Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])[CH3:2].Cl.[NH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[OH:33][NH:32][C:28]([C:26]1[CH:25]=[CH:24][C:17]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:14]([CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]3=[O:30])=[N:15][C:16]=2[CH:27]=1)=[NH:29]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C#N)ccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C(=N)NO)ccc21
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
A mixture containing 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile (152 mg, 0.379 mmol), hydroxylamine hydrochloride (95 mg, 1.36 mmole) and potassium carbonate (105 mg, 0.758 mmole) in ethanol (4 mL) and water (2 mL) in a sealed tube was placed in a microwave oven (Smith Creator, Personal Chemistry) and heated at 140° C. for 15 min, followed by 150° C. for 10 min while stirring. The solvents were removed in vacuo and the residue was triturated with water. The white precipitate was collected by filtration, washed with water and dried in vacuo to give N-hydroxy-2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxamidine (140 mg, 85%) as a white solid:
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:15]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[S:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[CH:15]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: ClC(Cn1ccnc1)c1cccs1
Reactant: COC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.8 %

Procedure:
204 mg of methyl 4-mercaptobenzoate were dissolved in 1.3 ml of dry dimethylformamide, and 53 mg of a 55% w/w suspension of sodium hydride in mineral oil were added to the resulting solution, whilst ice-cooling. The mixture was then stirred at room temperature for 30 minutes. 258 mg of 1-[2-chloro-2-(2-thienyl)ethyl]imidazole dissolved in 1.3 ml of dry dimethylformamide were added to the resulting solution, and the mixture was then heated at 60° to 70° C. for 8 hours. At the end of this time, the resulting mixture was treated and purified similarly to the procedure described in Example 1, to give 20 mg of the title compound as an oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24](C(OCC4C=CC=CC=4)=O)[CH2:23][CH:22]3[O:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]4[O:47][CH2:46][CH2:45][N:44]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:43]=4[CH:53]=3)=[CH:17][CH:16]=2)[CH2:11]1.CO.[OH-].[K+]>O1CCOCC1.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:11][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH:22]3[O:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]4[O:47][CH2:46][CH2:45][N:44]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:43]=4[CH:53]=3)=[CH:17][CH:16]=2)[CH2:13]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CN(c5nc6ccccc6s5)C4)cc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: COCCCN1CCOc2ccc(COC3CNCCC3c3ccc(OC4CN(c5nc6ccccc6s5)C4)cc3)cc21
Temperature: 100 °C
Reaction time: 5 h

Procedure:
0.207 g of benzyl 4-[4-(1-benzothiazol-2-ylazetidin-3-yloxy)phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidinecarboxylate is dissolved in 8 ml of dioxane. 8 ml each of methanol and 40% KOH are added and the reaction mixture is stirred in a sealed flask at 100° C. over 5 hours. The reaction mixture is subsequently cooled to room temperature, diluted with 40 ml of water and extracted with ethyl acetate (3×40 ml). The combined organic phases are washed with 40 ml of water, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [CH2:1]1[CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=2[O:2]1.[CH:13]1([NH:19][OH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH2:1]1[CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[N+:19]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[O-:20])=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: ONC1CCCCC1
Product: [O-][N+](=Cc1ccc2c(c1)OCCO2)C1CCCCC1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 3,4-ethylenedioxybenzaldehyde and N-cyclohexylhydroxylamine. The title compound was isolated in 74.5% yield as a solid, m.p. 96.7° C.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].[F:13][C:14]1[CH:15]=[C:16]2C(=[CH:21][CH:22]=1)NC=C2>CN(C)C1C=CN=CC=1.C(#N)C>[F:13][C:14]1[CH:22]=[C:21]2[C:9](=[CH:16][CH:15]=1)[N:8]([C:1]([N:3]1[C:4]3[C:16](=[CH:15][C:14]([F:13])=[CH:22][CH:21]=3)[CH:6]=[CH:7]1)=[O:2])[CH:12]=[CH:11]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: O=C(n1ccc2cc(F)ccc21)n1ccc2cc(F)ccc21

Procedure:
78.4 mmol of carbonyldiimidazole and 0.2 g of 4-dimethylaminopyridine are added to a solution of 74 mmol of 5-fluoroindole in 300 ml of acetonitrile. After refluxing for 8 hours, and then concentrating, the residue is taken up in a minimum of ether. The solidified product, which corresponds to the expected product, is filtered off.
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:3]=1[CH2:4][C:5]1[CH:13]=[C:12]([C:14](O)=[O:15])[C:11]([CH2:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2[CH3:25])=[CH:10][C:6]=1[C:7](O)=[O:8]>FC(F)(F)S(O)(=O)=O>[CH3:1][C:2]1[C:3]2[CH2:4][C:5]3[C:6](=[CH:10][C:11]4[CH2:17][C:18]5[C:23]([C:14](=[O:15])[C:12]=4[CH:13]=3)=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=5[CH3:25])[C:7](=[O:8])[C:26]=2[C:27]([CH3:30])=[CH:28][CH:29]=1
Reactant: Cc1ccc(C)c(Cc2cc(C(=O)O)c(Cc3cc(C)ccc3C)cc2C(=O)O)c1
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1ccc(C)c2c1Cc1cc3c(cc1C2=O)Cc1c(C)ccc(C)c1C3=O
Reaction time: 0.17 h

Procedure:
To 200 mL of trifluoromethanesulfonic acid cooled to 18° C. was added slowly 53 grams of 2,5-bis(2,5-dimethylbenzyl)terephthalic acid in small portions as a solid at a rate such that the temperature remained below 25° C. The mixture was allowed to stir for 10 minutes and the cooling bath was removed. The mixture was stirred overnight at room temperature. The mixture was poured over 600 grams of ice and the resulting solid was collected by filtration. The solid was washed with 1 L of water followed by 500 mL of saturated aqueous sodium bicarbonate solution. The solid was washed with water until the pH of the filtrate was neutral to pH paper. The solid was stirred for one hour with 500 mL of tetrahydrofuran and collected by filtration. The solid was washed with tetrahydrofuran and dried to give 7,14-dihydro-1,4,8,11-tetramethylpentacene-5,12-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)#[CH:25].CO>C(N(CC)CC)C.C1C=CC=CC=1.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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:25]#[C:24][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[S:22][C:13]=12
Reactant: C#Cc1ccccn1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: c1ccccc1
Product: COc1cc(Nc2c(C#N)cnc3cc(C#Cc4ccccn4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 32.4 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (300 mg, 0.63 mmol), 2-ethynylpyridine (90 μL, 0.82 mmol), 7.3 mg of tetrakis(triphenylphosphine)palladium(0) and 3 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux overnight. The mixture is cooled to room temperature and 5 mL of methanol are added. The solvents are removed in vacuo and the residue is treated with 10 mL of ethyl acetate. The insoluble material is removed by filtration, washing with ethyl acetate. The filtrate is washed with 10% aqueous hydrochloric acid, water, and saturated aqueous sodium chloride. The combined aqueous layers are extracted with dichloromethane. The organic layer is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The aqueous layer is adjusted to pH 6 and extracted with chloroform. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residues are combined and purified by flash column chromatography eluting with 5% methanol in dichloromethane. The fractions containing product are combined and concentrated. The resultant solid is recrystallized from ethyl acetate and hexane to provide 92 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(pyridin-2-ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile as light brown crystals, mp 237-239° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.35-7.52 (m, 2H), 7.73 (d, J=8 Hz, 1H), 7.80 (s, 1H), 7.83-7.92 (m, 2H), 8.60-8.72 (m, 2H), 9.89 (s, 1H); MS 449.1, 450.9 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[OH:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:12]=1[CH:13]=O.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[CH:13][C:12]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]=2[OH:10])=[C:4]([F:9])[CH:3]=1
Reactant: Cc1cccc(O)c1C=O
Reactant: Nc1ccc(Br)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc(O)c1C=Nc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A solution of 4-bromo-2-fluoroaniline (19.6 g, 103.16 mmol), 2-hydroxy-6-methyl-benzaldehyde (14.03 g, 103.16 mmol) and p-toluenesulfonic acid (188 mg, 0.99 mmol) in toluene (300 mL) was heated to reflux in a Dean-Stark apparatus for 1 h and then allowed to cool to ambient temperature. After adding triethylamine (0.8 mL) the reaction mixture was concentrated to give the crude title compound (31.7 g, 99%) which was used without further purification. Data: 1H-NMR (400 MHz, CDCl3) δ 2.52 (s, 3H), 6.72 (d, J=7.6 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 5.15 (t, J=7.8 Hz, 1H), 7.26-7.38 (m, 3H), 9.03 (s, 1H), 13.63 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1F.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[O:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13]
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2ccc(C(F)(F)F)cc2Br)c(F)c1
Temperature: 80 °C
Yield: 80.5 %

Procedure:
A mixture of 3-bromo-4-fluorobenzotrifluoride (0.5 mL, 3.52 mmol), 2,4-difluorophenol (0.337 mL, 3.52 mmol), and potassium carbonate (0.486 g, 3.52 mmol) in dimethylformamide (7 mL) was heated at 80° C. for 16 hours. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (silica gel, 0-10% ethyl acetate/hexanes gradient) to provide the title compound (1.0 g, 80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=O)[C:10]([CH3:13])(C)C)[CH:5]=[C:4]([Cl:15])[N:3]=1.C([Li])CCC.CN(C)/C=C/C=O.C(OCC)C>C1COCC1.C1CCCCC1>[Cl:15][C:4]1[N:3]=[C:2]([Cl:1])[CH:7]=[C:6]2[C:5]=1[CH:13]=[CH:10][CH:9]=[N:8]2
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)nc(Cl)c1
Agent: CN(C)/C=C/C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: Clc1cc2ncccc2c(Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.1 %

Procedure:
N-(2,6-Dichloro-4-pyridinyl)-2,2-dimethylpropanamide (1 g, 4.05 mmol) was taken up in THF (10 ml) under nitrogen and cooled to <−70° C. n-Butyl lithium (4.05 ml, 10.12 mmol, 2.5M solution in hexanes) was added over 30 min keeping the temperature below −60° C. and then stirred at below −70° C. for 1 h. (2E)-3-(dimethylamino)-2-propenal (0.607 ml, 6.07 mmol) in THF (2 ml) was added over 30 min keeping the temperature below −60° C. The reaction was stirred at below −70° C. for 20 min and then allowed to warm to room temperature. LCMS showed that no starting material remained so the reaction was quenched with 5M HCl (5 ml) and refluxed overnight. LCMS showed good conversion to product so the reaction was cooled to room temperature. The reaction mixture was basified with solid K2CO3 and extracted with EtOAc (4×25 ml). The combined organics were dried with Na2SO4, filtered and concentrated to yield a brown solid. The crude product was applied to a samplet and columned using a 40+M eluting with 12% diethyl ether in cyclohexane for 2 CVs, then with 12%-63% diethyl ether in cyclohexane over 10 CVs then held at 63% for SCVs. Appropriate fractions were combined and evaporated to give the title compound as a yellow solid (0.42 g).
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]1)[CH3:3].[OH-].[Na+].[BH4-].[Na+]>C(O)C.O>[CH3:3][N:2]([CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)[CH3:1]
Reactant: CN(C)C(c1cccc(F)c1)C1CCC(C=O)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)C(c1cccc(F)c1)C1CCC(CO)CC1
Reaction time: 8 h

Procedure:
The aldehyde 34 (7.11 g, 27 mmol) was dissolved, under argon, in ethanol (120 ml), water (60 ml) and 1N NaOH (27 ml, 27 mmol) and stirred for 30 minutes at RT. A solution of NaBH4 (2.04 g, 54 mmol) in water (200 ml) was then slowly added dropwise and the mixture was stirred overnight. Ethanol was removed in vacuo, the aqueous residue was extracted three times with ethyl acetate (100 ml each time), and the organic phase was washed with water (100 ml) and saturated NaCl solution (100 ml), dried (Na2SO4) and concentrated in vacuo.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][N:49]1[C:53]([CH2:54][NH2:55])=[CH:52][N:51]=[CH:50]1>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:55][CH2:54][C:53]4[N:49]([CH3:48])[CH:50]=[N:51][CH:52]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cn1cncc1CN
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cncn1C
Yield: 75 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1-methyl-1H-imidazol-5-yl)methanamine, the title compound was obtained as a colorless solid in 75% yield: 1H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 7.30-7.22 (m, 2H), 7.08-6.98 (m, 3H), 6.08 (s, 1H), 5.86 (t, J=5.0 Hz, 1H), 4.59 (d, J=5.0 Hz, 2H), 4.42 (s, 2H), 3.84-3.75 (m, 2H), 3.65 (s, 3H), 3.49-3.40 (m, 2H), 2.48 (s, 3H); MS (ES+) m/z 428.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[NH:30][C:29]4=[O:34])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)C(C)C)(C)C.CN([P+](O[N:55]1[N:63]=[N:62][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.C(OCC)(=O)C>[N:62]1([O:12][C:11](=[O:13])[C:10]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[NH:30][C:29]4=[O:34])=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)=[CH:9][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[N:55]=[N:63]1
Reactant: Cc1cc(C)cc(C=C(C(=O)O)c2ccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C)cc(C=C(C(=O)On2nnc3ccccc32)c2ccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.7 %

Procedure:
To a mixture of 47 (0.81 g, 1.7 mmol) and N,N-diisopropylethylamine (0.33 mL, 1.9 mmol) in dichloromethane (20 mL) was added BOP reagent (0.76 g, 1.7 mmol). After 45 min of stirring at room temperature, the mixture was diluted with ethyl acetate (150 mL) then washed with 1N HCl (100 mL), water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using hexanes:ethyl acetate (3:2). The solid obtained after concentration was further triturated with hexanes:ethyl acetate (4:1) to yield 0.75 g (76%) of 48.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:36][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Agent: Cl
Solvent: CO
Product: Cc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)cn1
Yield: 80.1 %

Procedure:
A solution of the compound (342 mg, 0.66 mmol) obtained in Example 18-1) and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (2 mL) was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (215 mg, 81%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[S:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH2:13]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:30])[C:27](O)=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:13]([CH:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:30])[C:27]([NH:1][C:2]2[CH:12]=[CH:11][C:5]3[NH:6][C:7](=[S:10])[CH2:8][O:9][C:4]=3[CH:3]=2)=[O:28])[CH2:24][CH2:25]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc2c(c1)OCC(=S)N2
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccc2c(c1)OCC(=S)N2)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 7-amino-4H-benzo[1,4]oxazin-3-thione and (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) according to the method described in Example 1c. Melting Point: 193-196° C. (diethylether)
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCCc2ccc(OC)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(CCCCCc2ccc(O)cc2)cc1
Yield: 98.5 %

Procedure:
A mixture of 1,5-bis(4-methoxyphenyl)pentane of Example 8 (60 g, 0.21 mole), 150 ml of hydrobromic acid (47%) and 200 ml of glacial acetic acid was refluxed for 4.5 hours. It was concentrated to a thick liquid, dissolved in ethyl acetate, washed with water, dried over anhydrous magensium sulfate and concentrated to give 53.0 g of a thick oil. NMR and TLC confirmed the structure.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]3[CH:16]=[CH:15][C:14]([C@@H:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:13][CH:12]=3)[CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:32]([CH3:34])[CH3:33]>CN(C=O)C>[CH:32]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([C@@H:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:13][CH:12]=3)[CH2:10]2)=[CH:23][CH:24]=1)([CH3:34])[CH3:33]
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccc(O)cc3)C2)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccc(OC(C)C)cc3)C2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To 0.050 g (0.15 mmol) (S)—N-(1-{4-[3-(4-hydroxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide (VI.1) in 1.0 mL DMF are added 0.053 g (0.38 mmol) potassium carbonate and 17.2 μL (0.18 mmol) 2-bromopropane. The mixture is stirred for 12 h at 80° C. After cooling the mixture is directly purified by HPLC (XBridge, MeOH/water (+0.3% NH4OH)) to yield the desired product.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:16]=[CH:15][C:9](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:8][C:7]=1[O:17][CH3:18])[CH2:2][CH2:3][CH3:4].Cl[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[C:9]1[CH:15]=[CH:16][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:7]([O:17][CH3:18])[CH:8]=1
Reactant: CCCCOc1ccc(/C=C/C(=O)O)cc1OC
Reactant: OCCCCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Product: CCCCOc1ccc(/C=C/C(=O)OCCCCCCO)cc1OC
Yield: 79.3 %

Procedure:
1.38 g (5.50 mmol) (E)-4-butyloxy-3-methoxycinnamic acid was suspended in 3 ml acetonitrile. A mixture of 0.84 g (5.50 mmol) 1,8-diazabicyclo[5 4.0]undec-7-ene(1,5-5) (DBU) and 3 ml acetonitrile was added dropwise over a period of 5 minutes. 0.46 g (1.25 mmol) tetrabutylammonium iodide and 0.68 g (5.00 mmol) 6-chlorohexanol was added and the resulting mixture was then refluxed for 6 hours. The reaction mixture was cooled and then extracted using ethyl acetate and water. The ethyl acetate phase was washed with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by chromatography using a silica gel column (120 g) and toluene:ethyl acetate (1:1) as eluant to give 1.39 g (79%) (E)-4-butyloxy-3-methoxycinnamic acid 6-hydroxyhexyl ester as colourless oil.