Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21]C)=O)[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1[CH:27]=[CH:26]N=C1.OC1C=CC2C3C(=CC=CC=3)C(=O)C=2C=1.[Si](Cl)(C(C)(C)C)(C)C>CN(C=O)C>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:16]2[C:15]3[C:14](=[CH:13][CH:12]=[CH:26][CH:27]=3)[C:19](=[O:21])[C:17]=2[CH:18]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: O=C1c2ccccc2-c2ccc(O)cc21
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)C(=O)c1ccccc1-2
Yield: 84 %

Procedure:
The procedure for this reaction was the same as described above for methyl 6-tert-butyldimethylsilyloxy-2-naphthoate. A solution of imidazole (0.5 g, 7.4 mmol) in 2 mL of dry DMF was added to a solution of 2-hydroxy-9-fluorenone (Aldrich, 0.55 g, 2.8 mmol) and tert-butyldimethylsilyl chloride (0.5 g, 3.3 mmol) in 5 ML of dry DMF to give after workup 0.74 g (84%) of a yellow oil: 1H NMR (CDCl3) delta 7.612-6.891 (m, 7H), 0.994 (s, 9H), 0.224 (s, 6H); 13C NMR (CDCl3 delta 193.69, 157.04, 144.87, 137.52, 136.04, 134.73, 134.50, 127.92, 125.59, 124.28, 121.24, 119.56, 116.22, 25.60, 18.18, -4.46. ##STR34##
Reaction SMILES: P(Cl)(Cl)[Cl:2].[CH2:5]([O:7][P:8]([O:12]CC)[O:9][CH2:10][CH3:11])[CH3:6].C(OP(Cl)Cl)C.P(Cl)(OCC)OCC>>[Cl-:2].[CH2:5]([O:7][P:8]([OH:12])[O:9][CH2:10][CH3:11])[CH3:6]
Reactant: ClP(Cl)Cl
Reactant: CCOP(OCC)OCC
Agent: CCOP(Cl)Cl
Agent: CCOP(Cl)OCC
Product: CCOP(O)OCC
Product: [Cl-]

Procedure:
68.7 g (0.5 mol) of phosphorustrichloride and 166 g (1 mol) of triethylphosphite, in which 2 grams of tris-2-ethylhexyl-phosphineoxide were dissolved, were simultaneously added dropwise into a flask within 30 minutes and mixed together by stirring while cooling at 48° to 52° C. At the end of the mixing process, the colorless slightly cloudy solution had the following composition: 6% C2H5OPCl2 ; 85% (C2H5O)2PCl; 5% (C2H5O)3P. In order to obtain pure phosphorous acid-diethyl ester-chloride, the high boiling constituents were first separated off at 10mm Hg and at a head temperature of 38° to 50° C. in a rapid distillation and the distillate was subsequently subjected to fine distillation. The product obtained at 33mm Hg and a head temperature of 60° to 62° C. was of 96% priority and its H-NMR agreed with the expected structure.
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[CH:8]=[C:9]([CH2:11][CH2:12][NH2:13])[N:10]=1)[CH2:3][CH2:4][CH3:5].O.[C:33]([OH:37])(=[O:36])[CH:34]=O.[OH-].[Na+].Cl.O1CCOC[CH2:42]1>>[CH2:2]([C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]2[CH:34]([C:33]([O:37][CH3:42])=[O:36])[NH:13][CH2:12][CH2:11][C:9]=2[N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1nc(CCN)cn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: C1COCCO1
Reactant: O=CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)NCC2
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of 2-n-butyl-4-(2-aminoethyl)-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole hydrochloride (8.09 g), glyoxylic acid hydrate (1.73 g), 1N aqueous sodium hydroxide solution (53 ml) and dioxane (50 ml) is stirred at 50° C. for two days. The reaction solution is acidified with hydrochloric acid, and evaporated under reduced pressure. The residue is dissolved in methanol (100 ml), and the mixture is cooled to -30° C., and thereto is added dropwise thionyl chloride (12.4 g). After addition, the mixture is stirred at 60° C. for two days. The mixture is evaporated under reduced pressure to remove the solvent. The mixture is neutralized with aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The extract is dried, and evaporated under reduced pressure, and the resulting oily product is purified by silica gel column chromatography (solvent; chloroform/methanol=15:1) to give methyl 2-n-butyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5,c]pyridine-4 -carboxylate (3.74 g) as a powder.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[ClH:21]>C(#N)C.C(Cl)Cl.[Cu](Cl)Cl>[Cl:21][C:9]1[S:10][C:11]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Cl
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Combine tert-butyl nitrite, (35 mL, 292 mmol, technical 90%) and copper (II) chloride (31.7 g, 236 mmol) in acetonitrile (400 mL) and warm to 65° C. under nitrogen for 1 hour. Slowly add 2-amino-6-nitrobenzthiazole (41.7 g, 214 mmol) over 15 min. Continue to stir at 65° C. for 30 min. Cool to room temperature, dilute with CH2Cl2, and add 0.1 N HCl to precipitate the product. Filter and dry in a vacuum oven overnight to afford 2-chloro-6-nitrobenzthiazole (35.1 g, 77%). 1H NMR (400 MHz, DMSO-d6): δ 9.18 (d, 1H, J=2.2 Hz), 8.37 (dd, 1H, J=9.0, 2.4 Hz), 8.18 (d, 1H, J=8.8 Hz).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[S:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)(Cl)Cl>[C:1]1([CH2:7][CH2:8][N:9]2[S:10](=[O:23])[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CCN2Sc3ccccc3S2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S1c2ccccc2SN1CCc1ccccc1
Temperature: 0 °C
Yield: 70.6 %

Procedure:
To a solution of 2-(2-phenylethyl)-1,3,2-benzodithiazole (0.538 g, 2.08 mmol), from Step 2, in 30 mL of chloroform at -20° C., was added portionwise 56% meta-chloroperoxybenzoic acid (mCPBA) (0.64 g, 2 mmol). The reaction mixture was allowed to warm to 0° C. over a 2 hour period and then the reaction was quenched at 10° C. with 20 mL of 1M aqueous sodium bicarbonate solution. The organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with chloroform (CHCl3) to give 389 mg (65.7% yield) of the title compound. Analysis calculated for C14H13NOS2 : C, 61.08; H, 4.76; N, 5.09. Found: C, 60.92; H, 4.75; N, 5.04.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[H-].[Na+].Cl.Cl[CH2:16][CH2:17][NH2:18]>O1CCCC1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:16][CH2:17][NH2:18]
Reactant: NCCCl
Reactant: Oc1ccccc1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCCOc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add 5.0 g (30.9 mmol) of 2-trifluoromethylphenol to a 0° C. suspension of 2.72 g (67.9 mmol, 2.2 eq, 60% by wt. in mineral oil) of sodium hydride in 100 mL of dry tetrahydrofuran. Once the 2-trifluoromethylphenol is dissolved add 7.88 g (67.9 mmol, 2.2 eq) of 2-chloroethylamine hydrochloride and stir at room temperature for 18 hr. Concentrate the reaction mixture and partition between 200 mL of methylene chloride and 50 mL water. Dry the organic layer over Na2SO4 and concentrate in vacuo to obtain the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.O=P(Cl)(Cl)[Cl:9].O[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>>[Cl:9][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnccc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnccc1Cl
Temperature: 140 °C
Yield: 76 %

Procedure:
In a reaction flask under nitrogen, were reacted at 70° C., 51.5 g of PCl5 and 75 ml of POCl3. At the same temperature was added carefully 34.6 g of (8). The temperature was increased to 140° C. and the reaction refluxed for 4 hours under nitrogen. To the cooled mixture, evaporated under vacuum, was added 100 ml of iced water. The pH was adjusted to 7.5 by the addition of granular sodium carbonate, and 60 ml of methylene chloride added and the mixture stirred vigorously until all the residue had completely dissolved. The phases were separated and the aqueous part was extracted with more methylene chloride (5×30 ml). The combined organic phases were treated with anhydrous sodium sulphate and evaporated to obtain 29.9 g of (9) as a yellow, waxy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[C:8](=[O:11])[C:7]1[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[CH:15][C:6]=1[O:5]2.[CH3:21][N:22]([CH3:27])[S:23](Cl)(=[O:25])=[O:24]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:21][N:22]([CH3:27])[S:23](=[O:25])(=[O:24])[O:16][C:14]1[C:13]([CH2:17][CH2:18][CH3:19])=[C:12]([OH:20])[C:7]2[C:8](=[O:11])[N:9]3[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:5][C:6]=2[CH:15]=1
Reactant: CCCc1c(O)cc2oc3cc(Cl)cn3c(=O)c2c1O
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(OS(=O)(=O)N(C)C)cc2oc3cc(Cl)cn3c(=O)c2c1O
Temperature: 85 °C
Yield: 71.1 %

Procedure:
To 80 mg (0.27 mmol) of 2-chloro-6,8-dihydroxy-7-propyl-9H-pyrrolo [2,1-b][1,3]benzoxazin-9-one in 3 mL of toluene was added 0.3 mL (2.77 mmol) of dimethylsulfamylchloride and 0.066 g (0.54 mmol) of 4-dimethylaminopyridine (DMAP). The mixture was heated to 85° C. for 2 hr. It was cooled, diluted with ethyl acetate and extracted two times with 1N HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative TLC (hexane: CH2Cl2 ; 1:1) to give 77 mg of the title compound mp 159-160° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:32][CH2:33]O)[CH:29]=2)[CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:28]2[CH:29]=[C:30]3[C:25]([CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:26][CH:27]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1ccc2cccnc2c1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3cccnc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.267 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.305 g), stirred for 15 minutes and treated with the mesylate prepared from 1.135 g of 2-(7quinolyloxy)ethanol. The mixture was heated under argon at 60° C. for 5 hours. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with dichloromethane and dilute cold sodium bicarbonate solution. The dichloromethane extracts were washed with water, dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate) and crystallized from dichloromethane-hexane to provide 0.93 g of alpha-oxo-4-[[2-(7-quinolyloxy)ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 92°-94° C.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH3:15])[C:11]2=O)=[C:7]([C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=2)[C:6]=1[O:30][CH3:31])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:13]=[C:12]2[C:8](=[C:7]([C:16]3[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=3)[C:6]=1[O:30][CH3:31])[CH2:9][C:10]([CH3:15])=[CH:11]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1cc(C(C)(C)C)cc(C(C)(C)C)c1)CC(C)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1c(C(C)(C)C)cc2c(c1-c1cc(C(C)(C)C)cc(C(C)(C)C)c1)CC(C)=C2
Temperature: 5 °C
Reaction time: 7 h
Yield: 100 %

Procedure:
To a solution of 16.3 g (38.8 mmol) of 6-tert-butyl-4-(3,5-di-tert-butylphenyl)-5-methoxy-2-methylindan-1-one in 200 ml of THF cooled to 5° C. 1.47 g (38.9 mmol) of NaBH4 was added. Further on, 80 ml of methanol was added dropwise to this mixture by vigorous stirring for ca. 7 h at 5° C. The resulting mixture was evaporated to dryness, and the residue was treated by 300 ml of dichloromethane and 300 ml of 2 M HCl. The organic layer was separated, the aqueous layer was additionally extracted with 100 ml of dichloromethane. The combined organic extract was evaporated to dryness to give a colorless oil. To a solution of this oil in 250 ml of toluene 0.1 g of TsOH was added, this mixture was refluxed with Dean-Stark head for 15 min and then cooled to room temperature using water bath. The resulting solution was washed by 10% aqueous Na2CO3. The organic layer was separated, the aqueous layer was extracted with 2×50 ml of dichloromethane. The combined organic extract was dried over K2CO3 and then passed through a short layer of silica gel 60 (40-63 um). The silica gel layer was additionally washed by 100 ml of dichloromethane. The combined organic elute was evaporated to dryness to give 15.7 g (99%) of a white crystalline product which was further used without an additional purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[Si:11]([O:28][CH2:29][CH2:30][CH:31]=O)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Si:11]([O:28][CH2:29][CH2:30]/[CH:31]=[N:10]/[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=1)([C:24]([CH3:25])([CH3:26])[CH3:27])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](OCCC=O)(c1ccccc1)c1ccccc1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCC/C=N/Nc1cccc(Cl)c1)(c1ccccc1)c1ccccc1

Procedure:
A solution of (3-chlorophenyl)hydrazine hydrochloride and TEA (3 mL, 21.5 mmol) and 3-(tert-butyldiphenylsilyloxy)propanal (21.5 mmol) in toluene was stirred at rt overnight. The reaction mixture was then quenched with H2O (100 mL) and extracted with EtOAc (2×). The organic layers were dried (MgSO4) and evaporated to a reddish oil. The crude product was then purified using silica gel chromatography. The desired product was isolated as a red oil. MS(ESI) m/z: 437.1 (M-Boc)+. 1H NMR (400 MHz, CDCl3) δ 7.84-7.59 (m, 4H), 7.50-7.29 (m, 6H), 7.18-6.90 (m, 1H), 6.77 (dt, J=8.1, 2.0 Hz, 1H), 3.98-3.68 (m, 2H), 2.63-2.38 (m, 2H), 1.12-0.90 (m, 9H) ppm.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH2:6])=[S:5].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].[CH2:19]=O>CO>[CH2:14]([N:16]([CH2:19][NH:6][C:4](=[S:5])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH:2]([CH3:13])[CH3:1])[CH2:17][CH3:18])[CH3:15]
Reactant: CC(C)C(C(N)=S)c1ccccn1
Reactant: CCNCC
Reactant: C=O
Solvent: CO
Product: CCN(CC)CNC(=S)C(c1ccccn1)C(C)C
Reaction time: 48 h

Procedure:
A solution of 1.94 g. (0.01 mole) of 3-methyl-2-(2-pyridyl)thiobutanamide in 40 ml. of methanol is treated with 1.1 g. (0.015 mole) of diethylamine and 0.45 g. of formaldehyde. The mixture is kept for 48 hours at 25°C., then at 0°C. for 48 hours. The solvent is evaporated and the residue is dissolved in chloroform and washed with water. The solution is dried and the solvent is evaporated off. The residue is vacuum dried at 0.005 mm. and 25°C. for 6 hours to give N-diethylaminomethyl-3-methyl-2-(2-pyridyl)thiobutanamide
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.N1([C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=2)CCCC1.CN(C)C=[O:26]>O>[OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:17]2=[O:26])=[CH:4][CH:3]=1
Reactant: C1=C(N2CCCC2)CCCC1
Reactant: CN(C)C=O
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: O
Product: O=C(CC1CCCCC1=O)c1ccc(O)cc1

Procedure:
43 g (0.2 mole) of (p-hydroxyphenacyl bromide) are added dropwise during 1/2 hour to a cooled (25° C) solution of 30 g (0.2 mole) of 1-pyrrolidino-1-cyclohexene in dimethylformamide. After 51/2 hours, the solution is diluted with water and extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulfate and concentrated to an oil. Distillation gives a liquid which solidifies to give 2-(p-hydroxyphenacyl) cyclohexanone, m.p. 120°-125° C.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[S:3].[CH3:16][C:17]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)([CH3:20])[C:18]#N.C[OH:30].Cl>CN(C=O)C.O>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([N:21]2[C:17]([CH3:16])([CH3:20])[C:18](=[O:30])[N:1]([C:4]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:13])([F:15])[F:14])[CH:5]=3)[C:2]2=[S:3])=[CH:23][CH:24]=1
Reactant: Cc1ccc(NC(C)(C)C#N)cc1
Reactant: CO
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 1a (0.547 g, 2.4 mmol) and 5a (0.348 g, 2 mmol) in dry DMF (0.6 ml) was stirred for 36 h. To this mixture were added methanol (20 ml) and 2N HCl (5 ml). The second mixture was refluxed for 6 h. After being cooled to room temperature, the reaction mixture was poured into cold water (30 ml) and extracted with ethyl acetate (40 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane) to yield 4-[3-(4-methylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-trifluoromethyl-benzonitrile, 5c, [RD7] (0.596 g, 1.48 mmol, 74%) as a white powder.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C([O:8][C:9](=[O:21])[C:10]1[CH:20]=[C:17]([O:18][CH3:19])[C:15]([OH:16])=[C:12]([O:13][CH3:14])[CH:11]=1)(=O)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:16][C:15]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:9]([OH:8])=[O:21])=[C:20]([N+:1]([O-:4])=[O:2])[C:17]=1[O:18][CH3:19])(=[O:24])[CH3:23]
Reactant: COc1cc(C(=O)OC(C)=O)cc(OC)c1O
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])O
Product: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Fuming nitric acid (5.2 mL) was added, carefully, to a solution of o-acetylsyringic acid 82 (11.1 g, 46.2 mmol) in acetic anhydride (33 g, mmol) at 5° C. and the reaction mixture was then allowed to stir for 3 hours at room temperature. The reaction mixture was poured over ice (300 mL) and the yellow precipitate was collected by filtration, washed with water (3×100 mL) and dried in vacuo to afford the product as a pale yellow solid (12.4 g). H1 NMR (270 MHz, CDCl3) δ7.37 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: O[CH:2]1[CH2:7]SC(O)C[S:3]1.[C:9]([CH2:11][C:12]([NH2:14])=[O:13])#[N:10]>C(O)C.C(N(CC)CC)C>[NH2:10][C:9]1[S:3][CH:2]=[CH:7][C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: N#CCC(N)=O
Reactant: OC1CSC(O)CS1
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=O)c1ccsc1N
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
To a solution of 2,5-dihydroxy-1,4-dithiane (10 g, 65.78 mmol) in ethanol (200 mL) and triethylamine (2 mL) was added cyanoacetamide (5.52 g, 65.78 mmol) at rt for 5 min. The reaction mixture was refluxed for 3 h and attained to rt. Ethanol (appr. 150 mL) was removed under reduced pressure and poured the contents into ice cold water and stirred for 15 min. The solution was extracted with ethyl acetate (3×100 mL) and the combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product as a pale yellow color solid (4.9 g, 53%), mp 150-152° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][N+:12]#[C-:13].C(=O)([O-])[O-:15].[Ca+2].Cl>CC(C)=O.O>[CH3:13][NH:12][C:11](=[O:15])[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])=[O:5]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: [C-]#[N+]C
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Ca+2]
Solvent: O
Solvent: CC(C)=O
Product: CNC(=O)C(=O)c1ccccc1C
Temperature: 60 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
A mixture of 2-methylbenzoyl chloride (1.55 g) and methyl isocyanide (492 mg) was stirred at 60° C. for 6 hours. Then, the mixture was diluted with acetone (20 ml), and water (4 ml) and calcium carbonate (1.00 g) were added. The stirring of the resulting mixture was continued for 1 hour. The mixture was neutralized with dilute hydrochloric acid and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with hexane-ethyl acetate (5:1) to obtain the title compound (1.71 g, Yield: 96.6%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:13].[Na+].Cl>>[Cl:1][C:2]1[NH:10][C:9](=[O:13])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cc(F)c(=O)[nH]c1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
A mixture of 2,6-dichloro-5-fluoronicotinic acid (15.00 g, 71.43 mmol, Lancaster Synthesis) and 2 N NaOH (178.6 ml, 357.2 mmol) was stirred at reflux for 2 hours and then at room temperature for 16 hours. The reaction mixture was cooled to 0° C. and acidified with 12 N HCl (32.74 ml, 392.9 mmol). The mixture was cooled for 30 minutes in an ice bath, the solid filtered and washed with H2O. The isolated solid was slurried in warm EtOH, filtered and then washed with warm EtOH. The solids were collected and dried under vacuum overnight to yield the desired product (6.4 g, 47%) as a beige solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([N:10]1[C:15](=[O:16])[CH:14]2[CH2:17][CH:11]1[CH2:12][CH2:13]2)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(O)(=O)C>CO>[C:3]([NH:10][C@@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:15][OH:16])[CH2:17]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2CCC1C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CO)C1

Procedure:
2.7 g (0.0714 mol) of sodium borohydride are added in portions to a solution of 3.8 g (0.018 mol)of N-BOC-2-azabicyclo[2.2.1 ]heptan3-one in 125 ml of methanol in the course of 20 minutes, while stirring and cooling in an ice-bath. The reaction mixture is further stirred at 0° C. for 1 hour and at room temperature for 1 hour, a solution of 4.08 ml (0.0714 mol) of acetic acid in 8 ml of methanol is then added dropwise and the mixture is evaporated to dryness in vacuo. The crystalline residue is partitioned between methylene chloride and water. After the organic phase has been washed with brine, dried over sodium sulfate and evaporated in vacuo, the title compound is obtained as crystalline residue, m.p. 73°-74° C.