Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[CH:4][S:5][C:6]=1[N+:7]([O-:9])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[N:18]=[CH:19][S:20][CH:21]=1)CCC.O1CCOCC1>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.CN(C=O)C>[N+:7]([C:6]1[S:5][CH:4]=[C:3]([C:10]#[N:11])[C:2]=1[C:17]1[N:18]=[CH:19][S:20][CH:21]=1)([O-:9])=[O:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: N#Cc1csc([N+](=O)[O-])c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#Cc1csc([N+](=O)[O-])c1-c1cscn1
Temperature: 110 °C
Yield: 45.3 %

Procedure:
A microwave vial equipped with a stir bar was added 4-bromo-5-nitrothiophene-3-carbonitrile (0.15 g, 0.66 mmole) and tetrakis(triphenylphosphine)palladium (0) (0.077 g, 0.066 mmol) and then purged with N2 (g) inlet prior to addition of 4-(tributylstannyl)thiazole (0.42 g, 1.13 mmol), dioxane (1.2 mL) and few drops of DMF. The reaction mixture was heated at 110° C. for 30 min and then concentrated under reduced pressure. Purification by flash chromatography (silica, 50:50 ethyl acetate/hexane) gave 5-nitro-4-(thiazol-4-yl)thiophene-3-carbonitrile (71 mgs, 45%) Retention time (min)=1.656, method [4], MS (ESI) 238.0 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC([O-])(C)C.[K+].[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-])=O>CS(C)=O>[NH2:4][C:3]1[N:5]=[N:12][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:2]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1nnc2ccccc2n1
Reaction time: 0.02 h
Yield: 71.8 %

Procedure:
To a stirring mixture of guanidine hydrochloride (160 mg, 1.7 mmol) and t-BuOK (670 mg, 6 mmol) in DMSO (4 mL) was added one portion of nitrobenzene (123 mg, 1 mmol) at room temperature. The mixture turned red in one minute. In 20 to 30 minutes the mixture was quenched with a saturated, aqueous solution of ammonium chloride. A yellow precipitate was formed and removed by filtration. The precipitate was then washed with water, dried in the air, and recrystallized from benzene or ethanol to give 105 mg (72%) of 3-amino-1,2,4-benzotriazine. The melting point was determined to be 203–205° C., consistent with the melting point (207° C.) of 3-amino-1,2,4-benzotriazine synthesized by other known methods (J. Chem. Soc. (B) (1970) 911).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3[C:20]([CH3:30])=[CH:21][C:22]([CH3:29])=[C:23]([S:25](O)(=[O:27])=[O:26])[CH:24]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:33])=O>CN(C=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C:19]3[CH:24]=[C:23]([S:25]([Cl:33])(=[O:27])=[O:26])[C:22]([CH3:29])=[CH:21][C:20]=3[CH3:30])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)c(S(=O)(=O)O)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)Cl)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2,4-dimethylbenzenesulfonic acid (5 g, 11.8 mmol) in DMF (5.9 mL) was added thionyl chloride (4.3 mL, 59.0 mmol). The reaction was stirred at room temperature for three hours and then quenched by the addition of water. The colorless precipitate was then collected by filtration and dried in vacuo to afford 9H-fluoren-9-ylmethyl[5-(chlorosulfonyl)-2,4-dimethylphenyl]carbamate as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: OCc1ccc(O)c(Br)n1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(CO)nc1Br
Temperature: 25 °C
Yield: 156.8 %

Procedure:
To a solution of 2-bromo-6-(hydroxymethyl)pyridin-3-ol (2.04 g, 10 mmol) and K2CO3 (2.07 g, 15 mmol) in acetone (50 mL) was added iodomethane (1.84 g, 13 mmol) at rt. The reaction mixture was refluxed for 4 h. After that time the reaction was cooled to rt, filtered to remove solids and concentrated under reduced pressure to give (6-bromo-5-methoxypyridin-2-yl)methanol (3.42 g, >99%) as a white solid: 1H NMR (400 MHz, CDCl3): δ 7.25 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 4.70 (s, 2H), 3.93 (s, 3H), 2.78 (br s, 1H).
Reaction SMILES: [CH2:1]([C@H:7]1[C@@H:12]([OH:13])[CH2:11][C@@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27].CCOCC>CN(C=O)C>[CH2:1]([C@H:7]1[C@@H:12]([O:13][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32])[CH2:11][C@@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCCCCCC[C@@H]1C[C@H](O)[C@H](CCCCCC)C(=O)O1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCC[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CCCCCC)C(=O)O1
Reaction time: 48 h
Yield: 63.5 %

Procedure:
M)d) 1.5 g of (3S,4S,6R)-tetrahydro-3-hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one were dissolved in 8 ml of DMF. 0.85 g of t-butyldimethylchlorosilane in 4 ml of DMF were then added dropwise. The mixture was stirred for 48 hours. The reaction mixture was poured in to 100 ml of ether and washed with 1N hydrochloric acid. The organic phase was dried, filtered and evaporated. The material obtained was chromatographed on silica gel. There were obtained 1.26 g of (3S,4S,6R)-tetrahydro-3-hexyl-4-[(t-butyldimethylsilyl)oxy]-6-undecyl-2H-pyran-2-one, MS: 411 (M+ -t-butyl).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: Cc1cnc2ccccc2c1
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cnc2c(S(=O)(=O)Cl)cccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.3 %

Procedure:
To 9.0 mL (135 mmol, Fisher) of chlorosulfonic acid was added dropwise with stirring at room temperature 5.00 g (35.0 mmol, Lancaster) of 3-methyl-quinoline over ~5 minutes. The addition was exothermic. The resulting dark solution was heated to 140°-145°, stirring for 5 h, then cooled to 125°. To the cooled reaction mixture was added dropwise over 15 rain 3.3 mL (45 mmol, Mallinckrodt) of thionyl chloride, and the reaction mixture was then heated to 1400 for 1 h. The reaction mixture was cooled to room temperature, then cooled in an ice-bath and added slowly to 50 g of ice. Chloroform (50 mL) was added to the resulting slurry and stirred until the ice melted to give two layers. The aqueous layer was separated and extracted with 30 mL of chloroform. The chloroform layers were combined, washed with two-50 mL portions of 5% aqueous sodium bicarbonate solution, 50 mL of water, dried (sodium sulfate) and concentrated in vacuo to give 4.6 g of a crude light brown solid. The crude material was recrystallized (~20 mL toluene), and the crystals were washed with hexane and dried in vacuo to afford 2.89 g (12.0 mmol, 34%) of title compound as small pale brown crystals, mp 158°-159°.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].OC1C=CC(C[CH2:20][C:21]([O:23][CH3:24])=O)=CC=1>>[O:23]1[CH2:24][CH:21]1[CH2:20][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1O
Product: COC(=O)c1ccccc1OCC1CO1

Procedure:
The procedure of Example VII for producing methyl 3-[4-(2,3-epoxypropoxy)phenyl]propionate was repeated in all essential details, except methyl salicylate was substituted for methyl 3-(4-hydroxyphenyl)propionate. The boiling point of the product was 148° (p=75μ). The NMR spectrum was consistent with the assigned structure and the elemental analysis with the formula C11H12O4.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C@@H:7]2[CH2:9][C@H:8]2[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[CH3:20][O:21][NH2:22]>CO>[CH3:20][O:21][N:22]=[C:10]([C@@H:8]1[CH2:9][C@H:7]1[C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CC(=O)[C@@H]1C[C@H]1c1ccc(Cl)s1
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C(C)[C@@H]1C[C@H]1c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.1 %

Procedure:
To a stirred solution of trans 1-[2-(5-chloro-thiophen-2-yl)-cyclopropyl]-ethanone (1.0 g; 5.0 mmol) in methanol (10 ml) at ambient temperature was added pyridine (0.85 ml; 10.3 mmol) and methoxyamine hydrochloride (0.86 g; 10.3 mmol). The reaction mixture was stirred for 20 hours at ambient temperature then poured on water (50 ml) and extracted with dichloromethane (3×20 ml). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was removed in vacuo to afford 1.0 g (92% of theory) of trans 1-[2-(5-Chloro-thiophen-2-yl)-cyclopropyl]-ethanone O-methyl-oxime as an E/Z mixture in form of a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[CH2:10][C:11]1[NH:15][C:14]2[CH2:16][CH:17]([CH3:21])[CH:18]([CH3:20])[CH2:19][C:13]=2[N:12]=1.[C:23](O)(=[O:26])[C:24]#[CH:25].N1(C(N2C=CN=C2)=O)C=CN=C1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:10]1[CH:25]=[CH:24][C:23](=[O:26])[N:15]2[C:14]3[CH2:16][CH:17]([CH3:21])[CH:18]([CH3:20])[CH2:19][C:13]=3[NH:12][C:11]=12)=[O:22]
Reactant: CC1Cc2nc(CC(=O)c3ccc(F)cc3F)[nH]c2CC1C
Reactant: C#CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC1Cc2[nH]c3c(C(=O)c4ccc(F)cc4F)ccc(=O)n3c2CC1C

Procedure:
The compounds are prepared as described in example 15 with 200 mg (0.66 mmol) of 1-(2,4-Difluorophenyl)-2-(5,6-dimethyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example XV), 69 mg (0.99 mmol) of propiolic acid and 192 mg (1.18 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][C@@H:19]([NH2:22])[CH2:18]2)=[CH:13][CH:12]=1)([O-:10])=[O:9].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:3](=[O:5])[CH3:2])[CH2:18]2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Yield: 84.2 %

Procedure:
(3R)-1-(4-Nitrophenyl)pyrrolidin-3-amine trifluoroacetate salt (Method 41; 0.96 g, 3 mmol) and sodium acetate (0.245 g, 3 mmol) in acetic acid (10 ml) were reacted with acetic anhydride (0.57 ml, 6 mmol) for 18 hours at room temperature. After filtration and washing with ether gave the title compound as a yellow solid (0.63 g, 84%). NMR: 1.79 (s, 3H), 1.85-1.98 (m, 1H), 2.09-2.23 (m, 1H), 3.19-3.30 (m, 1H), 3.39-3.52 (m, 2H), 3.55-3.67 (m, 1H), 4.30-4.43 (m, 1H), 6.60 (d, 2H), 8.04 (d, 2H), 8.15 (d, 1H); m/z 250.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([S:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][C:18](O)=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:39][NH2:40]>CN(C)C=O.ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([S:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][C:18]([NH:40][OH:39])=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(SC(CCCCc2ccccc2)CC(=O)O)cc1OC1CCCC1
Reactant: C[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(SC(CCCCc2ccccc2)CC(=O)NO)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of (±)-3-(3-cyclopentyloxy-4-methoxyphenyl)sulfanyl-7-phenylheptanoic acid (0.40 g, Example 4) in a mixture of dimethylformamide (0.07 ml) and dichloromethane (20 ml) was treated dropwise with a solution of oxalyl chloride in dichloromethane (1.17 ml, 2.0 M). After stirring at room temperature for a further 30 minutes the mixture was treated dropwise with O-(trimethylsilyl)hydroxylamine (0.57 ml). The resulting white suspension was stirred for 10 minutes then partitioned between hydrochloric acid (50 ml, 1N) and ethyl acetate (50 ml). The aqueous layer was extracted twice with ethyl acetate (50 ml). The combined organic phases were washed with water (50 ml), then with brine (50 ml), then dried over magnesium sulphate and then evaporated to give the title compound (0.26 g) as a white foam. NMR (CDCl3): δ1.60 (m,8H), 1.86 (m,6H), 2.35 (br d,2H), 2.60 (br t,2H), 3.30 (m,1H), 3.80 (s,3H), 3.73 (m,1H), 6.76 (d,1H), 6.95 (d,2H), 7.10-7.30 (m,5H). Mass spectrum (FAB): m/z 444 (M+H)+.
Reaction SMILES: [CH2:1]=[C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]1=[O:9].[I-].[I-].[CH4:12]>C(OCC)C.[Zn]>[C:2]12([C:3](=[O:9])[CH:4]3[CH2:8][CH:7]1[CH2:6][CH2:5]3)[CH2:12][CH2:1]2
Reactant: C=C1C(=O)C2CCC1C2
Reactant: C
Agent: [I-]
Agent: [Zn]
Solvent: CCOCC
Product: O=C1C2CCC(C2)C12CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Zinc powder (15.10 g) was suspended in diethyl ether (70 mL) and to which cuprous chloride (2.29 g) was added at room temperature, followed by 30 minutes' refluxing in nitrogen atmosphere. The suspension was cooled to 0° C. and to which 3-methylenebicyclo[2.2.1]heptan-2-one (7.0 mL) was added at 0° C. Into the reaction mixture, methane diiodide (7.0 mL) was slowly dropped at 0° C. and after the end of the dropping, the reaction mixture was refluxed for 30 hours in nitrogen atmosphere. Cooling the reaction mixture to room temperature, the insoluble matter was filtered off with Celite® and the filterate washed twice with 5% aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by distillation, and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate=100/1−7/1) to provide 4.89 g of the title compound as a colorless oily substance.
Reaction SMILES: [CH:1]([Si:4]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[C:5]1[S:6][C:7]2[CH:12]([CH2:13][OH:14])[CH2:11][O:10][C:8]=2[N:9]=1)([CH3:3])[CH3:2].[O-:21]Cl=O.[Na+]>C(Cl)Cl.O>[CH:18]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:15]([CH3:17])[CH3:16])[C:5]1[S:6][C:7]2[CH:12]([C:13]([OH:21])=[O:14])[CH2:11][O:10][C:8]=2[N:9]=1)([CH3:20])[CH3:19]
Reactant: CC(C)[Si](c1nc2c(s1)C(CO)CO2)(C(C)C)C(C)C
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)[Si](c1nc2c(s1)C(C(=O)O)CO2)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A soln. of (2-(triisopropylsilyl)-5,6-dihydrofuro[2,3-d]thiazol-6-yl)methanol (1.77 g, 5.64 mmol)) in DCM (56 mL) was treated at 0° C. with DMP (2.87 g, 6.77 mmol) portionwise over 1 h. The mixture was stirred at 0° C. for 2 h, then, it was allowed to warm to RT and stirred for 2 h. Subsequently, the mixture was quenched with aq. sat. Na2S2O3 and aq. sat. NaHCO3 and was extracted with DCM. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. The residue was dissolved in tert-BuOH (16 mL) and 2-methyl-2-butene (4 mL) and treated at 0° C. dropwise over 30 min with a soln. of NaH2PO4 (2.64 g, 16.9 mmol) and NaClO2 (0.96 g, 8.46 mmol) in H2O (5 mL). The mixture was stirred at RT for 45 min, then, the volatiles were removed in vacuo, the residue was diluted with H2O and extracted with EtOAc. The comb. org. layers were dried over MgSO4 and conc. in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27](=[O:52])[O:28][C@H:29]([CH3:51])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3C4C=CC(C(=O)C)=CC=4N=[C:38]3[CH2:49][CH3:50])=[CH:33][CH:32]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27](=[O:52])[O:28][C@H:29]([CH3:51])[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([N:37]3[C:6]4[CH:7]=[C:2]([Cl:1])[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]=4[N:9]=[C:38]3[CH2:49][CH3:50])=[CH:35][CH:36]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CCc1nc2cc(C(C)=O)ccc2n1-c1ccc(C[C@@H](C)OC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(C[C@@H](C)OC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 2,4-dichloro-5-nitrobenzotrifluoride and (2R)-1-(4-aminophenyl)-2-propanol (step 2 of Example 249).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[CH2:34]([N:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O>[CH2:34]([N:41]1[CH2:46][CH2:45][CH:44]([NH:47][C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[CH:8]=2)=[O:14])[CH2:43][CH2:42]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a stirred mixture of 6-hydroxy-2-napthoic acid (100 mg, 0.531 mmol) in anhydrous dimethylormamide (5 mL) was added triethylamine (163 μl, 1.168 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (112 mg, 0.584 mmol), and 1-benzyl-piperidine-4-amine (100 μl, 0.531 mmol). The mixture was allowed to stir at room temperature overnight, then poured into water. The resulting solids were collected by filtration and purified by column chromatography to yield N-(1-benzylpiperidin-4-yl)-6-hydroxy-2-naphthamide as a light brown solid (0.191 g, 80%).
Reaction SMILES: O=O.[K+].Br[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10].C1OCCOCCOCCOCCOCC[O:23]C1.O>CS(C)=O>[OH:23][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: O=C(CCCCBr)N1CCCc2ccccc21
Agent: O=O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(CCCCO)N1CCCc2ccccc21

Procedure:
Potassium superoxide (0.50 g) was added to a solution of 1-(5-bromopentanoyl)-1,2,3,4-tetrahydroquinoline (1.8 g) and 18-Crown-6 (0.4 g) in dimethylsulfoxide (25 ml). After 8 hours the solution was added to water and extracted with ether. The extract was washed, dried and evaporated and the residue was chromatographed on silica gel, eluting with 95:5 methylene chloride:methanol, to yield 1-(5-hydroxypentanoyl)-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O>[Br:1][C:2]1[C:9]([O:10][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(Br)c1O
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOc1c(OC)ccc(C=O)c1Br
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
2-Bromo-3-hydroxy-4-methoxybenzaldehyde (225.2 g, 975 mmol) and DMF (660 ml) were mixed, and potassium carbonate (148.2 g, 1.07 mol) and bromopentane (133 ml, 1.07 mol) were successively added to this solution. The mixture was stirred at 90° C. for 1.5 hours and cooled to room temperature. Water (800 ml) was added to stop the reaction. The aqueous layer was extracted successively with diethyl ether (1000 ml, 500 ml) and ethyl acetate (500 ml). The organic layers were combined, washed successively with water (200 ml) and saturated brine (200 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of 2-bromo4-methoxy-3-pentyloxybenzaldehyde.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:10]([CH:11]=[O:12])=[C:9]([C:13]([F:16])([F:15])[F:14])[N:8]=[CH:7][N:6]=1.O>CO>[CH3:3][O:4][C:5]1[C:10]([CH2:11][OH:12])=[C:9]([C:13]([F:15])([F:14])[F:16])[N:8]=[CH:7][N:6]=1
Reactant: COc1ncnc(C(F)(F)F)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ncnc(C(F)(F)F)c1CO
Reaction time: 3 h
Yield: 32 %

Procedure:
0.24 g (6.3 mmoles) of sodium borohydride was gradually added, at room temperature, to a solution of 1.3 g (6.3 mmoles) of 4-methoxy-6-trifluoromethylpyrimidine-5-carboaldehyde dissolved in 30 ml of methanol. The mixture was stirred for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 0.42 g (yield: 32.1%) of (4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methanol
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:16]2[C:17](=[O:23])[NH:18][C:19]3=[CH:20][CH:21]=[CH:22][C:14](=[C:15]23)[O:13][CH2:12]1)[CH3:10]>C(#N)C.C(O)(=O)C>[Br:1][C:22]1[C:14]2[O:13][CH2:12][C:11]([CH2:9][CH3:10])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:16]3[C:17](=[O:23])[NH:18][C:19]([C:15]=23)=[CH:20][CH:21]=1
Reactant: CCC1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: CC#N
Product: CCC1(c2ccccn2)COc2c(Br)ccc3[nH]c(=O)n1c23
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
N-Bromosuccinimide (70 mg, 0.4 mmol) was added to a solution of 4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (80 mg, 0.4 mmol) in acetonitrile (5 mL) and acetic acid (10 mL) cooled to 0° C. The reaction was stirred for 30 min, was concentrated to remove residual acetic acid, and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 7-bromo-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (0.07 g. 80%). LCMS calculated for C16H15BrN3O2 (M+H)+: m/z=360.1, 362.1. found: 359.8, 361.8.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH3:10]C(C)=O>>[CH3:10][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9]
Reactant: CC(C)=O
Reactant: O=c1ncc(Cl)c[nH]1
Agent: [K]
Product: Cn1cc(Cl)cnc1=O
Yield: 50 %

Procedure:
1-Methyl-5-chloropyrimid-2-one was prepared as above from the potassium salt of 5-chloropyrimid-2-one (prepared as described in Crosby, G. D. and Berthold, V. R. J. Org. Chem. 25 (1960) 1916) in 50% yield, m.p. 210° C. (acetone). (Found: C, 41.61; H, 3.65; Calc. for C5H5ClN2O: C, 41.54; H, 3.48)