Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH3:2].[Br:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:8][C:5]=1[CH:6]=[O:7].[NH4+].[Cl-]>CCOCC>[Br:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:8][C:5]=1[CH:6]([OH:7])[CH3:2]
Reactant: CI
Reactant: COc1cc(Br)c(C=O)cc1OC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cc(Br)c(C(C)O)cc1OC(C)C
Temperature: 0 °C
Yield: 99.2 %

Procedure:
A mixture of Mg turnings (231 mg, 9.51 g·atom) in dry Et2O (3.0 mL) was stirred at 0° C. under a nitrogen atmosphere then treated, dropwise, with a solution of iodomethane (680 μL, 10.9 mmol) in dry Et2O (2.0 mL). After 0.5 h a solution of aldehyde 36 (1.00 g, 3.66 mmol) in dry Et2O (10 mL) was added, dropwise, to the reaction mixture that was then allowed to warm to 18° C. at which temperature it was stirred for a further 1 h. After this time NH4Cl (15 mL of a 20% w/v aqueous solution) then Et2O (20 mL) were added to the reaction mixture. The separated organic phase was washed with H2O (1×20 mL) then dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound 37 (1.05 g, 99%) as an orange oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:15])[CH2:11][N:12]([CH3:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].CS(O[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=O)=O>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH:10]([O:15][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:11][N:12]([CH3:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C)CC(O)CO[Si](C)(C)C(C)(C)C
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC(CO[Si](C)(C)C(C)(C)C)CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5.3 %

Procedure:
A toluene (10 mL) solution of crude 1-(tert-butyldimethylsilyloxy)-3-(dimethylamino)propan-2-ol (1.0 g, 4.29 mmol, 1.0 equiv) was carefully added dropwise to a toluene suspension (5 mL) of NaH (60%, 0.17 g, 4.29 mmol, 1.0 equiv) at 0° C. under argon and the resultant was stirred for 15 minutes. A toluene solution (5 mL) of linoleyl methanesulfonate (1.47 g, 4.29 mmol, 1.0 equiv) was added dropwise to the stirring mixture and the reaction was then stirred for 18 hours at 90° C. The mixture was then cooled to room temperature and quenched by the slow addition of ethanol (10 mL). The mixture was then concentrated and the residue was taken up with deionized water (15 mL) and extracted three times with EtOAc (20 mL). The combined organic extracts were washed with deionized water (15 mL), dried (MgSO4), filtered, and concentrated. Chromatographic purification of the residue (0-5% MeOH in chloroform) yielded 109 mg (53% yield) of 3-(tert-butyldimethylsilyloxy)-N,N-dimethyl-2-((9Z,12Z)-octadeca-9,12-dienyloxy)propan-1-amine, a thick clear oil.
Reaction SMILES: I[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](=[S:24])([O-:23])=[O:22])=[CH:17][CH:16]=1.[K+]>C(O)C>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][CH:2]([S:24][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:3][CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)SC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 41.9 %

Procedure:
4-Iodo-piperidine-1-carboxylic acid, tert-butyl ester (1.3 g) and potassium toluene-4-thiosulfonate (1.0 g) were combined in ethanol (10 ml) with cis-dicyclohexane 18-crown-6 (10 mg) and heated under reflux for 12 h. After cooling the reaction mixture was partitioned between ethyl acetate and water, the organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with iso-hexane/ethyl acetate 4:1 to 7:3), to yield the subtitle compound as an oil (0.65 g).
Reaction SMILES: [NH:1]([C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O)[NH2:2].[C:18]([C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)#[N:19]>C(O)CCC>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[C:18]1[NH:2][N:1]=[C:3]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: N#Cc1ncccn1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3ncccn3)n2)CC1

Procedure:
A mixture of tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate (10.1 g, 41.5 mmol) and 2-cyanopyrimidine (4.36 g, 41.5 mmol) in 1-butanol (20 mL) was heated to reflux for 48 hours. The mixture was concentrated, suspended in ether, and filtered to give tert-butyl 4-(5-pyrimidin-2-yl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate as a solid. MS (M+H+): 331.2 observed; 1H-NMR (400 MHz, CD3OD): δ 8.92 (d, J=4.0 Hz, 2H), 7.52 (t, J=4.0 Hz, 1H), 4.18-4.15 (m, 2H), 3.14-3.08 (m, 1H), 2.98 (br.s, 2H), 2.07-2.01 (m, 2H), 1.85-1.77 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)#[N:25]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:29]3[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: N#Cc1ccc(O)cc1
Product: COc1ccc(-c2cc(Oc3ccc(C#N)cc3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150 mg, 0.459 mmol) and 4-cyanophenol were reacted as starting materials at 150° C. for 13 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow crystalline powder (108.0 mg, 57.5%). Melting point: 167.3-170.5° C. (ethyl acetate-hexane).
Reaction SMILES: [F:1][S:2]([F:18])([F:17])([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[C:6]([OH:8])=[O:7].[H][H]>CO.[Ni]>[NH2:12][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([S:2]([F:18])([F:1])([F:15])([F:16])[F:17])[CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(S(F)(F)(F)(F)F)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reaction time: 3 h
Yield: 86.9 %

Procedure:
Subsequently, the 3-pentafluorosulfanyl-5-nitrobenzoic acid (5 g) was dissolved in methanol (300 ml), Raney nickel (about 750 mg) was added and hydrogenation was effected under a hydrogen atmosphere (hydrogen balloon). After 3 h, the catalyst was filtered off and the filter residue was washed thoroughly with methanol. The filtrate was concentrated and dried. The residue was purified using silica gel (2×50 g cartridge, n-heptane/EA gradient of 0-100% within 60 min). 3.9 g of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:8]2.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>>[Cl:24][CH2:25][C:26]([N:13]([CH:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:8]1)[CH2:14][CH2:15][CH3:16])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: CCCNC1CCc2c(cccc2OC)C1
Solvent: CCN(CC)CC
Product: CCCN(C(=O)CCl)C1CCc2c(cccc2OC)C1
Yield: 92.9 %

Procedure:
This compound was prepared from 32b (4.63 g, 21.1 mmol), triethyl amine (5.1 ml, 42.2 mmol), and chloroacetyl chloride (1.80 ml, 25.4 mmol) by following Procedure B to give 33b (5.8 g, 93%). 1H NMR (400 MHz, CDCl3) 0.90-0.98 (m, 3H), 1.64-1.72 (m, 2H), 3.19-3.27 (m, 2H), 4.00 (s, 3H), 6.61-6.68 (m, 2H), 6.96-7.04 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:19])[CH2:8][O:7][C:6](=[N:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[NH:5]1.I[CH3:21]>C1COCC1>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([N:9]=[C:6]2[N:5]([CH3:21])[C:4]([CH3:19])([CH3:3])[CH2:8][O:7]2)=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: CC1(C)COC(=Nc2ccc([N+](=O)[O-])cc2)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=Nc2ccc([N+](=O)[O-])cc2)OCC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a stirred suspension of sodium hydride (0.2 g of 50% in mineral oil, 4.2 mmol) in THF was added (4,4-dimethyl-oxazolidin-2-ylidene)-(4-nitro-phenyl)-amine (1 g, 4.25 mmol), stirred for 30 min at r.t., followed by addition of iodomethane (0.71 g, 5.0 mmol). After a further 6 hours at r.t. the reaction was quenched with water and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography over silica gel (60-120 mesh) using 15% ethyl acetate/petroleum ether as eluent to give (4-nitro phenyl)-(3,4,4-trimethyl-oxazolidin-2-ylidene)-amine (0.7 g, 66%).
Reaction SMILES: [OH:1][CH:2]([CH2:42][OH:43])[CH2:3][CH2:4][CH2:5][C:6]1([CH2:35][CH2:36][CH2:37][CH:38]([OH:41])[CH2:39][OH:40])[CH2:11][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][C:15]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[C:34]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)=[C:16]([CH2:17][CH2:18][CH3:19])[C:8]=2[O:7]1.C(O[C:48](=[O:50])[CH3:49])(=O)C>N1C=CC=CC=1.C(OCC)(=O)C>[C:2]([O:41][CH:38]([CH2:39][O:40][C:48](=[O:50])[CH3:49])[CH2:37][CH2:36][CH2:35][C:6]1([CH2:5][CH2:4][CH2:3][CH:2]([O:1][C:10](=[O:12])[CH3:9])[CH2:42][O:43][C:6](=[O:7])[CH3:5])[CH2:11][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][C:15]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[C:34]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)=[C:16]([CH2:17][CH2:18][CH3:19])[C:8]=2[O:7]1)(=[O:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCCC(O)CO)(CCCC(O)CO)CC2=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCCC(COC(C)=O)OC(C)=O)(CCCC(COC(C)=O)OC(C)=O)CC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.7 %

Procedure:
To a solution of 404 mg (0.708 mmol) of the title product of Example 71 in 4.4 ml of pyridine was added 0.70 ml (7.4 mmol) of acetic anhydride. After stirring overnight at room temperature, the mixture was taken up in ethyl acetate, and washed sequentially with two portions of aqueous sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. Chromatography of the residue over silica gel, using 40% ethyl acetate/hexane as the eluent, gave the title compound (314 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14]O.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][Br:17]
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Cc1oc(-c2ccccc2)nc1CCBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
2-(5-Methyl-2-phenyl-4-oxazolyl)ethanol (0.203 g, 1.0 mmol; European patentapplication 177353) and CBr4 (0.662 g, 2.0 mmol) were dissolved in 10 mL of ether and cooled to 0° C. Triphenylphosphine (0.524 g, 2.0 mmol) was added and the mixture stirred for 3 hours at room temperature. The mixture was filtered, the filtrate was stripped of solvent and the residue filtered through a plug of silica gel using CHCl3 as eluant to yield 0.16 g of present title product as a white solid; mp 59°-61° C.; tlc Rf 0.22 (CHCl3).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:16])([F:15])[C:5]1[C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1>C1COCC1>[F:16][C:4]([F:3])([F:15])[C:5]1[C:10]([CH2:11][OH:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1cccnc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cccnc1C(F)(F)F
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a suspension of sodium borohydride (0.24 g, 6.32 mmol) in anhydrous THF (40 mL) at 0° C. was added dropwise a solution of methyl 2-(trifluoromethyl)pyridine-3-carboxylate (650 mg, 3.16 mmol) in THF (50 mL). After stirring for 1 hour, the reaction mixture was slowly quenched with 15% NaOH and then diluted with water. Ethyl acetate was added, the reaction mixture was stirred for 10 minutes, and the precipitated white solid was filtered off. The solid was washed with ethyl acetate (3×100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to provide [2-(trifluoromethyl)pyridin-3-yl]methanol as a thick oil (0.505 g, 90% yield), which was used for the next step without any further purification; M+177.1.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][C@@H:5]([CH3:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+].Cl>C1COCC1.CO>[C:9]([O:8][C:6](=[O:7])[C@H:5]([CH3:13])[CH2:4][C:3]([OH:14])=[O:2])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)C[C@@H](C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](CC(=O)O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 2.55 g (9.89 mmol) of (R)-2-methyl-succinic acid 1-tert-butylester 4-methyl ester in 20 ml of THF/MeOH (1/1) are added at 0° C. 10 ml (20 mmol) of 2 M sodium hydroxide. The mixture is stirred for 4 h at 0° C. and then acidified to pH 2-3 by addition of 1 M HCl. The organic solvents are evaporated. The residual aq. solution is extracted with DCM (3×30 ml), and the combined organic layers are dried over sodium sulfate and concentrated to give the product in the form of a colorless oil.
Reaction SMILES: [BrH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>Br>[BrH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8]
Reactant: OCc1ccccc1
Reactant: NCC(=O)CCC(=O)O
Agent: Br
Product: NCC(=O)CCC(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 43 %

Procedure:
A stirred mixture of 5-amino-4-oxopentanoic acid hydrobromide (1.60 g, 7.5 mmol), benzyl alcohol (15 ml), and 48% hydrobromic acid (8 drops) was heated to 80° C. (bath temperature) for 2 days. The mixture was cooled to room temperature and excess benzyl alcohol was removed with a rotary evaporator at 0.12 mm Hg. The residue was titrated with diethyl ether (2×50 ml) and the residue was purified by flash chromatography on a 160×55 mm silica gel 60 column eluted sequentially with acetonitrile, 50 methanol in acetonitrile, and 10% methanol in acetonitrile. Fractions containing the product were combined and evaporated. The residue was titruated with diethyl ether (5×15 ml), filtered, and dried at 30° C. and 15 mm Hg to give 0.97 g (43%) tan powder, mp 62-67° C.
Reaction SMILES: [Cl:1][CH:2]([Cl:24])[C:3]([NH:5][C@H:6]([CH2:22][F:23])[C@H:7]([OH:21])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][NH:17][C:16](=[O:20])[CH:15]=2)=[CH:10][CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:32][C:33]#[N:34]>CN(C)C=O.O>[Cl:24][CH:2]([Cl:1])[C:3]([NH:5][C@H:6]([CH2:22][F:23])[C@@H:7]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][N:17]([CH2:32][C:33]#[N:34])[C:16](=[O:20])[CH:15]=2)=[CH:12][CH:13]=1)[OH:21])=[O:4]
Reactant: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2cc[nH]c(=O)c2)cc1)C(Cl)Cl
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCn1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cc1=O
Temperature: 65 °C
Yield: 58.7 %

Procedure:
A microwave tube is charged with the product of step 2, Example 20 (185 mg, 0.496 mmol) in dimethylformamide (4.9 mL), cesium carbonate (194 mg, 0.595 mmol) and chloroacetonitrile (313.7 uL, 4.957 mmol) were added under nitrogen, and the tube is capped. The reaction mixture is heated at 65° C. for 2.5 hours using the microwave (max power—100 W). The mixture is diluted with water (20 mL), extracted with ethylacetate (2×20 mL), and the combined organic phase is washed with water (3×15 mL), brine (15 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel chromatography (40 g, 50-90% ethyl acetate/hexanes) gave the title compound (120 mg): 1H NMR (300 MHz, DMSO) δ 4.25 (m, 1.5H), 4.44 (m, 0.5H), 4.53 (m, 0.5H), 4.72 (m, 0.5H), 4.91 (m, 1H), 5.02 (s, 2H), 6.01 (d, 1H), 6.51 (s, 1H), 6.72 (dd, 1H), 6.77 (m, 1H), 7.47 (d, 2H), 7.70 (d, 2H), 7.83 (d, 1H), 8.60 (bd, 1H). MS (ESI+) m/z 412 [M+H].
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.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[BH4-].[Na+].[OH-].[Na+]>>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][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:15][CH:14]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CNc2ccc3nc[nH]c3c2)cc1

Procedure:
Alternatively the compound was synthesized starting from benzimidazol-5-amine (2.66 g; 20 mmol; 1 eq.), 4-methoxybenzaldehyde (3.26 g; 2.9 ml; 24 mmol; 1.2 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: 4.53 g (89.5%); MS m/z: 254.3 [M+H]+
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1)=[O:10].[F-].[K+]>C(Cl)(Cl)Cl>[CH2:3]([O:2][P:1]([CH:9]([OH:10])[C:11]1[CH:12]=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:16]=1)([O:5][CH2:6][CH3:7])=[O:8])[CH3:4]
Reactant: CCOP([O-])OCC
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [F-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(OCC)C(O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethyl phosphite (16 mL) was added to methyl 4-formylbenzenecarboxylate (10.2 g) and potassium fluoride (18.0 g), and stirred at room temperature for 30 minutes. The reaction liquid was diluted with chloroform (200 mL) added thereto, and filtrated through Celite. The solvent was evaporated off under reduced pressure from the filtrate, and the resulting solid was washed with diethyl ether to obtain the entitled compound (14.1 g) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:14]([NH2:17])=[N:15][OH:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]([C:23]#[C:24][C:25]([O:27][CH3:28])=[O:26])=[O:22]>C(Cl)(Cl)Cl>[CH3:19][O:20][C:21](=[O:22])[C:23]([O:16][N:15]=[C:14]([NH2:17])[C:8]1([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:18])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)=[CH:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC(C)(C)OC(=O)NC1(C(N)=NO)CCOCC1
Solvent: ClC(Cl)Cl
Product: COC(=O)C=C(ON=C(N)C1(NC(=O)OC(C)(C)C)CCOCC1)C(=O)OC

Procedure:
A solution of tert-butyl-4-[amino(hydroxyimino)methyl]tetrahydro-2H-pyran-4-yl-carbamate (C-27) and dimethylacetylendicarboxylate (1.2 eq.) in chloroform was refluxed for 1 hour under nitrogen and the solution was concentrated. Residue was purified bysflash chromatography on silica gel (eluent: petroleum ether:ethyl acetate=7:3) to give the desired product (C-28) as a mixture of isomers in ratio 7:3.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]=2[CH:32]=1.[OH-].[Li+]>>[CH2:19]([S:18][C:16]1[N:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:14]2[CH:32]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:33])=[O:2])[CH:11]=[CH:12][C:13]=2[N:17]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(SCc3ccccc3)n(-c3ccccc3)c2c1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)CCCCCOc1ccc2nc(SCc3ccccc3)n(-c3ccccc3)c2c1

Procedure:
235 mg of 6-[(2-benzylmercapto-1-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with lithium hydroxide according to general operating instructions 3. 179 mg was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9]I.[Cu](C#N)[C:21]#[N:22].[Br-].[Li+].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][C:21]#[N:22]
Reactant: N#C[Cu]C#N
Reactant: CCC[C@H]1CC[C@H](c2ccc(C#CI)c(F)c2)CC1
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](c2ccc(C#CC#N)c(F)c2)CC1
Reaction time: 5 h

Procedure:
To a solution of 10 mmol of 3-fluoro-4-iodoethynyl-1-(trans-4-propylcyclohexyl)benzene in 3 ml of tetrahydrofuran were added 11 mmol of copper cyanide and 3 mmol of lithium bromide, and the solution was stirred for 5 hours under reflux. To the reaction solution were added 10 ml of 6N hydrochloric acid saturated solution of ferric chloride and the solution was stirred at room temperature for one hour. After completion of the agitation, the reaction solution was extracted with toluene, the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentratred under reduced pressure. The resulting brown, oily product was isolated and purified by a silica gel column chromatography to afford a colourless oily substance which was recrystallized from ethanol to afford colourless crystal. This was identified as the title compound by analytical results.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3cccnc3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([OH:14])[C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([O:14][C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC(=O)N(O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CNC(=O)N(OC(=O)Oc1ccccc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 1-(3,4-dichlorophenyl)-1-hydroxy-3-methylurea (6 grams; 0.025 mol) in diethyl ether (200 ml), and triethylamine (4 ml) were charged into a glass reaction flask equipped with a mechanical stirrer. Phenyl chloroformate (4.2 grams; 0.027 mol) was added thereto. The reaction mixture was stirred, at room temperature, for a period of about one-half hour resulting in the formation of a precipitate. The precipitate was recovered by filtration, was washed with water, dried, and was recrystallized from a methylene chloride-pentane mixture to yield 1-(3,4-dichlorophenyl)-1-phenoxycarbonyloxy-3-methylurea melting at 93°C with decomposition and having the following elemental analysis as calculated for C15H12Cl2N2O4 :