Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[O:21]=[C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:22])[N:12]1[CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][O:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(CCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc(CCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 2 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of 2-{2-[4-(2-hydroxy-ethyl)phenyl]-ethyl}-isoindole-1,3-dione (Preparation 10, 21.0 g, 71.25 mmol) in methyl ethyl ketone (315 mL) was cooled to 0° C. Triethylamine (14.9 mL, 106.87 mmol) was added followed by the dropwise addition of methane sulfonyl chloride (6.07 mL, 78.37 mmol). The reaction was stirred at 0-4° C. for 1 hour and then allowed to warm to room temperature. An aqueous solution of potassium carbonate (1M, 210 mL) was added and the mixture stirred. The organic and aqueous layers were separated and the aqueous re-extracted with methyl ethyl ketone (50 mL). The combined organic layers were concentrated to 40 mL by distillation. Tert-butyl methyl ether (300 mL) was slowly added to the hot solution causing crystallisation to occur. The mixture was allowed to cool to room temperature and then allowed to stir for 72 hours. The solid was removed by filtration and washed with tert-butyl methyl ether (3×25 mL). The solid was dried in vacuo at 45° C. for 4 hours to yield the title compound as a light brown solid, in 92% yield, 24.6 g.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[C:22]([C:25]1[S:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33](I)[C:27]=2[CH:26]=1)(=[O:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.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>[C:22]([C:25]1[S:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:6]3[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=3[O:16][CH2:17][C:18]([F:19])([F:20])[F:21])[C:27]=2[CH:26]=1)(=[O:24])[CH3:23]
Reactant: CC(C)c1cc(B(O)O)c(OCC(F)(F)F)c(C(C)C)c1
Reactant: CC(=O)c1cc2c(I)cccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cc2c(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)(F)F)cccc2s1

Procedure:
A mixture of 1.08 mmol of 3,5-di-iso-propyl-2-(2,2,2-trifluoroethoxy)-phenylboronic acid, 1.62 mmol of 2-acetyl-4-iodo-benzo[b]thiophene and 62 mg (0.05 mmol) of Pd(PPh3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 2-acetyl-4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]thiophene.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[C:2]1C=O.[H-].[Na+].[CH3:14][S:15](Cl)(=[O:17])=[O:16].CN([CH:22]=[O:23])C>C(OCC)(=O)C>[CH3:14][S:15]([N:1]1[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[C:3]([CH:22]=[O:23])=[CH:2]1)(=[O:17])=[O:16]
Reactant: O=Cc1cc2cccnc2[nH]1
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)n1cc(C=O)c2cccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
7-Azaindole-2-carboxaldehyde (2.31 g, 15.8 mmoles) from step 1 was dissolved in DMF (50 ml). Sodium hydride (0.76 g, 19 mmol) was added and the reaction was stirred at room temperature for 15 min. Methanesulfonyl chloride (1.8 ml, 24 mmoles) was added and the reaction was stirred for 3 h. The reaction mixture was diluted with ethyl acetate and washed trice with 5% lithium chloride solution, then brine. The organic layer was dried (magnesium sulfate) and concentrated to provide 1-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2.84 g, 80% yield). 1H NMR (CDCl3) δ: 3.71 (3H, s), 7.42 (1H, dd, J=4.7 Hz, 8.1 Hz), 8.30 (1H, s), 8.57 (1H, dd, J=1.7 Hz, 4.7 Hz), 8.63 (1H, dd, J=1.7 Hz, 8.1 Hz), 10.07 (s, 1H).
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.[CH:14]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)=[CH2:15].C(C1C=CC=CN=1)=C.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH2:14][CH2:15][N:2]1[CH2:3][CH2:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[CH2:1]1
Reactant: c1ccc2c3c([nH]c2c1)CCNC3
Reactant: C=Cc1ccc2ccccc2n1
Agent: C=Cc1ccccn1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: c1ccc2nc(CCN3CCc4[nH]c5ccccc5c4C3)ccc2c1

Procedure:
The title compound was prepared following the procedure of Example 2 with the exception that 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole was used instead of 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and 2-vinylquinoline replaced 2-vinylpyridine. The product was converted to the dihydrochloride; mp 195°-197° C.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].CC[O:9][CH2:10][CH3:11].[Cl:12][C:13]1[C:14]([CH2:22][PH:23](COCC)=[O:24])=C([CH:19]=[CH:20][CH:21]=1)C(O)=O.Cl>O>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:1]2[C:14]=1[CH2:22][P:23]([O:9][CH2:10][CH3:11])(=[O:24])[CH2:3][C:2]2=[O:4]
Reactant: CC(C)(C)[O-]
Reactant: CCOC[PH](=O)Cc1c(Cl)cccc1C(=O)O
Reactant: CCOCC
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCOP1(=O)CC(=O)c2cccc(Cl)c2C1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a rapidly stirred suspension of 16 g. (140 mmol.) of potassium t-butoxide in 600 mL. of anhydrous ether was added dropwise under nitrogen 11.7 g. (35 mmol.) of ethyl ester of 3-chloro-2-[(ethoxymethylphosphinyl)methyl]benzoic acid previously prepared as in Step A of Part B above in 50 mL. of ether. The reaction mixture was stirred for an additional 30 minutes. 100 mL. of water was added followed by concentrated hydrochloric acid to provide a pH of 7. The ether layer was separated, washed with brine and concentrated. Crystallization from hexane/methylene chloride gave 7.5 g. (83% yield) of 8-chloro-2-ethoxy-2,3-dihydro-2-oxo-4(1H)-isophosphinolinone as a representative species of compounds of formula (II).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)(=O)C(Cl)=O.[NH2:21][C@@H:22]([C:26]([OH:28])=[O:27])[C@@H:23]([CH3:25])[OH:24].[OH-].[Na+]>C1(C)C=CC=CC=1.C(#N)C.C1COCC1>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]([NH:21][C@@H:22]([C:26]([OH:28])=[O:27])[C@@H:23]([CH3:25])[OH:24])=[O:14])[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](C(=O)N[C@@H](C(=O)O)[C@@H](C)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of trans-4-pentylcyclohexane carboxylic acid (198 mg, 1.0 mmol) in dry toluene (1 mL) is treated with oxalyl chloride (760 mg, 5.9 mmol) at 0° C. and the mixture is stirred for 2 h at the same temperature and 1 h at room temperature. Excess reagent is removed in vacuo. A solution of the crude acid chloride in dry acetonitrile (2 mL) is added to a mixture of D-allo-Thr (100 mg, 0.85 mmol), 2N aq. NaOH (600 μl, 1.20 meq) and TEA (85 mg, 0.85 mmol) in THF (1.5 mL), following the procedure described in Example 1. The crude product 2c-6 is purified by chromatography (1.5×18 cm column, 5% CH3OH and 0.4% HOAc in CH2Cl2): NMR δ 0.88 (t, J≃7, 3 H), 4.15 (m, 1 H), 4.54 (m, 1 H), 6.49 (d, 1H); MS (CI, CH4) m/z 300 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29](#[N:32])[CH2:30][CH3:31].[CH:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>>[OH:40][CH:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:30]([CH3:31])[C:29]#[N:32]
Reactant: O=Cc1ccccc1
Reactant: CCC#N
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: CC(C#N)C(O)c1ccccc1
Reaction time: 2 h
Yield: 90 %

Procedure:
Under an argon atmosphere, CuO(tert-Bu) (0.03 mmol, 60 μL in THF) and 1,2-bis(diphenylphosphino)ethane (hereinafter, referred to as dppe) (18 mg, 0.045 mmol) were mix dried under vacuum for 1 hour. To the residue, dimethylsufoxide (hereinafter, referred to as DMSO) (0.3 mL), propionitrile (0.3 mL), and benzaldehyde (30 μL, 0.3 mmol) were added to start the reaction. After 2 hours, saturated ammonium chloride was added, and the product was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over sodium sulfate. Filtration, evaporation, and purification by silica gel column chromatography (ethyl acetate/hexane=1/3) gave the product in 90% yield (44 mg). A diastereomeric rate of the obtained compound was determined to be 1.5:1 (syn:anti).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([O:12][N:13]=[C:14]([C:18]2[N:19]=[C:20]([NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:21][CH:22]=2)[C:15]([OH:17])=O)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:43][CH:44]1[C:51](=[O:52])[N:50]2[CH:45]1[S:46](=[O:82])[CH2:47][C:48]([CH:69]=[CH:70][O:71][S:72]([C:75]1[CH:81]=[CH:80][C:78]([CH3:79])=[CH:77][CH:76]=1)(=[O:74])=[O:73])=[C:49]2[C:53]([O:55][CH:56]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:56]([O:55][C:53]([C:49]1[N:50]2[CH:45]([S:46](=[O:82])[CH2:47][C:48]=1[CH:69]=[CH:70][O:71][S:72]([C:75]1[CH:76]=[CH:77][C:78]([CH3:79])=[CH:80][CH:81]=1)(=[O:73])=[O:74])[CH:44]([NH:43][C:15](=[O:17])[C:14](=[N:13][O:12][C:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11][CH2:10][CH2:9]1)[C:18]1[N:19]=[C:20]([NH:23][C:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[S:21][CH:22]=1)[C:51]2=[O:52])=[O:54])([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CC(C)(C)OC(=O)C1(ON=C(C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Reactant: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3S(=O)C2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC4(C(=O)OC(C)(C)C)CCC4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C3S(=O)C2)cc1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
The syn isomer of 2-(1-t-butoxycarbonylcyclobutoxyimino)-2-(2-tritylaminothiazol-4-yl)-acetic acid prepared according to Belgian Patent 876,541 (4.42 g) and 4-dimethylaminopyridine (0.25 g) are added to a solution of the E form of 7-amino-2-benzhydryloxycarbonyl-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (product 7d) (4.34 g) in methylene chloride (50 cc). The mixture is cooled to 5° C. and a solution of N,N'-dicyclohexylcarbodiimide (1.69 g) in methylene chloride (30 cc) is added dropwise in the course of 10 minutes. The temperature is left to rise, the mixture is stirred for 4 hours at 20° C. and concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa) and the residue is taken up in ethyl acetate (200 cc). The solution is washed with water (2×100 cc), 0.1 N hydrochloric acid (100 cc), a saturated aqueous solution of sodium bicarbonate (100 cc) and water (100 cc), dried over sodium sulphate and filtered and the filtrate is concentrated to dryness at 25° C. under 20 mm Hg (2.7 kPa). The residue is chromatographed on a column of Merck silica gel (0.06-0.2) (180 g) (diameter of the column: 3 cm, height: 60 cm). Elution is carried out with a 70/30 (by volume) cyclohexane/ethyl acetate mixture (1 liter), 60 cc fractions being collected. Fractions 6 to 10 are concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa) and this yields a product (7a) (2.7 g) in the form of a cream-coloured powder.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=2[O:26][CH2:27][C:28]([F:31])([F:30])[F:29])/[C:9]1=[O:32])=O)(C)(C)C.[F:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:49])=[C:38]([CH:40]=[N:41][C:42]([O:44][Si](C)(C)C)=[CH2:43])[CH:39]=1>C1(C)C=CC=CC=1.ClCCl>[F:29][C:28]([F:31])([F:30])[C:27]([OH:44])=[O:26].[Br:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][CH2:27][C:28]([F:30])([F:29])[F:31])=[C:19]([CH:18]2[CH2:43][C:42](=[O:44])[NH:41][CH:40]([C:38]3[CH:39]=[C:34]([F:33])[CH:35]=[CH:36][C:37]=3[CH3:49])[C:10]32[C:11]2[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[NH:8][C:9]3=[O:32])[CH:24]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cc(Br)ccc2OCC(F)(F)F)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Br)ccc2OCC(F)(F)F)C12C(=O)Nc1cc(Cl)ccc12
Product: O=C(O)C(F)(F)F
Yield: 9.8 %

Procedure:
In a manner similar to the method described in Example 228d, E/Z-3-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.06 g, 2 mmol) was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (0.06 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:33][CH2:34][C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][C:3]=1[C:4]([NH:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=1)=[O:6]
Reactant: O=C(O)c1cc(OCc2cccc(Cl)c2)ccc1Cl
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNC(=O)c2cc(OCc3cccc(Cl)c3)ccc2Cl)cc1
Temperature: 40 °C

Procedure:
A solution of 2-chloro-5-{[(3-chlorophenyl)methyl]oxy}benzoic acid (250 mg, 0.84 mmol) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (250 mg, 1.3 mmol) in DCM (3 ml) was stirred at room temperature for 30 min. A solution of methyl 4-(aminomethyl)benzoate hydrochloride (262 mg, 1.3 mmol) in DCM (2 ml) was added followed by N-ethyl-N-(1-methylethyl)-2-propanamine (220 ul, 1.3 mmol). The mixture was heated at 40° C. overnight. The mixture was then diluted with methanol and purified by SCX cartridge eluting with methanol. The fractions were combined and evaporated to give the title compound as a white solid. MS (ES+) m/z 444 [M+H]− (C23H1935Cl2NO4). 1H-NMR (400 MHz, d6-DMSO) δ 3.85 (3H, s), 4.51 (2H, d, J 4), 5.17 (2H, s), 7.12 (2H, d, J 8), 7.42-7.49 (7H, m), 7.95 (2H, d, J 8), 9.06 (1H, s).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][C:6]=1[Cl:15])[CH:2]=[CH2:3].[CH:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18](O)[CH:17]=1.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1.C(Cl)(Cl)Cl>[N+:22]([C:21]1[CH:16]=[CH:17][C:18]([O:13][C:12](=[O:14])[CH2:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[C:6]([Cl:15])[CH:7]=2)=[CH:19][CH:20]=1)([O-:24])=[O:23]
Reactant: C=CCOc1ccc(CC(=O)O)cc1Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C=CCOc1ccc(CC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Allyloxy-3-chloro-phenylacetic acid (4.3 g) was dissolved in dry tetrahydrofuran (20 ml). To the solution was added p-nitrophenol (2.28 g) in dry chloroform (30 ml). DCC (4.1 g) was then added and the whole was then stirred at room temperature overnight.
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](O)(=[O:22])[CH2:19][CH:20]=[CH2:21]>ClCCl.N1(C2C=CN=CC=2)CCCC1>[O:1]([C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][O:15][C:18](=[O:22])[CH2:19][CH:20]=[CH2:21])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCOc1ccc(Oc2ccccc2)cc1
Reactant: C=CCC(=O)O
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C=CCC(=O)OCCOc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
0.05 g of 4-pyrrolidinopyridine and 17.25 g of 2-(4-phenoxyphenoxy)-ethanol are added at room temperature, with stirring, to a solution of 6.45 g of 3-butenoic acid in 100 ml of dichloromethane. At a temperature of 0° C., 17.0 g (82.5 mmol) of N,N-dicyclohexylcarbodiimide are then added in portions, and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is filtered. The precipitate which has been separated off is discarded, and the filtrate is washed with water and dried over sodium sulfate. After concentration by evaporation, the oily residue is purified by column chromatography on silica gel with hexane/ethyl acetate (9:1), yielding 20.0 g of 3-butenoic acid 2-(4-phenoxyphenoxy)-ethyl ester of the formula ##STR12## in the form of a colourless oil having a refractive index of nD23 : 1.5538.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O>>[CH:1]1([NH:4][CH2:5][C:6]2[CH:13]=[CH:12][CH:11]=[C:8]([CH3:9])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: Cc1cccc(C=O)c1
Product: Cc1cccc(CNC2CC2)c1

Procedure:
prepared by reaction of cyclopropylamine with 3-methyl-benzaldehyde
Reaction SMILES: [Cl:1][O-].[Ca+2].Cl[O-].[F:6][CH:7]([F:20])[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][CH2:16][CH2:15][C:14]2=[O:19]>O.C(O)(=O)C.C(#N)C.O>[Cl:1][C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([O:8][CH:7]([F:6])[F:20])[CH:10]=1)[O:17][CH2:16][CH2:15][C:14]2=[O:19]
Reactant: [O-]Cl
Reactant: O=C1CCOc2c(OC(F)F)cccc21
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: O=C1CCOc2c(OC(F)F)cc(Cl)cc21
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of calcium hypochlorite (29.4 g, 137.8 mmol) in water:acetic acid (125:9.5) was added a solution of 8-difluoromethoxychroman-4-one (7.4 g, 34.6 mmol, see step (iv) above) in acetonitrile (20 mL), whereafter the reaction mixture was stirred overnight. The mixture was diluted with water and extracted with ether (3×) and with EtOAc (1×). The combined organic layers were washed with water (3×), dried (Na2SO4) and evaporated, yielding 8.0 g (93%) of the sub-title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([C:38](=[O:40])[CH3:39])[CH2:13][CH2:12]1)[C:17]([CH:19]1[CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.5 %

Procedure:
To 3-[(4-Methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (58 mg, 0.132 mmol) in dichloromethane (1.3 ml) was added pyridine (64 ul, 0.789 mmol), followed by acetic anhydride (50 ul, 0.526 mmol) and a catalytic amount of DMAP. The resulting solution was stirred for 18 hours at room temperature and then quenched with a saturated solution of NaHCO3 (5 ml). The aqueous phase was separated and washed with ethyl acetate (2×5 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was then purified by preparative chromatography (100/90/16/1 CH2Cl2/CHCl3/MeOH/Et3N) to obtain 50 mg (78%) of 3-[(1-Acetyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[NH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12]>C(Cl)(Cl)Cl>[CH3:7][C:3]([C:4]1[O:5][CH2:11][C:10]([CH3:14])([CH3:13])[N:9]=1)([CH3:8])[CH2:2][Cl:1].[OH:12][CH2:11][C:10]([NH:9][C:4](=[O:5])[C:3]([CH3:8])([CH3:7])[CH2:2][Cl:1])([CH3:14])[CH3:13]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: CC(C)(N)CO
Solvent: ClC(Cl)Cl
Product: CC(C)(CO)NC(=O)C(C)(C)CCl
Product: CC1(C)COC(C(C)(C)CCl)=N1
Reaction time: 8 h

Procedure:
2-(1,1-dimethyl-2-chloroethyl)-4,4-dimethyl-2-oxazoline was prepared as follows. Initially, N-(2-hydroxy-1,1-dimethylethyl)-3-chloropivalamide was prepared by adding dropwise, at room temperature, a solution of 3-chloropivaloyl chloride (1.0 eq., 56 g, 0.36 mol) in CHCl3 (100 mL) to a stirred mixture of 2-amino-2-methyl-1-propanol (2.0 eq., 64.4 g, 0.72 mol) in CHCl3 (300 mL) over a period of one (1) hour. This mixture was allowed to auto-reflux for twenty (20) minutes and was then stirred overnight. The whitish-yellow precipitate that formed was gravity filtered, and the resulting yellow-brown solution was concentrated and purified by vacuum distillation (140-150° C., 1 mm Hg). The resulting yellow oil (61 g, 81%) was pure N-(2-hydroxy-1,1-dimethylethyl)-3-chloropivalamide as evidenced by 1H NMR (CDCl3): δ1.13 (s, 6H, CH3, CH3), 1.30 (s, 6H, CH3, CH3), 2.2 (br s, 1H, OH), 3.3 (s, 2H, CH2,—Cl), 3.6 (s, 2CH2—OH), 5.78 (br s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[F:11].CO[CH:14](OC)[CH2:15][NH2:16].Cl.[S-:20][C:21]#[N:22].[K+]>C(O)C.[Pd].CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:16]2[CH:15]=[CH:14][NH:22][C:21]2=[S:20])=[CH:5][C:4]=1[F:11]
Reactant: COc1ccc(C=O)cc1F
Reactant: COC(CN)OC
Reactant: N#C[S-]
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CCO
Product: COc1ccc(Cn2cc[nH]c2=S)cc1F
Temperature: 95 °C
Yield: 65 %

Procedure:
A mixture of 4-methoxy-3-fluorobenzaldehyde (15.4 g, 0.1 mol), aminoacetaldehyde dimethyl acetal (10.5 g, 0.1 mol), and methanol (1 ml) was heated at 95° C. for 10 minutes. The resulting mixture was dissolved in ethanol (150 ml) and hydrogenated over 10% Pd on carbon (1 g) until H2 uptake slowed (about 2 hours). The catalyst was filtered and the filtrate was treated with 1.5N hydrochloric acid (80 ml) and potassium thiocyanate (10.4 g, 0.11 mol). The resulting mixture was boiled until the volume was reduced to 100 ml, then it was heated at reflux an additional 1 hour and cooled to 5° C. The crystalline precipitate was filtered, washed with water, and dried. Recrystallization from ethanol gave 1-(4'-methoxy-3'-fluorobenzyl)-1,3-dihydro-2H-imidazole-2-thione, 65% yield, m.p. 156°-157° C.