Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+].CC(=O)OCC>O>[OH:13][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(N)cc1C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4.27 g 5-amino-2-methylbenzoic acid (see below), 6 ml concentrated sulfuric acid and 10 ml water, 50 ml ice are added, and a solution of 2.1 g sodium nitrite in 15 ml water is added drop wise, maintaining a temperature of the reaction mixture below 7° C. After stirring this mixture for further 30 min, it is added drop wise to a refluxing mixture of 20 ml concentrated sulfuric acid and 20 ml water. The resulting mixture is held under reflux for further 10 min and stirred over night allowing the temperature to cool down to RT. The mixture is portioned between water and EA, the phases are separated, the organic phase is dried over MgSO4, and the solvent is removed under reduced pressure. For further purification the remaining crude product is solved in diethyl ether, and the organic phase is washed with water, dried over MgSO4, and the solvent is removed under reduced pressure, resulting in 5-hydroxy-2-methylbenzoic acid as the product, which is used for the next step without further purification.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[BH4-].[Na+].[OH-].[Na+]>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:10][C:8]2[CH:7]=[CH:6][C:5]3[N:1]=[CH:2][NH:3][C:4]=3[CH:9]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(CNc2ccc3nc[nH]c3c2)cc1

Procedure:
Alternatively the compound was synthesized starting from benzimidazol-5-amine (2.66 g; 20 mmol; 1 eq.), 4-chlorobenzaldehyde (3.09 g; 22 mmol; 1.1 eq.), NaBH4 (1.14 g; 30 mmol; 1.5 eq.) and 5 N NaOH (20 ml; 100 mmol; 5 eq.) according to method 2; Yield: 3.94 g (76.7%); MS m/z: 258.3/260.3 [M+H]+
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[AsH3:5]>CCCCCCCC.CS(O)(=O)=O>[CH3:4][C:2]([AsH:5][C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:3])[CH3:1]
Reactant: C=C(C)C
Reactant: [AsH3]
Agent: CS(=O)(=O)O
Solvent: CCCCCCCC
Product: CC(C)(C)[AsH]C(C)(C)C
Temperature: 8 °C
Yield: 6.3 %

Procedure:
An autoclave reactor having approximately 3.8 liter capacity is charged with 400 grams of isobutylene reactant, 600 grams of n-octane solvent and 1000 grams of aqueous 70% methanesulfonic acid catalyst. The reactor is pressurized to about 12.3 atmospheres at room temperature by addition of arsine reactant in molar excess with respect to isobutylene. The autoclave is sealed and its contents are heated at 80°-95° C. with constant agitation for four hours reaction time. The contents are then cooled to 8° C. before the reactor is opened. Unreacted arsine is vented from the reactor. By gas chromatographic analysis of the liquid reaction product mixture, yields of 350 grams mono-1,1-dimethylethylarsine (36.6% yield) and 85 grams bis(1,1-dimethylethyl)arsine (6.3% yield) are measured. The organic phase separated from the liquid product mixture is washed with water, dried and then distilled at 68°-69° C. to separate the mono-1,1-dimethylethylarsine. The bis(dimethylethyl)arsine is separated by further distillation of the reaction product.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[N:13][OH:14].[H-].[Na+].Br[CH2:18][CH2:19][OH:20].C[O-].[Na+]>CN(C)C=O.O>[CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[N:13][O:14][CH2:18][CH2:19][OH:20]
Reactant: CON=C1C(=NO)Oc2ccccc21
Reactant: OCCBr
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON=C1C(=NOCCO)Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
49 g (0.0234 mol) of benzofuran-2,3-dione3-(O-methyl-oxime)2-oxime (VIII-1) are dissolved in 25 ml of dimethylformamide. 1 g (0.025 mol) of 60% strength sodium hydride is added to this solution which is then stirred at room temperature for one hour. 3.1 g (0.0248 mol) of 2-bromoethanol are added and the mixture is stirred at 25° C. for 12 hours. After the addition of 0.5 g of sodium methoxide and 1.22 g of 2-bromoethanol, the mixture is stirred at room temperature for 2 hours. A further 0.5 g of sodium methoxide and 1.22 g of 2-bromoethanol are added and the mixture is stirred for a further 2 hours at room temperature. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate and the organic phase is washed 3 times with 20 ml of 2 N aqueous sodium hydroxide solution. The solvent is distilled off under reduced pressure and the residue is chromatographed over silica gel using diethyl ether/petroleum ether (1:1). The eluent is distilled off under reduced pressure, affording 2.26 g (39.6% of theory) of benzofuran-2,3-dione2-[O-(2-hydroxy-ethyl)-oxime] 3-(O-methyl-oxime) (II-1) which, according to HPLC, comprises 84.29% of stereoisomer A and 12.58% of stereoisomer B.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[N:11][CH:12]=1.[CH3:22][CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1.[Cl-].[NH4+]>C(OCC)C.C1COCC1.CCOC(C)=O>[Si:15]([C:14]#[C:13][C:10]1[N:11]=[CH:12][C:7]([C:26]2([OH:29])[CH2:27][CH2:28][CH:23]([CH3:22])[CH2:24][CH2:25]2)=[CH:8][CH:9]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)C#Cc1ccc(Br)cn1
Reactant: CC1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1CCC(O)(c2ccc(C#C[Si](C)(C)C(C)(C)C)nc2)CC1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
9.5 mL (16.19 mmol) of n-BuLi (1.6 M in THF) was slowly added under argon at −70° C. to a solution of 4.50 g (15.19 mmol) of 5-bromo-2-[(tert-butyldimethylsilanyl)ethynyl]pyridine in 50 mL of diethyl ether and 60 mL of THF and after the addition had ended the mixture was stirred for another 2 minutes. 1.86 mL (15.19 mmol) of 4-methylcyclohexanone was added and the mixture was slowly heated to RT. 150 mL of saturated aqueous ammonium chloride solution were added and the aqueous phase was exhaustively extracted with EtOAc. The combined organic extracts were with washed with semisaturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. The residue was purified by chromatography (silica gel, PE/EtOAc 4:1). 2 fractions were isolated. Fraction 1: cis-1-{6-[(tert-butyldimethylsilanyl)ethynyl]pyridin-3-yl}-4-methylcyclohexanol; yield: 1.40 g (28% of theoretical); C20H31NOSi (M=329.552); calc.: molpeak (M+H)+: 330; found: molpeak (M+H)+: 330; Rf value: 0.40 (silica gel, PE/EtOAc 4:1). Fraction 2: trans-1-{6-[(tert-butyldimethylsilanyl)ethynyl]pyridin-3-yl}-4-methylcyclohexanol; yield: 1.00 g (20% of theoretical); C20H31NOSi (M=329.552); calc.: molpeak (M+H)+: 330; found: molpeak (M+H)+: 330; Rf value: 0.30 (silica gel, PE/EtOAc 4:1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-])=O.[CH2:16]=[CH:17][CH:18]=[CH2:19].[H][H]>[Pd].COCCO>[NH2:1][C:4]1[C:5]2[C:6](=[O:15])[C:7]3[C:8](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9](=[O:14])[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: C=CC=C
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: COCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
6.1 Grams of 5-nitro-1,4-naphthoquinone, 140 grams of methyl cellosolve (i.e., β-hydroxyethyl methyl ether) and 2.4 grams of 1,3-butadiene were introduced into an autoclave and heated to 80° C. for reaction for 2.5 hours. After allowing to cool, 0.06 gram of a 5% palladium on carbon catalyst was added to the solution into which was fed hydrogen while agitating at room temperature under normal pressure for hydrogen absorption in the amount of 2 mols per mol of the starting 5-nitro material. Thereafter, the catalyst was separated by filtration. To the resultant filtrate was added 6 grams of a 20% aqueous sodium hydroxide solution, which was agitated at 60° C. for 1.5 hours for reaction. After completion of the reaction, hydrochloric acid was added to the reaction solution for neutralization, followed by removing methyl cellosolve by distillation under a reduced pressure of 0.2 kg/cm2 for concentration. The thus concentrated solution was allowed to cool thereby to obtain crystals of 1-aminoanthraquinone. After separation by filtration, the crystals were washed with water and dried to obtain 5.6 grams of 1-aminoanthraquinone having a purity of 98.5%.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>O1CCOCC1>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(OC2CCNC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 0.75 mmol 3-(4-trifluoromethyl-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester in 20 ml dioxane at 0° C. was added dropwise 9.20 mmol trifluoroacetic acid, and the reaction mixture was then stirred at RT for 3 h. The reaction mixture was then concentrated in vacuo, and the residue resuspended in ethyl acetate and washed with 1 M aqueous hydrochloric acid. The aqueous phase was separated and then made basic by addition of 1 M aqueous sodium hydroxide solution and subsequently extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white amorphous solid (yield 69%). MS (m/e): 232.1 (M+H+, 100%).
Reaction SMILES: [Mg].CI.C[O:5][C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]([O:17]C)[C:7]=1[C@H:19]1[C@H:24]([C:25]([CH3:27])=[CH2:26])[CH2:23][CH2:22][C:21](=[CH2:28])[CH:20]1[OH:29]>CCOCC>[OH:5][C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]([OH:17])[C:7]=1[C@H:19]1[C@H:24]([C:25]([CH3:27])=[CH2:26])[CH2:23][CH2:22][C:21](=[CH2:28])[CH:20]1[OH:29]
Reactant: C=C1CC[C@@H](C(=C)C)[C@H](c2c(OC)cc(CCCCC)cc2OC)C1O
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Product: C=C1CC[C@@H](C(=C)C)[C@H](c2c(O)cc(CCCCC)cc2O)C1O
Temperature: 210 °C
Yield: 40 %

Procedure:
A Grignard reagent was prepared with magnesium (84 mg, 3.5 mmol) and CH3I (0.2 ml, 3.5 mmol) in dry ether (1 ml, distilled over sodium) under N2 atmosphere. (6a) (360 mg, 1 mmol) in ether (0.5 ml) was added to the stirred solution and the ether was distilled. The residue was heated under N2 atmosphere till 210° C. for 45 min. Then the flask was cooled till room temperature and the reaction was quenched with ice water. The aqueous solution was extracted several times with ether. The combined organic extracts were dried on MgSO4 and filtered. Removal of the solvents under reduced pressure afforded a residue that was chromatographed on silica gel (25% Ether/P.E.) to give 132 mg of the pure (11a) (yield 40%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]2[CH2:22][CH2:23][CH2:24][C:19]([OH:25])([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=3)[CH2:20]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(F)cc3)C2)c1

Procedure:
The compound of Example 3 was prepared according to the general preparation protocol A from 4-fluorobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[C:5](=[NH:8])[O:6][CH3:7])[CH3:2].C(N(CC)CC)C.[CH3:19][N:20]1[C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=[N:21]1>C1COCC1>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])/[C:5](=[N:8]/[C:25]([C:24]1[N:20]([CH3:19])[N:21]=[CH:22][CH:23]=1)=[O:26])/[O:6][CH3:7])[CH3:11]
Reactant: CCOC(OCC)C(=N)OC
Reactant: Cn1nccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(OCC)/C(=N/C(=O)c1ccnn1C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.1 %

Procedure:
To a stirred solution of diethoxyacetonitrile (60 g, 0.465 mol) in absolute methanol (150 mL) under an atmosphere of argon was added a solution of sodium methylate (2.5 g; 0.047 mol) in absolute methanol (20 mL), and the reaction mixture was stirred at room temperature until the nitrile disappeared completely (70-75 h). The reaction was monitored by 1H NMR. The reaction mixture was treated, while stirring, with CO2 until the precipitate of sodium carbonate ceased to form. The latter was filtered off and washed with methanol (50 mL). The filtrate was evaporated under on a rotary evaporator at a bath temperature less than 30° C. The resulting liquid was dissolved in ether (250 mL), filtered to remove the remaining inorganic salts, and evaporated again to give the crude methyl 2,2-diethoxyethanimidoate (71.0 g, 95%). It was distilled under vacuum through a 15-cm Vigreux column, affording 56.2 g (75%) of methyl 2,2-diethoxyethanimidoate (bp. 77-78° C. at 20-22 mm Hg) with a purity of more than 95% by 1H NMR. To a solution of the methyl 2,2-diethoxyethanimidoate (52.1 g, 0.321 mol) and triethylamine (49 mL, 0.353 mol) in absolute THF (300 mL) was added a solution of 1-methyl-1H-pyrazole-5-carbonyl Chloride (46.5 g, 0.321 mol, from Step 1) in absolute THF (150 mL) dropwise under an atmosphere of argon at 0-5° C. over a period of 2 h. The reaction mixture was stirred overnight at a room temperature. The residue the formed was filtered off, and the filtrate was evaporated on a rotary evaporator to give methyl (1Z)-2,2-Diethoxy-N-[(1-methyl-1H-pyrazol-5-yl)carbonyl]ethanimidoate (90 g) as a yellow viscous mass, which was used at the next stage without additional purification. The 90 g of the crude product N-acylated imidate ester obtained at the previous stage was dissolved in absolute dichloromethane (450 mL), and treated with methylhydrazine (17.1 mL, 0.321 mol) with stirring over a period of 10 min. The reaction mixture was stirred at room temperature for 3 h, washed with water (3×300 mL), and dried with anhydrous sodium sulfate. The solvent was removed under vacuum on a rotary evaporator, and the residue (56.5 g) was purified chromatographically on silica gel using hexane/ethyl acetate (1:2) as the eluent. The solvent was evaporated to give 40.1 g (47% based on 1-methyl-1H-pyrazole-5-carbonyl chloride) of the pure title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1I)[NH2:5].[CH2:10]([CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][C:14]1=[O:19])[CH:11]=[CH2:12]>>[CH2:10]([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:8]2[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=2[Cl:1])[C:14]1=[O:19])[CH:11]=[CH2:12]
Reactant: C=CCC1CCCNC1=O
Reactant: Nc1ccc(I)c(Cl)c1
Product: C=CCC1CCCN(c2ccc(N)cc2Cl)C1=O

Procedure:
Analogously to the process described under example 93A, 6.00 g (23.7 mmol) of 3-chloro-4-iodoaniline and 4.11 g (29.6 mmol) of the compound from example 96A are used to obtain 1.57 g (25% of theory) of the title compound. The purification is effected by suction filtration using silica gel with 2:1→1:2 cyclohexane/ethyl acetate as the eluent.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([NH:19][CH:20]1[C:23](=[O:24])[NH:22][CH:21]1[CH2:25][OH:26])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O)(=O)C(C)O.C(OCC)(=O)C>N1C=CC=CC=1>[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)([O:26][CH2:25][C@H:21]1[C@@H:20]([NH:19][C:17]([O:16][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:18])[C:23](=[O:24])[NH:22]1)(=[O:9])=[O:8]
Reactant: CC(C)(C)OC(=O)NC1C(=O)NC1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(O)C(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2NC(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a solution of 0.9 g (4.3 mmole) of 98% p-toluenesulfonyl chloride in 10 ml of dry pyridine at 0° is added 0.9 g (4.15 mmole) of 3-t-butoxycarbonylamino-2-hydroxymethyl-4-oxoazetidine. The mixture is stirred for 2 hr at 0° and then stored at 5° overnight. After addition of 0.5 ml of 85% lactic acid, the mixture is stirred for 1 hr, poured into ethyl acetate and washed with dilute HCl, 5% NaHCO3, and brine. The extract is dried over magnesium sulfate and evaporated to dryness to give 1.1 g (70%) of crystalline title product.
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:17][S:14]([CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:18])=[CH:9][CH:8]=1)(=[O:15])=[O:16]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: COC(=O)c1ccc(OCCCS(C)(=O)=O)cc1
Product: CS(=O)(=O)CCCOc1ccc(C(=O)N2CCC[C@H]2CN2CCCC2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B and D starting from 4-(3-methanesulfonyl-propoxy)-benzoic acid methyl ester and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 395.3.
Reaction SMILES: [CH3:1]N(C)C=O.[CH:6](=[O:18])[C:7]1[CH:17]=[C:14]([O:15][CH3:16])[C:12]([OH:13])=[C:9]([O:10][CH3:11])[CH:8]=1.[CH:19]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[I-].[K+]>O>[CH:19]1([CH2:1][O:13][C:12]2[C:14]([O:15][CH3:16])=[CH:17][C:7]([CH:6]=[O:18])=[CH:8][C:9]=2[O:10][CH3:11])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CN(C)C=O
Reactant: BrC1CCCCC1
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: COc1cc(C=O)cc(OC)c1OCC1CCCCC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
49 g hydrogenated sodium was added to 1.8 lit. of N,N-dimethylformamide solution of 171.6 g of syringaldehyde, and these were stirred at 60° C. for 30 minutes. Under incubation on ice 200 g of cyclohexylbromide and 92 g of potassium iodide were further added, and the whole was stirred again at 80° C. for 1 hour. After cooling down, 1.5 lit. of water was poured to extract with ethylacetate. Then this was dried up with magnesium sulfate.
Reaction SMILES: CI.[F:3][C:4]([F:21])([F:20])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[C:22](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:21][C:4]([F:3])([F:20])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:22])=[O:18])[CH2:13][CH2:12]2)=[N:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
Methyl iodide (0.30 mL, 4.82 mmol) was added to a solution of 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid (1.00 g, 3.65 mmol) and potassium carbonate (800 mg, 5.79 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, followed by extraction with diethyl ether twice. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=100/0-60/40 (gradient)] to obtain the title compound (1.03 g, yield: 98%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[C:18]([N+:28]([O-:30])=[O:29])=[C:19]([CH:25]=[CH:26][CH:27]=1)[CH:20]=[CH:21][C:22](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][CH:27]=[C:17]([O:16][CH3:15])[C:18]=3[N+:28]([O-:30])=[O:29])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: COc1cccc(C=CC(=O)O)c1[N+](=O)[O-]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(OC)c3[N+](=O)[O-])nc2n(CC)c1=O
Yield: 47 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.10 g (13.9 mmol) of 3-methoxy-2-nitrocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.28 g (yield 47%) of Compound 126 as orange needles.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C.Br[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][N:24]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)C1
Temperature: 80 °C
Yield: 26.6 %

Procedure:
To a solution of 9-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (Example 31) (260 mg, 0.62 mmol) in acetonitrile (15 ml) was added N,N-diisopropylethylamine (0.214 ml, 1.23 mmol) followed by ethyl 3-bromopropanoate (0.158 ml, 1.231 mmol). The reaction mixture was heated at 80° C. overnight. A further 1 equiv. of N,N-diisopropylethylamine and ethyl 3-bromopropanoate were added and heating continued overnight. The reaction mixture was cooled and evaporated. Purification of the residue by column chromatography, eluting with 50-65% ethyl acetate in cyclohexane to give the title compound as a yellow oil (80 mg).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:30]=[O:31])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[C:26]([F:29])([F:28])[F:27])[CH2:16][CH2:17][CH2:18][N:11]21>O1CCCC1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[C:26]([F:28])([F:27])[F:29])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:30]([OH:31])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.35 mL, 1.05 mmol) was added to a stirred solution of 9-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (400 mg, 0.966 mmol) in tetrahydrofuran (3.0 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction was quenched by water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from ethanol to give the title compound as a colorless crystal (411 mg, 0.925 mmol, 96%).