Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[NH2:48][C@@H:49]([C:51]([O:53]C(C)(C)C)=[O:52])[CH3:50].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:16])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C@H:9]2[C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:48][C@@H:49]([C:51]([OH:53])=[O:52])[CH3:50])=[O:36])=[O:32])=[CH:27][CH:26]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: COc1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(C(O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)N[C@H](C)C(=O)O)cc2)cc1
Reaction time: 2 h
Yield: 66.6 %

Procedure:
N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-methoxyphenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.04 g, 0.072 mmol) and N-methylmorpholine (0.022 g, 0.217 mmol) were dissolved in CH2Cl2 (4 ml). tert-Butyl D-alaninate hydrochloride (0.016 g, 0.087 mmol) and TBTU (0.030 g, 0.094 mmol) were added. After 2 h, the reaction mixture was purified on silica gel and eluted with EtOAc/CH2Cl2 (25/75). Pure fractions were collected and concentrated. The residue was dissolved in CH2Cl2 (3 ml) and TFA (2 ml). The hydrolysis was completed after 2 h. The reaction mixture was concentrated and MeOH (3 ml) and NABH4 (0.011 g, 0.290 mmol) were added. The mixture was stirred for 5 minutes. The reaction was quenched by the addition of 0.1M NH4OAc buffer (2 ml) and the solvent evaporated. The residue was purified by preparative HPLC using an eluent of 0-50% CH3CN in 0.1M NH4OAc buffer. Freeze-drying of the pure fractions afforded the title compound (0.030 g, 66%) as a colourless solid. M/z: 624.2, (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 1.16 (d, 3H), 2.83-2.93 (m, 2H), 3.68-3.74 (m, 5H), 3.88-3.95 (m, 1H), 4.23-4.26 (m, 1H), 4.51 (s, 2H), 4.60-4.70 (m, 1H), 5.00-5.03 (m, 1H), 6.81-7.37 (m, 12H), 7.74-7.79 (m, 1H), 8.29-8.34 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[CH2:2].[OH:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].N1C=CC=CC=1>ClCCCl.O.Cl[Cu]>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(B(O)O)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl[Cu]
Solvent: ClCCCl
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1ccc(ON2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
To a stirred solution of 4-vinylphenylboronic acid (2 g, 13 mmol), 2-hydroxyisoindoline-1,3-dione (3.63 g, 24.53 mmol), and CuCl (1.214 g 12.26 mmol) in 1,2-dichloroethane (50 mL) was added pyridine (1.065 g, 13.48 mmol), and the resultant reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was diluted with H2O and extracted with CHCl3. The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 20% EtOAc in petroleum ether) afforded the title compound as a white solid (2 g, 63%): mp 129-131° C.; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=2.0 Hz, 2H), 7.82 (d, J=3.2 Hz, 2H), 7.38 (d, J=2.0 Hz, 2H), 7.14 (d, J=2.0 Hz, 2H), 6.70 (m, 1H), 5.83 (d, J=16.0 Hz, 1H), 5.22 (d, J=10.8 Hz, 1H); ESIMS m/z 266.12 ([M+H]+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([CH:11]2[N:16]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:15][CH:14]3[C:12]2([C:27](Cl)=[O:28])[CH2:13]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.CC(C)=O>[C:5]1([CH:11]2[N:16]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)(=[O:18])=[O:19])[CH2:15][CH:14]3[C:12]2([C:27]([N:1]=[N+:2]=[N-:3])=[O:28])[CH2:13]3)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC3CC3(C(=O)Cl)C2c2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)N2CC3CC3(C(=O)N=[N+]=[N-])C2c2ccccc2)cc1
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a stirred solution of sodium azide (5.63 g, 86.62 mmol) in 17 mL of water was added in a dropwise fashion to a solution of racemic 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carbonyl chloride (5.0 g, 13.3 mmol) (Intermediate 3) in 30 mL of acetone. 3 mL of water was then added to the reaction and the reaction mixture was stirred for 16 hours. The acetone was removed at reduced pressure and the reaction diluted with both methylene chloride and brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carbonyl azide (5.1 g, 100% crude yield).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=2)[CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:17].COC(C)(C)C>C(OCC)C>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=2)[CH2:12][Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: Cc1ccc(-c2ccccc2)cc1CO
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: Cc1ccc(-c2ccccc2)cc1CBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 180.1 %

Procedure:
To a solution of 1.33 g (6.71 mmol) of 5-phenyl-2-methylbenzylalcohol in 30 ml of dry diethyl ether was added dropwise 0.91 g (3.02 mmol) of phosphorous tribromide with ice-cooling. After the mixture was stirred for 3 hours with ice-cooling, to the reaction solution were added ice water and tert-butyl methyl ether with ice-cooling. The mixture was stirred for 30 minutes and separated. The organic layer was washed successively with an about 5% aqueous solution of sodium hydrogencarbonate and water, then dried and concentrated to obtain 1.42 g (5.44 mmol) of 5-phenyl-2-methylbenzylbromide as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:5]=[CH:4][N:3]=1.[CH3:21][P:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([O:32][CH3:33])[CH:26]=1)([CH3:24])=[O:23].Cl>COCCO>[CH3:24][P:22]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:5]=[CH:4][N:3]=2)=[C:27]([O:32][CH3:33])[CH:26]=1)([CH3:21])=[O:23]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1ccnc(Cl)n1
Reactant: COc1cc(P(C)(C)=O)ccc1N
Agent: Cl
Solvent: COCCO
Product: COc1cc(P(C)(C)=O)ccc1Nc1nccc(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 90 °C
Yield: 71.8 %

Procedure:
To a solution of 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine (0.017 g, 0.054 mmol) in 0.5 mL of 2-methoxyethanol in a vial was added 4-(dimethylphosphoryl)-2-methyoxyaniline (0.010 g, 0.044 mmol) as the HCl salt. The vial was sealed and the reaction was heated at 90° C. for 16 h. The reaction was quenched with 1N NaOH solution and the solution extracted ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the desired compound (15 mg, 72% yield). MS/ES+: m/z=475.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[CH3:7][O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.[Cl-].[Na+]>CN(C)C=O.O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:14]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:25][CH:24]=2)=[CH:17][CH:18]=1
Reactant: N#CCCCBr
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(CCCC#N)Cc2ccc(OC)cc2)cc1
Temperature: 110 °C
Yield: 110.8 %

Procedure:
A solution of 4-bromobutyronitrile (14.80g) in dry dimethylformamide (100 ml) was added dropwise over 15 minutes to a stirred solution of bis-(4-methoxybenzyl )amine (25.73g) and N,N-diisopropylethylamine (35 ml, 26 g) in dry dimethylformamide (100 ml ). The yellow solution was heated under nitrogen at 110° C. for 4 hours and was allowed to cool. The solution was poured onto a mixture of water (400 ml) and saturated aqueous sodium chloride (400 ml ) and then extracted with ether (2×200 ml). The extracts were dried (Na2SO4) and concentrated in vacuo to give an oil (35.93 g). The product was chromatographed on silica with eluant diisopropyl ether, and was triturated with cyclohexane to give the title compound (26.00g), m.p. 56°-58° C.
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[NH:7][C:6]=2[CH:5]=[C:4]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[CH:3]=1.F[C:30]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:31]=1[C:32]#[N:33]>>[C:32]([C:31]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:30]=1[O:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[NH:7][C:6]=2[CH:5]=[C:4]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH2:27][CH3:28])(=[O:25])=[O:26])=[CH:22][CH:23]=2)[CH:3]=1)#[N:33]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(O)c3nc(-c4ccccn4)[nH]c3c2)cn1
Reactant: N#Cc1cccc(F)c1F
Product: CCS(=O)(=O)c1ccc(Oc2cc(Oc3c(F)cccc3C#N)c3nc(-c4ccccn4)[nH]c3c2)cn1

Procedure:
The entitled compound was obtained in the same method as in Example 251 (step 2) or in accordance with the method or by combining it with an ordinary method but using 4-hydroxy-6-(6-ethanesulfonyl-pyridin-3-yloxy)-2-pyridin-2-yl-1H-benzimidazole and 2,3-difluorobenzonitrile.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:29]3[C:30]([CH3:39])=[C:31]4[C:36](=[CH:37][CH:38]=3)[O:35][CH2:34][CH2:33][CH2:32]4)=[C:14]([CH:21]([O:24][Si](C)(C)C)[C:22]#N)[N:15]([CH3:20])[C:16]2=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[OH:40]S(O)(=O)=O.[CH3:45][OH:46]>>[CH3:45][O:46][C:22](=[O:40])[CH:21]([OH:24])[C:14]1[N:15]([CH3:20])[C:16](=[O:19])[C:17]2[C:12]([C:13]=1[C:29]1[C:30]([CH3:39])=[C:31]3[C:36](=[CH:37][CH:38]=1)[O:35][CH2:34][CH2:33][CH2:32]3)=[CH:11][CH:10]=[C:9]([OH:8])[CH:18]=2
Reactant: CO
Reactant: O=S(=O)(O)O
Reactant: Cc1c(-c2c(C(C#N)O[Si](C)(C)C)n(C)c(=O)c3cc(OCc4ccccc4)ccc23)ccc2c1CCCO2
Product: COC(=O)C(O)c1c(-c2ccc3c(c2C)CCCO3)c2ccc(O)cc2c(=O)n1C
Temperature: 80 °C
Yield: 32 %

Procedure:
To a solution of [7-Benzyloxy-2-methyl-4-(5-methyl-chroman-6-yl)-1-oxo-1,2-dihydro-isoquinolin-3-yl]-trimethylsilanyloxy-acetonitrile (2.5 g, 4.64 mmol) in H2SO4/CH3OH (30 mL, V/V=1:3). The resulting mixture was heated to 80° C. under N2 for 12 h. The reaction mixture was poured into ice water and extracted with DCM (50 mL*3), dried over sodium sulfate and concentrated to dryness. The mixture was purified by chromatography column on silica gel to afford the title product (0.6 g, 32%). LCMS (10-80 AB—2MIN.M): Rt=0.993, purity=75%, M+1=410.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:12](=CC=O)[CH:11]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH3:36][CH2:37][OH:38]>>[CH2:1]([O:8][CH:9]1[CH2:14][CH:13]([O:15][Si:16]([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:18])[CH3:17])[C:12](=[C:37]([OH:38])[CH3:36])[CH:11]([O:26][Si:27]([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:28])[CH3:29])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CC(OCc2ccccc2)CC(O[Si](C)(C)C(C)(C)C)C1=CC=O
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)=C1C(O[Si](C)(C)C(C)(C)C)CC(OCc2ccccc2)CC1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of Compound 31 (288 mg, 0.587 mmol, 31a:31b=ca. 1:2) in EtOH (1 mL) cooled to 0° C. was added NaBH4 (26.6 mg, 0.704 mmol). After, the reaction mixture was stirred for 1 h at 0° C., into the reaction mixture was poured ice water, and extracted with AcOEt. The organic layer was washed with saturated brine, and dried over anhydrous MgSO4. Solvents were removed in vacuo, and the residue was purified by silica gel column chromatography (10 g; 15% AcOEt/hexane) to yield Compound 32 (283.3 mg, 98%) as a mixture of two stereoisomers. The ratio of the stereoisomers constituting the mixture was ca. 2:1. It was impossible to know whether the major product was aS*,2R,6R isomer or aR*,2R,6R isomer.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[CH3:15][N:16]([CH3:19])[C:17]#[N:18]>>[CH3:15][N:16]([CH3:19])[C:17]([NH2:18])=[N:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CN(C)C#N
Agent: Cl
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1
Temperature: 10 °C

Procedure:
A mixture of 4-(2-aminophenyl)morpholine hydrochloride (2.1 g) and N,N-dimethylcyanamide (7 ml) was heated under nitrogen at 165°-170° C. for 12 hours. The reaction mixture was cooled to 10° C. and the precipitate collected by filtration, washed with ether and stirred with 40% aqueous sodium hydroxide solution. The resulting mixture was extracted with dichloromethane and the extract washed with brine and dried. Removal of the solvent yielded a residue which was recrystallised from hexane to give 1,1-dimethyl-2 (2-morpholinophenyl)guanidine (m.p. 144°-145° C.).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.Cl[C:21]1[C:22]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:23]=2[S:24][C:25]=1[C:26]#[N:27]>CN(C=O)C>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:22]2[C:21]([O:19][C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[C:25]([C:26]#[N:27])[S:24][C:23]=2[CH:28]=1)(=[O:34])=[O:33]
Reactant: COc1ccc(O)cc1
Reactant: CS(=O)(=O)c1ccc2c(Cl)c(C#N)sc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(C#N)sc3cc(S(C)(=O)=O)ccc23)cc1
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A solution of KHMDS (0.18 g, 0.90 mmol) in DMF (7 mL) was treated by sequential addition of 4-methoxyphenol (0.12 g, 0.99 mmol) then 3-chloro-6-methanesulfonyl-benzo[b]thiophene-2-carbonitrile 8 (0.20 g, 0.75 mmol). After 2 h, the mixture was partitioned between EtOAc and brine. The organic layer was washed with brine (2×), dried (Na2SO4), filtered, and evaporated. Chromatography, followed by recrystallization (EtOAc/hexane) gave 0.20 g (74%) of 6-methanesulfonyl-3-(4-methoxy-phenoxy)-benzo[b]thiophene-2-carbonitrile 15 as white needles; (m+H)+ 360.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]([CH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=O)=[O:14])[CH3:11].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:10]([O:12][C:13]([C:15]1[CH2:19][CH2:18][CH2:17][C:16]=1[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)=[O:14])[CH3:11]
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)C1CCCC1=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NCc2ccc(F)cc2)CCC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4-Fluorobenzylamine (12.1 g, 97.5 mmol) was added to a solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (15.25 g, 97.6 mmol) in toluene (225 mL) at 23° C. Glacial acetic acid (6.15 mL, 107 mmol) was then added, producing a large amount of white solid. The reaction mixture was heated to 70° C. in an oil bath, whereupon most of the solids dissolved. After stirring for 2 h at 70° C., a Dean-Stark apparatus and reflux condenser were fitted to the reaction flask and approximately 40 mL of liquid (predominantly toluene) was removed by distillation over 45 min (oil bath temperature=145° C.). The mixture was allowed to cool to 23° C. and was used in the next step. A small aliquot of the crude reaction mixture was concentrated under reduced pressure to afford the desired product, 2-(4-fluoro-benzylamino)-cyclopent-1-enecarboxylic acid ethyl ester as an orange oil: 1H NMR (CDCl3) δ: 1.28 (3H, t, J=7.5), 1.79-1.86 (2H, m), 2.51-2.56 (4H, m), 4.15 (2H, q, J=6.9), 4.34-4.36 (2H, m), 6.98-7.03 (2H, m), 7.19-7.23 (2H, m), 7.73 (1H, bs).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35]([N:42]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH2:35]([N:42]1[CH2:46][CH2:45][CH:44]([NH:47][C:27]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[O:33])[CH2:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5)C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
Chloroform (10 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) to prepare a solution. Triphosgene (110 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. 1-Benzyl-3-aminopyrrolidine (89 mg) was then added thereto, and the mixture was stirred at room temperature for 3 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (76 mg, yield 45%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:20][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CN(C)CCCOc1ccccc1C=O
Reactant: CCCCN
Solvent: Cc1ccccc1
Product: CCCCN=Cc1ccccc1OCCCN(C)C
Yield: 92.1 %

Procedure:
2-(3-Dimethylaminopropoxy)benzaldehyde (32.5 g) is reacted with 11.5 g of n-butylamine in 150 ml of toluene as described in Example 1 to give 37.9 g of oily product; boiling point 124°-128° C./0.1-0.2 mm of Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:16]([S:29][CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])[N:4]=1.C(O)(=[O:33])C.OO>O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:16]([S:29]([CH3:30])=[O:33])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: COc1cc(OC)nc(OC(C(=O)O)C(SC)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: COc1cc(OC)nc(OC(C(=O)O)C(c2ccccc2)(c2ccccc2)S(C)=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.2 g (2.9 mmol) of 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methylthio-3,3-diphenylpropionic acid were introduced into 15 ml of glacial acetic acid at 0° C. and 294 μl of 30% strength H2O2 were added dropwise. The mixture was stirred at room temperature overnight, poured into water, extracted with CH2Cl2 and washed with sodium thiosulfate solution and brine. After drying, 1 g of substance was isolated as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[S:45][C:41]=2[C:40]([N:47]([CH2:49][CH2:50][O:51][CH3:52])[CH3:48])=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:46][C:44]1[S:45][C:41]2[C:40]([N:47]([CH2:49][CH2:50][O:51][CH3:52])[CH3:48])=[CH:39][CH:38]=[C:37]([O:36][CH3:35])[C:42]=2[N:43]=1)=[O:7]
Reactant: COCCN(C)c1ccc(OC)c2nc(N)sc12
Reactant: O=C(O)c1ccnc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCN(C)c1ccc(OC)c2nc(NC(=O)c3ccnc(Br)c3)sc12

Procedure:
From 2-bromo-isonicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-N7-(2-methoxy-ethyl)-N7-methyl-benzothiazole-2,7-diamine in dioxane and DMF. ES-MS m/e (%): 453 (M{81Br}+H+, 100), 451 (M{79Br}+H+, 71).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[P:5]([O:14]CCCl)([O:10]CCCl)[O:6]CCCl.[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH:21]=O)[CH3:19].N(C(P(=O)(O)O)CC)C(N)=O>O>[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH:21]([P:5](=[O:6])([OH:10])[OH:14])[NH:1][C:2]([NH2:4])=[O:3])[CH3:19]
Reactant: ClCCOP(OCCCl)OCCCl
Reactant: NC(N)=O
Reactant: CCCCC(C=O)CC
Agent: CCC(NC(N)=O)P(=O)(O)O
Solvent: O
Product: CCCCC(CC)C(NC(N)=O)P(=O)(O)O

Procedure:
This compound is prepared from urea, tris(2-chloroethyl) phosphite, 2-ethylhexaldehyde, and water under conditions similar to those used for the preparation of 1-ureidopropyl-phosphonic acid in Example 4. The product is obtained as a white solid: mp 206° C dec; 31P nmr (CD3SOCD3) -23.2 ppm; 1H nmr δ8.5 (broad, 4, HO and NH2), 6.2 (d, 1, J = 8Hz, NH), 4.3 (d, of d, 1, J = 8 and 20Hz, PCH), 1.3 and 0.9 (m, 15); acidity 2.00 equiv/mole, pK1 = 3.50, pK2 = 9.08.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[CH2:14]1[CH2:19][CH:18]2[O:20][CH:17]2[CH2:16][CH2:15]1.[C:21]([O-])([O-])=O.[K+].[K+]>C(O)C.C(Cl)Cl>[OH:20][CH:17]1[CH2:18][CH2:19][CH2:14][CH2:15][CH:16]1[O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH2:8][CH3:21])=[O:6]
Reactant: C1CCC2OC2C1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(OC)c(OC2CCCCC2O)c1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
To a solution of methyl 3-hydroxy-4-methoxybenzoate (210 mg, 1.15 mmol) and cyclohexane oxide (466 uL, 4.61 mmol) in ethanol (11 mL) was added K2CO3 (637 mg, 4.61 mmol) at room temperature. The reaction mixture was then refluxed overnight then cooled down to room temperature, and evapotreted under reduced pressure until a small amount of ethanol remained. The solution was diluted with DCM and successively washed with 1N HCl and brine, dried over Na2SO4 filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (Eluent: 0-20% EtOAc/Hexanes) to afford (±)-ethyl 3-((2-hydroxycyclohexyl)oxy)-4-methoxy-benzoate as a colorless oil (307 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ 1.16-1.34 (m, 7H), 1.61 (m, 2H), 1.84-1.94 (m, 2H), 3.55 (m, 1H), 3.83 (s, 3H), 4.03 (m, 1H), 4.28 (q, J=8.0 Hz, 2H), 4.85 (d, J=4.0 Hz, 1H), 7.05 (d, J=12.0 Hz, 1H), 7.55-7.58 (m, 2H).