Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4].[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]1[NH2:26]>>[OH:15][C:12]1[CH:13]=[CH:14][C:5]([C:3](=[O:4])[CH2:2][NH:26][CH:18]2[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:16])[CH:8]=[CH:7]2
Reactant: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: NC1Cc2ccccc2C1
Product: O=C(CNC1Cc2ccccc2C1)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
5-(Chloroacetyl)-8-hydroxy-2(1H)-quinolinone (25 mg, 0.105 mmol) prepared from literature procedure (Yoshizaki, Shiro; Tanimura, Kaoru; Tamada, Shigeharu; Yabuuchi, Youichi; Nakagawa, Kazuyuki, J. Med. Chem. (1976), 19(9), 1138-42) is reacted neat with indan-2-ylamine (205 mg, 1.21 mmol) at 2.5° C. for 2 hours. The reaction mixture is purified by flash chromatography (silica, CH2Cl2/methanol 9:1). ES+ MS m/e 335 (MH+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:17](Cl)(=[O:19])[CH3:18].Cl>ClC(Cl)C>[CH:11]1([C:5]2[CH:6]=[CH:7][C:8]([C:17](=[O:19])[CH3:18])=[CH:9][CH:10]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: c1ccc(C2CCCCC2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc(C2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
Anhydrous aluminium chloride (1.65 g, 0.012 mol) is added to a solution of cyclohexyl benzene (1 g, 0.006 mol) and acetyl chloride (0.7 mL, 0.009 mol) in dichloroethane (10 mL) at −5° C. to 0° C. temperature. The reaction mixture is stirred at this temperature for 30 minutes and then treated with 2N hydrochloric acid (7 mL). It is extracted with dichloromethane (2×20 mL) and the combined extract is dried over sodium sulfate. After removing the solvent under reduced pressure the residue is purified by column chromatography (silica gel, 230-400 mesh, ethyl acetate:n-hexane 7:93) to get 1-(4-cyclohexylphenyl)ethanone.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[C:15]([CH3:17])=[CH2:16])[CH2:6][CH2:5]1)[CH3:2].[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:25]3[CH:26]=[CH:27][C:22]([CH2:21][C:20]([O:19][CH3:18])=[O:29])=[CH:23][CH:24]=3)=[CH:9][C:8]=2[CH:15]([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(=C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC1(c2ccc(C#Cc3ccc(CC(=O)OC)cc3)cc2C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-isopropenylbenzene (Intermediate 103, 120.0 mg, 0.52 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 150.0 mg, 0.52 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (32.0 mg, 0.17 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (121 mg, 0.17 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 140.0 mg (71%) of the title compound as a pale-yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]([CH2:12][OH:13])[C:9]([CH3:14])=[C:8]2[C:4]=1[C:5]1[CH2:18][CH2:17][O:16][C:15]([CH2:22][C:23]([OH:25])=[O:24])([CH2:19][CH2:20][CH3:21])[C:6]=1[NH:7]2)#[N:2].Cl[CH:27](Cl)[CH3:28].C1C=CC=CC=1>CCOC(C)=O.O=[Mn]=O>[CH2:27]([O:24][C:23](=[O:25])[CH2:22][C:15]1([CH2:19][CH2:20][CH3:21])[C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH2:18][CH2:17][O:16]1)=[C:3]([C:1]#[N:2])[CH:11]=[C:10]([CH:12]=[O:13])[C:9]=3[CH3:14])[CH3:28]
Reactant: CCCC1(CC(=O)O)OCCc2c1[nH]c1c(C)c(CO)cc(C#N)c21
Reactant: CC(Cl)Cl
Agent: O=[Mn]=O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)c(C=O)cc(C#N)c21
Temperature: 40 °C
Reaction time: 1.3 h
Yield: 96 %

Procedure:
To a solution of (5-cyano-7-hydroxymethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (8.28 g, 22 mmol) in dichloroethane/benzene (85 mL/85 mL) was added a homogeneous mixture of activated MnO2 (19.4 g, 223 mmol) and Celite (19.4 g). The solution was heated to 40° C. and agitated vigorously for 1.3 hours. The reaction was cooled, diluted with EtOAc and filtered through Celite. Concentration of the filtrate in vacuo afforded 7.88 g (96%) of a pale yellow foam. 1H NMR (CDCl3) δ 10.31 (bs, 1 H), 10.27 (s, 1H), 7.90 (s, 1H), 4.27 (m, 2H), 4.11 (m, 1H), 3.95 (m, 1H), 3.09 (m, 2H), 3.04 (d, J=17.0 Hz, 1H), 2.95 (d, J=7.6 Hz, 1H), 2.57 (s, 3H), 2.00 (m, 2H), 1.30 (m, 4H), 0.90 (t, J=7.62 Hz, 2H).
Reaction SMILES: [Cl-].[Cl:2][CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:5]=1[NH3+:6].[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)CCl>[Cl:2][CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[C:5]=1[NH:6][C:17](=[O:18])[CH2:16][Cl:15]
Reactant: O=C(Cl)CCl
Reactant: [NH3+]c1c(CCl)cccc1C(F)(F)F
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCl)Nc1c(CCl)cccc1C(F)(F)F
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A slurry of 19.85 g (0.0947 mol) of 2-(chloromethyl)-6-(trifluoromethyl) anilinium chloride (prepared as in Example 1 from 20.0 g of sulfoxide) was refluxed in ethylene dichloride with 11.2 g (0.0991 mol) of chloroacetyl chloride for 30 minutes followed by addition of 1.0 g (0.0089 mol) of additional CAC and further reflux for 30 minutes. The virtually clear solution was then cooled to room temperature, washed with 10% aqueous sodium carbonate (80 ml) and dried using sodium sulfate. Evaporation and drying gave 22.14 g of white 2'-(chloromethyl)-6'-(trifluoromethyl)-2-chloroacetanilide assaying 93.5% for an overall yield from sulfoxide of 85.7%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCCCSc1ccccc1
Reactant: O=C1CCc2ccc(O)cc2N1
Product: O=C1CCc2ccc(OCCCCSc3ccccc3)cc2N1

Procedure:
Prepared analogous to Example 4 from 7-hydroxy-3,4-dihydro-carbostyril (see N. Shigematsu et al., Chem. Pharm. Bull. 1961, 970-975) and 4-phenylmercapto-butyl bromide (bp. 96° to 103° C. at 0.02 mm Hg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]#N)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([Mg]Br)[CH:24](C)[CH3:25]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:21][CH:24]([CH3:25])[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)C2CCCCC2)CC1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)CC(C1CCCCC1)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 49.2 %

Procedure:
A solution of product from Step I (750 mg, 2.44 mmol) in THF (15 mL) and isobutylmagnesium bromide (6.1 mL, 12.2 mmol, 2 M in THF) was heated at 70° C. for 24 h. The reaction was quenched with EtOAc and washed with brine, dried (Na2SO4), and evaporated. Final purification by flash chromatography (hexane-EtOAc 25:1) afforded,406 mg of the title compound. MS m/z 339.3 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].ClC(OCC)=O.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]1[O:35][CH3:36]>ClC(Cl)Cl>[NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:11])([CH3:12])[O:10][C:6]=2[C:5]([C:13]([NH:23][C@H:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][C@H:25]2[O:35][CH3:36])=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CCOC(=O)N1CCC(N)C(OC)C1
Reactant: CC1(C)Cc2c(N)c(Cl)cc(C(=O)O)c2O1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC[C@H](NC(=O)c2cc(Cl)c(N)c3c2OC(C)(C)C3)[C@H](OC)C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 8.1 parts of 4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylic acid in 218 parts of trichloromethane and 3.43 parts of N,N-diethylethanmine were added dropwise 3.63 parts of ethyl chloroformate, keeping the temperature below 10° C. After stirring for 1/2 hour at 10° C., the whole was added to a solution of 6.26 parts of ethyl 4-amino-3-methoxy-1-piperidinecarboxylate in 145 parts of trichloromethane at 10° C. Stirring was continued for 1/2 hour at room temperature. The reaction mixture was washed with water, NaOH 5% and water and was then dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 12.3 parts (93.2%) of ethyl cis-4-[(4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl)carbonylamino]-3-methoxy-1-piperidinecarboxylate (interm. 1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[F:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[C:29]([O:30][CH3:31])[CH:28]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: COc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1OC

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3,4-Dimethoxybenzene boronic acid. MS (M+H) 413.2
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:20]2[CH:24]=[N:23][N:22]=[C:21]2[CH2:25][N:26]2[C:30](=[O:31])[C:29]3=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]3[C:27]2=[O:36])=[C:8]([CH:19]=1)[C:9]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[F:18])=[O:10])([O-:3])=[O:2].[Cl:37]NC(=O)C>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:20]2[C:21]([CH2:25][N:26]3[C:27](=[O:36])[C:28]4=[CH:35][CH:34]=[CH:33][CH:32]=[C:29]4[C:30]3=[O:31])=[N:22][N:23]=[C:24]2[Cl:37])=[C:8]([CH:19]=1)[C:9]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[F:18])=[O:10])([O-:3])=[O:2]
Reactant: CC(=O)NCl
Reactant: O=C(c1cc([N+](=O)[O-])ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O)c1c(F)cccc1F
Product: O=C(c1cc([N+](=O)[O-])ccc1-n1c(Cl)nnc1CN1C(=O)c2ccccc2C1=O)c1c(F)cccc1F

Procedure:
Following the procedure of Example 1, 5-nitro-2-[3-phthalimidomethyl-4H- 1,2,4-triazol-4-yl]-2',6'-difluorobenzophenone is reacted with N-chloroacetamide to form 5-nitro-2-[3-chloro-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl]-2',6'-difluorobenzophenone.
Reaction SMILES: [Cl:1][C:2]1[S:11][C:10]2[C:9](=O)[C:8](=[CH:13][N:14](C)[CH3:15])[CH2:7][CH2:6][N:5]([C:17](=O)[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[C:4]=2[CH:3]=1.C[NH:29]N>CO>[Cl:1][C:2]1[S:11][C:10]2[C:9]3=[N:29][N:14]([CH3:15])[CH:13]=[C:8]3[CH2:7][CH2:6][N:5]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[C:4]=2[CH:3]=1
Reactant: CNN
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cc(Cl)sc2C1=O
Solvent: CO
Product: Cn1cc2c(n1)-c1sc(Cl)cc1N(Cc1ccc([N+](=O)[O-])cc1)CC2
Temperature: 80 °C

Procedure:
A mixture of 500 mg of 2-chloro-7-[(dimethylamino)methylene]-4,5,6,7-tetrahydro-4-(4-nitrobenzoyl)-8H-thieno[3,2-b]azepin-8-one in 15 ml of absolute methanol is stirred under argon while 131 μl of N-methylhydrazine is added. The reaction mixture is heated at 80° C. for 18 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo to give 420 mg of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]([CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:4](=[O:22])[C:3]=1[C:23]([O:25]CC)=[O:24].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:14])([F:13])[F:15])=[CH:9][CH:10]=2)[N:5]([CH:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[C:4](=[O:22])[C:3]=1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1c(C)c2ccc(C(F)(F)F)cc2n(C2CCOCC2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)c(=O)n(C2CCOCC2)c2cc(C(F)(F)F)ccc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
To a solution of 330 mg (0.86 mmol) ethyl 4-methyl-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylate in ethanol (6 ml) and water (0.6 ml) was added 140 mg (3.45 mmol) NaOH at RT. The reaction mixture was stirred at 80° C. for 16 h. Then the mixture was evaporated to dryness and the residue was diluted with water (5 ml) and acidified with 2N HCl to pH ˜3. The aq. part was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (10 ml), brine (10 ml), dried over anhydrous Na2SO4 and concentrated in vacuum to give 280 mg (0.79 mmol, 91%) 4-methyl-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid which is used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[CH:5][N:4]=1.[S:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=S.CCN(C(C)C)C(C)C>C(#N)C>[CH3:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:11]2[S:10][CH2:16][C:14](=[O:15])[N:13]=2)=[N:4][CH:5]=1
Reactant: O=C1CSC(=S)N1
Reactant: Cc1cnc(CN)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CNC2=NC(=O)CS2)cn1
Temperature: 0 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
To a solution of 2-(aminomethyl)-5-methyl-pyrazine (3.69 g, 30 mmol) and Rhodanine (3.59 g, 27 mmol) in acetonitrile (100 mL) was added DIPEA (10.45 mL, 60 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (8.15 g, 30 mmol) was added in two portions within 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with acetonitrile (1.0 L) and ethyl acetate (500 mL). The combined solvents were removed under the vacuum and the crude residue was dissolved in acetonitrile (25 mL) at hot condition. After cooling in the refrigerator overnight, the solids were collected by filtration and washed with acetonitrile. After drying in air, 1.5 g (25% yield) of 2-[(5-methyl-pyrazin-2-ylmethyl)-amino]-thiazol-4-one was isolated as a white solid: HRES(+) m/e calcd for C9H10N4OS (M+H)+223.0648, found 223.0648.
Reaction SMILES: [OH-].[Na+].CO.C[O:6][C:7](=[O:23])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O>[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:7]([OH:23])=[O:6])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)C=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
5N sodium hydroxide (18.58 ml) was added dropwise to a methanol solution (100 ml) of N-cinnamoyl-L-proline methyl ester (20.07 g) under ice cooling, and the mixture was stirred at room temperature for three hours. The pH value of the obtained reaction solution was adjusted to 5 with 5N hydrochloric acid, and the resultant solution was poured into 1 l of water. The precipitate was filtered out and dried to obtain 16.84 g of N-cinnamoyl-L-proline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]
Reactant: ClCCCCBr
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Product: ClCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl

Procedure:
In a first step as depicted in Scheme 1, an appropriately substituted phenol, for example, the known compound 2,6-dichloro-4-phenylmethoxyphenol, was reacted under basic conditions with a haloalkane derivative of a desired carbon chain length, for example 1-bromo-4-chlorobutane, to attach the bridging group B, thereby affording the corresponding 1,3-dichloro-2-(4-chlorobutoxy)-5-(phenylmethoxy)benzene (A). Intermediate (A) was then reacted under basic conditions with, for example, the known compound 2,2-dimethyl-2,3-dihydrobenzo[b]furan-7-ol, to attach moiety D, as well as the benzo-fused ring, affording the corresponding 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene (B). Intermediate (B), for example 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene, as set forth above, was then reduced with hydrogen gas in the presence of a catalyst, for example 10% palladium on carbon, providing the corresponding 4-[4-(2,2-dimethyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-3,5-dichlorophenol (C). Intermediate (C) was then reacted under basic conditions with, for example, 1,1,1,3-tetrachloropropane, which simultaneously dehydrohalogenates, thereby introducing the moiety -E-G-C(R4)═C(R5)(R5) into the molecule to provide Compound 12, a novel compound of formula I. Example 1 set forth below, provides a detailed method to how Compound 12 shown in Scheme 1 was prepared.
Reaction SMILES: Br[CH2:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH3:11])[CH2:7][CH2:6]1)=O.[C:12]([O:16][C:17](=[O:32])[CH2:18][CH2:19][N:20]([CH2:24][C:25]1[S:26][C:27]([CH2:30][CH3:31])=[CH:28][CH:29]=1)[C:21]([NH2:23])=[S:22])([CH3:15])([CH3:14])[CH3:13]>CO>[C:12]([O:16][C:17](=[O:32])[CH2:18][CH2:19][N:20]([C:21]1[S:22][CH:2]=[C:3]([C@H:5]2[CH2:10][CH2:9][C@H:8]([CH3:11])[CH2:7][CH2:6]2)[N:23]=1)[CH2:24][C:25]1[S:26][C:27]([CH2:30][CH3:31])=[CH:28][CH:29]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CCc1ccc(CN(CCC(=O)OC(C)(C)C)C(N)=S)s1
Reactant: C[C@H]1CC[C@H](C(=O)CBr)CC1
Solvent: CO
Product: CCc1ccc(CN(CCC(=O)OC(C)(C)C)c2nc([C@H]3CC[C@H](C)CC3)cs2)s1
Temperature: 60 °C

Procedure:
2-Bromo-1-(trans-4-methyl-cyclohexyl)-ethanone (61 mg, 0.277 mmol) was added to a methanol (about 4 mL) solution of 3-[1-(5-ethyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (100 mg, 0.304 mmol) and the reaction was heated at 60° C. overnight to obtain the 3-[[4-(trans-4-methyl-cyclohexyl)-thiazol-2-yl]-(5-ethyl-thiophen-2-ylmethyl)-amino]-propionic acid tert-butyl ester product following a method analogous to General Procedure C. The solvent was removed at reduced pressure and the residue was dissolved in aqueous saturated sodium bicarbonate solution and ethyl acetate. The aq portion was extracted two times with EtOAc, and the combined organic portion was dried over sodium sulfate. Solvent removal under reduced pressure gave the crude product which was purified by silica gel chromatography (eluent: hexanes→19:1 hexanes:EtOAc→9:1 hexanes:EtOAc) to give the aminothiazole derivative (52 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]([C:13](=O)[CH2:14][CH3:15])=[C:11](O)[C:10](=[O:18])[N:9]2[C:19]2[CH:20]=[C:21]([CH3:27])[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[CH:4][CH:3]=1.[NH:28]([C:30]1[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=1)[NH2:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH2:14][CH3:15])=[N:29][N:28]([C:30]4[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=4)[C:11]=3[C:10](=[O:18])[N:9]2[C:19]2[CH:20]=[C:21]([CH3:27])[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)C1=C(O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Reactant: Cn1nccc1NN
Product: CCc1nn(-c2ccnn2C)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 57 using 5-(2-(4-chlorophenyl)-4-hydroxy-5-oxo-3-propionyl-2,5-dihydro-1H-pyrrol-1-yl)-1,3-dimethylpyridin-2(1H)-one (Step 89.1) and 5-hydrazinyl-1-methyl-1H-pyrazole (Step 74.2). The crude material was first purified by silica gel column chromatography (1% ammonia/5% MeOH/CH2Cl2) followed by preparative achiral SFC (column 4-Ethyl-pyridine, gradient 10-15% in 6 min_total 11 min) and trituration in Et2O. tR: 1.01 min (LC-MS 2); ESI-MS: 463 [M+H]+ (LC-MS 2); Rf=0.42 (1% ammonia/5% MeOH/CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (t, J=7.6 Hz, 3H) 1.94 (s, 3H) 2.35-2.48 (m, 2H) 3.37 (s, 3H) 3.86 (s, 3H) 6.25 (s, 1H) 6.63 (d, J=2.0 Hz, 1H) 7.34-7.48 (m, 5H) 7.58 (d, J=1.9 Hz, 1H) 7.75 (d, J=2.4 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(O)C.ClCCl.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:16][CH:17]=1
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccc(C(=O)c2ccccc2)cc1

Procedure:
4-Nitrobenzophenone (5.0 g, 0.022 mol) is dissolved in ethanol-dichloromethane (40 ml:30 ml) and hydrogenated at room temperature with 10% palladium on carbon (0.5 g) as a catalyst. The catalyst is filtered off and the filtrate is evaporated to dryness. The product is used in the next reaction step without further purification. Yield 5.2 g.
Reaction SMILES: O[C@H:2]([CH2:22][CH3:23])[C@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@H:2]2[CH2:22][CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC[C@@H](O)[C@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2S*,3R*)-3-hydroxy-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid (0.07 g, 0.22 mmol) in dry CH2Cl2 (10 mL), at 0° C., Et3N (0.091 mL, 0.65 mmol) and subsequently TBTU (0.083 g, 0.26 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 90:10 to 70:30) to afford the pure title compound (0.043 g, 65%), as a white solid. MS (ESI) m/z: 323 [M−NH4]+; (ESI) m/z: 304 [M−H]−. 1H NMR (DMSO-d6) δ 0.89 (t, J=7.43 Hz, 3H), 1.27-1.41 (m, 2H), 1.45-1.64 (m, 4H), 1.64-1.95 (m, 2H), 2.58 (t, J=7.66 Hz, 2H), 4.01 (t, J=6.49 Hz, 2H), 4.60 (dt, J=6.08, 8.01 Hz, 1H), 5.45 (dd, J=6.02, 9.42 Hz, 1H), 7.05-7.38 (m, 5H), 8.23 (d, J=9.41 Hz, 1H).