3c2)C1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To an ice-cooled solution of 3.50 g (6.13 mmol) of the (3R,4R)-4-[4-(3-methanesulfonyloxy-propoxy)-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester and 4.97 ml (4.42 g, 61.33 mmol, 10.0 equiv.) of cyclopropyl carbinol in 25 ml of tetrahydrofuran was added 0.535 g (12.27 mmol, 2.0 equiv.) of sodium hydride dispersion (55% in mineral oil) in portions. The mixture was warmed to 55° C. and stirred for 1.5 h. The reaction mixture was poured into 200 ml of an ice/water mixture, the pH was adjusted to 8 by addition of saturated sodium bicarbonate solution, and the aqueous phase was extracted four times with 200 ml of ethyl acetate. The combined organic phases were washed twice with 25 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 1:2 v/v mixture of hexane and ethyl acetate as eluent to yield 3.32 g (6.07 mmol, 99.0% of theory) of the (3R,4R)-4-[4-(3-cyclopropylmethoxy-propoxy)-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil; MS: 547 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl[C:20]1[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][C:20]1[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
To a flask fitted with a drying tube is charged DMSO (10 ml), 2-chloro-4-trifluoromethylphenol (3.93 g, 0.02 mole) and anhydrous potassium carbonate (2.76 g, 0.02 mole). Then methyl 5-chloro-2-nitrobenzoate (4.3 g, 0.02 mole) is added and the reaction mixture warmed to 50° C. for 3 hours. (Gas-liquid chromatography analysis suggested a low conversion to desired product.) The temperature is raised to 60° C. for 16 hours and then to 70° C. for 16 hours. Additional potassium carbonate (1.38 g, 0.01 mole) is added and heating at 70° C. is continued for an additional 5 days, the reaction mixture is cooled to room temperature, poured into a benzene/hexane cosolvent and extracted twice with water. The organic layer is dried with anhydrous sodium sulfate, filtered and the solvent removed under vacuum (110° C., 0.1 mm) to afford 2.0 g, (27% yield) of methyl 5-(2-chloro-4trifluoromethylphenoxy)-2-nitrobenzoate which is determined by spectral data to be identical with the product of Example 1B.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([CH2:19]O)=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.CS([Cl:34])(=O)=O>ClCCl>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([CH2:19][Cl:34])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)sc1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)sc1CCl
Temperature: 0 °C

Procedure:
[2-(3,5-Bis-trifluoromethyl-phenyl)-4-methyl-thiazol-5-yl]-methanol (0.460 g, 1.35 mmol), is dissolved in anhydrous dichloromethane (6 mL) and cooled to 0° C. with stirring under nitrogen. Triethyl amine (0.350 mL, 2.60 mmol) and methane sulfonyl chloride (0.200 mL, 2.0 mmol) are added and the reaction is monitored by TLC. After the starting material is completely consumed, the reaction is diluted with dichloromethane and extracted against saturated sodium bicarbonate solution. The two phases are separated and the organic layer is washed with water and brine, dried over sodium sulfate, then concentrated. The residue is further purified using flash column chromatography. The 2-(3,5-Bis-trifluoromethyl-phenyl)-5-chloromethyl-4-methyl-thiazole is formed quantitatively and used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:19][CH:20]([CH3:22])[CH3:21])=[N:4][C:5]([NH:9]CC2C=CC(OC)=CC=2)=[C:6]([F:8])[CH:7]=1.FC(F)(F)C([O-])=O>>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([F:1])=[C:3]([NH:19][CH:20]([CH3:22])[CH3:21])[N:4]=1
Reactant: COc1ccc(CNc2nc(NC(C)C)c(F)cc2F)cc1
Agent: O=C([O-])C(F)(F)F
Product: CC(C)Nc1nc(N)c(F)cc1F
Reaction time: 0.25 h
Yield: 51.8 %

Procedure:
To 1.9 g of 3,5-difluoro-2-isopropylamino-6-(p-methoxybenzylamino)pyridine was added 4 ml of trifluoroacetate, and the mixture was allowed to stand at room temperature for 15 minutes. The solution was concentrated under reduced pressure, and 25 ml of chloroform was added to the residue, and the solution was washed with 25 ml of 5% aqueous solution of sodium carbonate. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, 40 g; eluent: chloroform) to obtain 0.6 g of the title compound as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:12][NH2:13]>C(Cl)(Cl)Cl.C(O)C>[Cl:11][C:3]1[C:2]([Cl:1])=[CH:10][C:6]([C:7]([NH:13][CH3:12])=[O:8])=[CH:5][N:4]=1
Reactant: CN
Reactant: O=C(Cl)c1cnc(Cl)c(Cl)c1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cnc(Cl)c(Cl)c1

Procedure:
A solution of 30 g of crude 5,6-dichloronicotinic acid chloride in 150 ml of chloroform is added dropwise to a solution of 50 g of methylamine in 250 ml of ethanol whilst stirring and cooling at 10°-15° C. The reaction mixture is stirred for a further 2 hours at 20°-30° C. and is then evaporated in vacuo. The evaporation residue is taken up in ethyl acetate and this solution is washed with 2 N sodium carbonate solution, dried over magnesium sulphate and evaporated. The residue is recrystallised from ethanol-ether. 2,3-Dichloro-5-methylaminocarbonyl-pyridine, thus obtained, melts at 134°-138° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH3:17][C:18]1([CH3:29])[C:22]([CH3:24])([CH3:23])[O:21][B:20](OC(C)C)[O:19]1>O1CCCC1>[CH3:17][C:18]1([CH3:29])[C:22]([CH3:24])([CH3:23])[O:21][B:20]([C:9]2[O:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)[O:19]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: c1ccc(-c2ccco2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(-c3ccccc3)o2)OC1(C)C
Temperature: -78 °C
Yield: 24.9 %

Procedure:
To a solution of 2-phenylfuran (1.20 g, 8.32 mmol) in dry tetrahydrofuran (100 mL) was added a solution of n-BuLi (4.9 mL, 2.5 M solution in hexane) dropwise with stirring at −78° C. under nitrogen. The resulting solution was warmed slowly to −40° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −78° C. followed by dropwise addition of 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (3.10 g, 16.66 mmol). After warming to room temperature, the mixture was quenched with NH4Cl (aq) and extracted with ethyl acetate (3×80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford 4,4,5,5-tetramethyl-2-(5-phenylfuran-2-yl)-1,3,2-dioxaborolane (560 mg, 25%).
Reaction SMILES: FC1C=C(OC)C=C(F)C=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[Cl:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[Cl:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: OB(O)c1cccc(F)c1Cl
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: O=C(O)c1csc(-c2cccc(F)c2Cl)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (2-chloro-3-fluorophenyl)boronic acid gave the title compound.
Reaction SMILES: C[C:2]1[C:10]([CH3:12])(C)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CC1S[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.IC>>[CH:21]1[CH:20]=[CH:19][C:17]([N:18]=[CH:12][CH2:10][CH:2]=[N:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][CH:22]=1
Reactant: Cc1nc2ccccc2s1
Reactant: CC1=Nc2ccccc2C1(C)C
Solvent: CI
Product: C(CC=Nc1ccccc1)=Nc1ccccc1

Procedure:
2,3,3-Trimethyl indolenine, methylbenzothiazole, iodomethane, and diidopropane were purchased from Aldrich and used without further purification. Malonaldehyde dianil was synthesized according to literature reports (Glauert, R. H. and Mann, F. G. J. Chem. Soc. (1952) 5012, by the method of Claisen (Ber. (1903) 36, 3664). Dry nitrobenzene was freshly distilled from CaH2. Dry triethylamine was distilled from Na°. DMF was predried with MgSO4, fractionally distilled and stored over molecular sieves. All dry solvents were stored under N2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[C:19]1([NH:25][CH2:26][CH:27]([NH2:29])[CH3:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:29][CH:27]([CH3:28])[CH2:26][NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CC(N)CNc1ccccc1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(CNc1ccccc1)Nc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 1-phenylamino-2-amino-propane hydrochloride and DBU in DME. ES-MS m/e (%): 335 (M+H+, 100).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][CH:5]=1)#[N:2].[OH-].[Na+]>C(O)C>[C:1]([CH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)#[N:2]
Reactant: CCOC(=O)c1ccc(CC#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CCc1ccc(C(=O)O)cc1

Procedure:
A solution of 10 g (53 mol) of ethyl 4-cyanomethyl-benzoate and 2.02 mL of a 1 M sodium hydroxide solution in 100 mL of ethanol is refluxed for one hour. Then the reaction solution is evaporated down and the residue is combined with ice water. Concentrated hydrochloric acid is added dropwise to the reaction solution until no more precipitate is formed. The precipitate is filtered off, washed twice with water and dried.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[C:11]1(=[O:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1.C(O)(=O)C>C1(C)C=CC=CC=1>[O:21]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH:12]1[C:1]([O:5][CH2:6][CH3:7])=[O:8]
Reactant: O=C1CCCc2ccccc21
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2ccccc2C1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of diethyl carbonate (200 g) in toluene (800 ml) was added 60% sodium hydride (27.4 g), and the mixture was stirred at 50° C. for 30 minutes, and thereto was added dropwise a solution of 3,4-dihydro-1(2H)-napthalenone (50 g) in toluene (200 ml). The mixture was refluxed for one hour, and poured into ice-water, and the mixture was neutralized with acetic acid. The toluene layer was collected, washed successively with an aqueous potassium carbonate solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by distillation under reduced pressure to give ethyl 1,2,3,4-tetrahydro-1-oxo-2-naphthalenecarboxylate (47 g) as an oily product, b.p. 135°-145° C./2 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:17])[NH:9][N:10]2[C:14]([CH3:15])=NN=[C:11]2[CH3:16])=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:20])C>>[C:14]([N:10]1[C:11]([CH3:16])=[N:17][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)(=[O:20])[CH3:15]
Reactant: Cc1nnc(C)n1NC(=N)c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1nc(-c2ccc(Cl)cc2)nc1C

Procedure:
63.6 g (254.0 mM) 4-Chloro-N-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)benzenecarboximidamide prepared in part B and 67 ml of acetic anhydride in a 300 ml round bottom flask equipped with a distillation head are heated to 170° in an oil bath. A solution forms from which acetic acid distills off in the first few minutes. The mixture is refluxed for 2.5 hours and the excess acetic anhydride is evaporated to dryness under vacuum to produce a residue comprising a mixture of the title compound and its 1-acetyl-5-(4-chlorophenyl)-3-methyl isomer. The residue is triturated with 120 ml of water at room temperature and filtered. The filter cake is dissolved in 1 liter of hot ethanol, filtered hot, and the product precipitated from the hot alcohol by adding 3 liters of cold water. The product is filtered off, washed with water, and dried at 80° under vacuum to yield 37.6 g of the 1-acetyl-3-(4-chlorophenyl)-5-methyl-1H-1,2,4-triazole as a crystalline material (99% pure), m.p. 132°-133°.
Reaction SMILES: [CH3:1][S:2][CH:3]([O:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)[C:4]([O:6]C(C)(C)C)=[O:5].[OH-].[Na+]>CO.O>[CH3:1][S:2][CH:3]([O:11][C:12]1[CH:13]=[C:14]([Cl:19])[CH:15]=[C:16]([Cl:18])[CH:17]=1)[C:4]([OH:6])=[O:5]
Reactant: CSC(Oc1cc(Cl)cc(Cl)c1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSC(Oc1cc(Cl)cc(Cl)c1)C(=O)O
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To the product of Step 1 (0.2 g) in methanol (3 ml) at ambient temperature was added a solution of sodium hydroxide (0.050 g) in water (1 ml). The reaction was stirred for 2 hours, the solvent evaporated then water and ethyl acetate were added. The aqueous phase was separated, acidified with dilute aqueous hydrochloric acid then extracted with ethyl acetate. The organic phases were combined, dried over magnesium sulphate, filtered and evaporated to give 2-methylthio-2-(3,5-dichlorophenoxy)acetic acid as a pale yellow gum (0.153 g) that was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:17](=[S:18])[N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)[C:15](=[O:31])[C:11]32[CH2:14][CH2:13][CH2:12]3)=[CH:6][CH:5]=1.[CH3:33][NH2:34]>>[CH3:33][NH:34][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:17](=[S:18])[N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:29])([F:30])[F:28])[CH:20]=3)[C:15](=[O:31])[C:11]32[CH2:12][CH2:13][CH2:14]3)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Reactant: CN
Product: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Reaction time: 15 h
Yield: 84 %

Procedure:
A mixture of 4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-benzoic acid methyl ester (51b) (0.046 g, 0.1 mmol) and methylamine (1 ml distilled from its 40% aqueous solution) was kept at −20° C. for 15 hours. After evaporation of the methylamine, the mixture was chromatographed (dichloromethane:acetone, 80:20) to yield N -methyl-4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]benzamide (51c) [RD161] (0.041 g, 0.085, 84%), the structure of which is illustrated in Formula 27.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O-:12].[K+].OP([O-])(O)=O.[Na+].C(#N)C.[O:23]1[C:25]2([CH2:30][CH2:29][S:28][CH2:27][CH2:26]2)[CH2:24]1>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH2:24][C:25]1([OH:23])[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1
Reactant: COc1cc([N+](=O)[O-])ccc1[O-]
Reactant: C1CC2(CCS1)CO2
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])ccc1OCC1(O)CCSCC1
Temperature: 150 °C
Yield: 41.9 %

Procedure:
A mixture of potassium 2-methoxy-4-nitrophenolate (3.02 g, 14.59 mmol), sodium phosphate monobasic, monohydrate (2.014 g, 14.59 mmol), acetonitrile (12 mL), water (3 mL) and 1-oxa-6-thiaspiro[2.5]octane (1.90 g, 14.59 mmol), prepared as described in patent WO 2005/063729 A1, was heated at 150° C. for 3.5 h in a microwave reactor. After cooling to RT, acetonitrile was mostly removed under vacuum, the remaining material was partitioned between EtOAc (100 mL) and H2O (15 mL). The aqueous layer was extracted with EtOAc (2×15 mL) and the combined organic layers were dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (silica gel, hexanes:EtOAc, 100:0 to 60:40) to afford 1.83 g (42%) of the title compound as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 7.87 (dd, J=9.07, 2.47 Hz, 1H), 7.73 (d, J=2.75 Hz, 1H), 7.18 (d, J=9.35 Hz, 1H), 4.75 (s, 1H), 3.89 (s, 3H), 3.85 (s, 2H), 2.87-2.97 (m, 2H), 2.49 (s, 1H), 2.38 (d, J=13.20 Hz, 2H), 1.82-1.89 (m, 2H), 1.72-1.82 (m, 2H). HPLC retention time: 2.985 min; LCMS (ES): m/z 282 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][CH:6]1[C:11]([C:12]2[CH:26]=[CH:25][C:15]3[N:16]=[C:17]([C:19]4[O:20][C:21]([NH2:24])=[CH:22][CH:23]=4)[NH:18][C:14]=3[CH:13]=2)=[N:10][NH:9][C:8](=[O:27])[CH2:7]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:5][CH:6]1[C:11]([C:12]2[CH:26]=[CH:25][C:15]3[N:16]=[C:17]([C:19]4[O:20][C:21]([NH:24][C:1](=[O:3])[CH3:2])=[CH:22][CH:23]=4)[NH:18][C:14]=3[CH:13]=2)=[N:10][NH:9][C:8](=[O:27])[CH2:7]1
Reactant: CC(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(N)o3)[nH]c2c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(-c2nc3ccc(C4=NNC(=O)CC4C)cc3[nH]2)o1
Reaction time: 3 h

Procedure:
0.3 ml of acetyl chloride in 3 ml of chloroform is added to a solution of 309 mg of 5-methyl-6-[2-(5-amino-2-furyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one and 0.2 ml of triethylamine in 10 ml of chloroform, and the mixture is boiled for 3 hours. The usual working up is carried out, and 5-methyl-6-[2-(5-acetamido-2-furyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one is obtained.
Reaction SMILES: Cl.[CH3:2][C:3]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:7])[C:4]([OH:6])=O.[CH3:28][NH2:29]>O1CCOCC1>[CH3:28][NH:29][C:4](=[O:6])[C:3]([CH3:7])([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH3:2]
Reactant: CN
Reactant: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)O)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)NC)ccc21

Procedure:
The above compound was prepared from 2-methyl-2-[2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-5-yloxy]propanoic acid hydrochloride and methylamine in dioxane using a procedure analogous to that of Example 128.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].[H-].[Na+]>CN(C)C=O>[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][O:11][C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]3[C:7]=2[N:6]([CH3:12])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4]3)=[CH:29][CH:28]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1cc2c(Cl)ccc(O)c2n1C
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)ccc(OCc3ccc(CNC(=O)OC(C)(C)C)cc3)c2n1C
Yield: 74.1 %

Procedure:
The reaction was carried out in a manner similar to Example 196 a) except for using 0.44 g (1.74 mmol) of ethyl 4-chloro-7-hydroxy-1-methyl-2-indolecarboxylate, 0.66 g (2.58 mmol) of 4-(tert-butoxycarbonylaminomethyl)-benzyl chloride, 0.07 9 (1.74 mmol) of 60% sodium hydride and 20 ml of dimethylformamide. Thus, 0.61 g (73.1%) of ethyl 7-[4-(tert-butoxycarbonylaminomethyl)benzyloxy]-4-chloro-1-methyl-2-indolecarboxylate was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1CCCCC1>[CH2:23]([O:22][C:16](=[O:21])[CH:17]=[C:18]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH3:20])[CH3:24]
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CCOC(=O)C=C(C)Nc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 9987.2 %

Procedure:
20 g (98.4 mmol)of 3-benyloxyaniline, 12.6 ml (0.984 mmol) of ethyl acetoacetate and 0.189 g (1 mmol) of p-toluenesulfonic acid monohydrate in 32 ml of cyclohexane were heated at reflux for 5.5 h in the presence of a water separator funnel. The reaction mixture was cooled to RT, some solid material was filtered off by suction and the filtrate was concentrated in vacuo to give 30.6 g (99%) of the desired 3-(3-benzyloxy-phenylamino)-but-2-enoic acid ethyl ester as a yellow oil. This was used without further purification in the next reaction step.