Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH:6]1[CH:8]([CH3:10])[CH3:9])=[O:4].[Li+].[OH-]>CO.O>[C:16]([O:15][C:13]([NH:12][CH2:11][C:5]1([C:3]([OH:4])=[O:2])[CH2:7][CH:6]1[CH:8]([CH3:9])[CH3:10])=[O:14])([CH3:17])([CH3:19])[CH3:18]
Reactant: COC(=O)C1(CNC(=O)OC(C)(C)C)CC1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C1CC1(CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-2-isopropyl-cyclopropanecarboxylic acid methyl ester (10.9 g, 40.2 mmol) in MeOH (320 mL) was added a solution of LiOH (4.2 g, 100 mmol) in water (98 mL). The reaction mixture was heated to reflux for 3 hours and cooled to room temperature. Excess of solvent was removed and the residue was dissolved in water (100 mL). The aqueous solution was washed with ether, acidified to pH=3 with 2N HCl and extracted with EtOAc (2×150 mL). The combined organic phase was washed with brine, dried (Na2SO4) and evaporation of the solvent provided 1-(tert-butoxycarbonylamino-methyl)-2-isopropyl-cyclopropanecarboxylic acid (9.0 g, 87%) as a colorless oil: 1H NMR (300 MHz, CD3OD) δ 0.72 (m, 1H), 0.99 (d, J=6.2 Hz, 3H), 1.06 (d, J=6.2 Hz, 3H), 1.28–1.36 (m, 3H), 1.42 (s, 9H), 3.23 (d, J=14.3 Hz, 1H), 3.54 (d, J=14.3 Hz, 1H); 13C NMR (75 MHz, CD3OD) δ 20.0, 23.0, 23.3, 28.8, 30.2, 37.6, 40.8, 80.2, 158.1, 178.5; MS (APCI) m/z 258 [M+H]+.
Reaction SMILES: [SiH3][CH:2]([SiH3])[C:3](N)=[O:4].C[O:8][P:9]([O:12][CH3:13])[O:10][CH3:11].CN(C)C1C=CC(C(O)C2C=CC(N(C)C)=CC=2)=CC=1.CO.[C:36]([O:39][CH2:40]C)(=[O:38])[CH3:37]>>[CH3:11][O:10][P:9]([O:12][CH3:13])([CH2:2][C:3](=[O:4])[CH2:37][C:36]([O:39][CH3:40])=[O:38])=[O:8]
Reactant: NC(=O)C([SiH3])[SiH3]
Reactant: CCOC(C)=O
Reactant: COP(OC)OC
Agent: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Solvent: CO
Product: COC(=O)CC(=O)CP(=O)(OC)OC
Temperature: 125 °C
Yield: 51 %

Procedure:
A mixture of the title A compound (83.9 g, 0.378 mol), bissilylacetamide (15.23 g, 0.075 mol) and trimethylphosphite (200 g, 1.61 mol) was refluxed (oil bath temp. 125° C.) under argon for 15 hours. TLC, silica gel, 10 methanol/ethyl acetate Rf =0.39, (UV and 4,4'-bis-dimethylaminobenzhydrol/heat). The reaction mixutre was cooled to 70° C., volatile components were distilled at 10 mm pressure, and then the product was kept at 0.5 mm pressure for ten minutes. The product was taken up in 250 mL ethyl acetate and washed with brine (2×50 mL), aqueous sodium bicarbonate (25 mL, vigorous reaction) and brine. The organic phase was dried (magnesium sulfate) and the solvent was removed under vaccum to give 55.79 g of the crude title compound. The product was heated to 100° C. under vaccum (0.4 mm) for five minutes to remove the more volatile impurities. The product was cooled, dissolved in 200 mL ethyl acetate, and treated with charcoal, and filtered through a pad of Celite. The filtrate was evaporated to give 43.01 g (yield 51% uncorrected) of the title compound
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[NH2:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:25][C:21]4[S:20][CH:24]=[CH:23][N:22]=4)=[O:19])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: O=C(O)c1cccc2[nH]c(-c3ccc(Cl)nc3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)c1cccc2[nH]c(-c3ccc(Cl)nc3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
2-(6-Chloropyridin-3-yl)-1H-benzo[d]imidazole-4-carboxylic acid (6; 340 mg, 1.24 mmol) was taken up in DMF (5 mL) along with thiazol-2-amine (4; 125 mg, 1.24 mmol) and HATU (943 mg, 2.48 mmol). DIEA (0.41 mL, 2.48 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and the resulting solids were collected by filtration. Purification by silica gel chromatography (pentane/EtOAc) afforded 2-(6-chloropyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide 7 as a pale yellow solid (215 mg, yield: 52%). MS (ESI) calcd for C16H10ClN5OS: 355.03; found: 356 [M+H].
Reaction SMILES: F[C:2]([F:17])(S(F)(=O)=O)[C:3](F)(F)[C:4](F)(F)[C:5](F)(F)F.O[C@@H]1C[C@@]2(C)[C@@H:30]([CH2:31][CH2:32][C:33]2=[O:37])[C@H:29]2[C@H:20]1[C@@H:21]1[C:26]([CH2:27][C@H:28]2[CH3:38])=[CH:25][C:24](=[O:39])[CH2:23][CH2:22]1.Cl.O>C1(C)C=CC=CC=1.N12CCCN=C1CCCCC2>[F:17][C@H:2]1[CH2:3][C@@:4]2([CH3:5])[C@@H:30]([CH2:31][CH2:32][C:33]2=[O:37])[C@H:29]2[C@H:20]1[C@@H:21]1[C:26]([CH2:27][C@H:28]2[CH3:38])=[CH:25][C:24](=[O:39])[CH2:23][CH2:22]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@H]2O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reaction time: 1 h

Procedure:
11.5 ml of perfluorobutane-1-sulfonic acid fluoride was added in drops at 0° C. to a solution of 13.08 g of 11α-hydroxy-7α-methyl-estr-4-ene-3,17-dione (produced by means of microbiological synthesis according to the invention [Part A]) in 250 ml of toluene and 18.2 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene. After 1 hour, it was neutralized with 2 M hydrochloric acid, added to water, extracted four times with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation in a vacuum. After the crude product was chromatographed on silica gel with a hexane/ethyl acetate gradient, 8.7 g of 11β-fluoro-7α-methyl-estr-4-ene-3,17-dione was obtained. Melting point: 101.4° C., [α]D: +135.8° (CHCl3).
Reaction SMILES: N1(N)C2C(=NC=CC=2)C=[CH:2]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([NH:22][C:23]([C:25]1[CH:26]=[N:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[N:29][CH:30]=1)=[O:24])[CH:17]=[CH:16]2>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([NH:22][C:23]([C:25]1[C:26]([CH3:2])=[N:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[N:29][CH:30]=1)=[O:24])[CH:17]=[CH:16]2
Reactant: Nn1ccc2ncccc21
Reactant: COc1ccc2c(ccn2NC(=O)c2cnc(-c3ccccn3)nc2)c1
Product: COc1ccc2c(ccn2NC(=O)c2cnc(-c3ccccn3)nc2C)c1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
Following procedures similar to those of Example 127, but substituting 5-methoxy-indol-1-ylamine for pyrrolo[3,2-b]pyridine-1-ylamine, and the reaction is stirred at 150° C. for 1 h, there is prepared 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-methoxy-indol-1-yl)-amide (22%) as a solid. MS: 360 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.88 (s, 3H), 3.84 (s, 3H), 6.50 (d, H) 6.90 (m, H), 7.13 (d, H), 7.25-7.34 (m, 2H), 7.60 (m, H), 8.05 (m, H), 8.65 (d, H), 8.79 (d, H), 9.20 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][C:5]([F:11])=[C:4]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:11][C:5]1[CH:6]=[C:7]([C:8](=[O:10])[CH3:9])[CH:2]=[N:3][C:4]=1[O:12][CH2:13][C:14]([F:15])([F:16])[F:17]
Reactant: CC(=O)c1cc(F)c(OCC(F)(F)F)nc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)c1cnc(OCC(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A mixture of 1-(2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.23 g, 0.86 mmol, Step-3) and triethylamine (0.17 mL, 1.20 mmol) in ethanol (9 mL) is stirred at rt for 1 hour. Then 10% palladium on carbon (0.03 g, 0.28 mmol) is added to the mixture. The mixture is stirred at rt under a balloon of hydrogen gas for 5 hours. After filtration through a pad of celite, the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (5:1) to give 0.15 g (76% yield) of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([NH:21][NH2:22])=O)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].COC(OC)OC.[C:34](#N)C.[CH3:37][C:38]1[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=1[NH2:40]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:40]([C:39]4[CH:41]=[CH:42][CH:43]=[CH:44][C:38]=4[CH3:37])[CH:34]=[N:22][N:21]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24]
Reactant: Cc1ccccc1N
Reactant: CC#N
Reactant: NNC(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: Cc1ccccc1-n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared according to general Method B using 4-Chloro-N-(5-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide (100 mg, 0.234 mmol), trimethylorthoformate (80 mg, 0.75 mmol), acetonitrile (2 mL), 2-methylaniline (62 mg, 0.50 mmol) and acetic acid (1.0 mL). 1H NMR: (CD3OD, ppm): 8.82 (s, 1H), 8.40 (s, 1H), 8.27 (d, 1H), 8.05 (m, 1H), 7.75 (d, 1H), 7.61 (s, 1H), 7.39 (m, 1H), 7.32 (m, 1H), 7.25 (m, 2H), 2.15 (s, 3H). MS (ES) [M+H]+ expected 528.0. found 528.0.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:54]([O:58][C:59]([NH:61][CH2:62][C:63](O)=[O:64])=[O:60])([CH3:57])([CH3:56])[CH3:55]>O1CCCC1>[C:54]([O:58][C:59]([NH:61][CH2:62][C:63]([NH:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:64])=[O:60])([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](N)CC(C)C
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](CC(C)C)NC(=O)CNC(=O)OC(C)(C)C
Yield: 79 %

Procedure:
from N-(2-L-leucyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-glycine. Yield 79%. [α]D =-1.4° (c=0.87, tetrahydrofuran).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1ncccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2ncccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (867 mg, 6.1 mmol) was dissolved in absolute ethanol (130 mL), and then triethylamine (3.75 mL, 27.3 mmol) and 2-(bromomethyl)pyrimidine (1.57 g, 9.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration, and the filtrate was evaporated. The residue was triturated in water, filtered, and washed with water followed with diethyl ether. The solid was then dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford 6-methyl-2-[(pyrimidin-2-ylmethyl)sulfanyl]pyrimidin-4-ol (326 mg, 23% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.13 (s, 3H), 4.67 (s, 2H), 6.02 (bs, 1H), 7.42 (t, J=4.9 Hz, 1H), 8.78 (d, J=4.9 Hz, 2H); LRMS (ES+) m/z 235 (100%, M+1).
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[CH:46][C:45]=2[S:52]([C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][C:55]=2[C:62]2[CH:67]=[CH:66][C:65]([NH2:68])=[C:64]([N+:69]([O-])=O)[CH:63]=2)=[O:53])=[CH:40][C:39]=1[N+:72]([O-])=O>>[NH2:69][C:64]1[CH:63]=[C:62]([C:55]2[CH:56]=[C:57]([O:60][CH3:61])[CH:58]=[CH:59][C:54]=2[S:52]([C:45]2[CH:46]=[CH:47][C:48]([O:50][CH3:51])=[CH:49][C:44]=2[C:41]2[CH:42]=[CH:43][C:38]([NH2:37])=[C:39]([NH2:72])[CH:40]=2)=[O:53])[CH:67]=[CH:66][C:65]=1[NH2:68]
Reactant: COc1ccc(S(=O)c2ccc(OC)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: COc1ccc(S(=O)c2ccc(OC)cc2-c2ccc(N)c(N)c2)c(-c2ccc(N)c(N)c2)c1
Yield: 90 %

Procedure:
Following the procedure described in Example 40 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of (4-amino-3-nitrophenyl)-4-methoxyphenyl sulfoxide, the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=[O:23])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]=[O:23])=[CH:14][CH:13]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cl)cc1Oc1ccc(C=O)c2ccccc12
Yield: 55.2 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.31 g, 2.0 mmol), 4-hydroxy-1-naphthaldehyde (0.34 g, 2.0 mmol) and cesium carbonate (0.64 g, 2.0 mmol) were heated with stirring in dry DMF (4 mL) at ambient temperature for 10 days. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (2×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(4-formylnaphthalen-1-yloxy)benzonitrile (0.34 g, 56%) as a tan solid, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[C-:14]#[N:15].[K+].I[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:10]([C:4]1[CH:5]=[C:6]([Cl:9])[C:7]([C:14]#[N:15])=[C:2]([Br:1])[C:3]=1[O:13][CH3:18])(=[O:12])[CH3:11]
Reactant: [C-]#N
Reactant: CC(=O)c1cc(Cl)c(F)c(Br)c1O
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(C(C)=O)cc(Cl)c(C#N)c1Br
Temperature: 85 °C
Yield: 76.2 %

Procedure:
1-(3-Bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (2.0 g, 7.5 mmol, Example 43, Step 1) was combined with potassium cyanide (0.58 g, 9.0 mmol) in N,N-dimethylformamide (16 mL) and heated to 85° C. in an oil bath. After heating for 18 hrs, the reaction was allowed to cool to room temperature and iodomethane (0.90 mL, 11 mmol) and potassium carbonate (2.1 g, 15 mmol) were added. The reaction was heated to 65° C. and monitored by LC/MS. After heating for 3 hrs the reaction was complete and allowed to cool to room temperature, then taken up in ethyl acetate and washed with water, brine, and dried over magnesium sulfate. The resultant solution was concentrated to give the crude product as a dark oil. The product was purified by FCC on silica gel eluting hexane:ethyl acetate gradient to give 4-acetyl-2-bromo-6-chloro-3-methoxybenzonitrile (1.65 g, 75%) as a solid residue. LCMS calculated for C10H8BrClNO2(M+H)+: m/z=287.9, 289.9; found: 288.1, 290.0.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]([C@@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)=[CH:16][N:17]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)[CH2:50][CH2:49]1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]([C@@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)=[CH:16][N:17]=2)=[CH:8][C:3]=1[C:4]([N:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)[CH2:50][CH2:49]1)=[O:6]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: COC(=O)c1cc(-c2ncc([C@@H]3CCCO3)[nH]2)c(C)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2ncc([C@@H]3CCCO3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.2 %

Procedure:
To a round-bottom flask was added a solution of (S)-methyl 2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate (compound 257.4, 143 mg, 0.500 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL). HBTU (285 mg, 0.750 mmol, 1.50 equiv) was added to the reaction, and it was stiffed for 30 min at 25° C. To this was added 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 133 mg, 0.600 mmol, 1.20 equiv) and DIEA (390 mg, 3.02 mmol, 6.04 equiv) dropwise. The resulting solution was stirred for 30 min at 25° C., then quenched with 20 mL of water. The mixture was extracted with 3×25 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with methanol/ethyl acetate (1:30) as eluent. The product (˜100 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.03% NH3H2O and CH3CN (35% CH3CN up to 52% in 8 min, up to 100% in 1 min, down to 35% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 34.6 mg (15%) of the title compound as a white solid. m/z (ES+) 455 (M+H)+.
Reaction SMILES: C(O[C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[C:7]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13](O)[CH2:12][CH2:11]1)=[O:8])C=C.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:7]([O:8][C:19]1[CH:20]=[CH:5][C:6]([C:7]([O:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[CH2:14][CH2:15]2)=[O:8])=[CH:17][CH:18]=1)[CH:6]=[CH2:5]
Reactant: O=C(Cl)CCCCCBr
Reactant: C=CCOc1ccccc1C(=O)O[C@H]1CC[C@H](O)CC1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: C=CCOc1ccc(C(=O)O[C@H]2CC[C@H](C(=O)CCCCCBr)CC2)cc1

Procedure:
55.2 g (0.2 mol) of trans-4-hydroxycyclohexyl allyloxybenzoate prepared as described in Example 1 were dissolved in 300 ml of dry toluene, and 43 g (0.205 mol) of 6-bromohexanoyl chloride (prepared from the free acid by conventional reaction with thionyl chloride; b.p. 60-62° C. at 0.04 mbar) were added dropwise at 105° C. over the course of 60 minutes with stirring. After the mixture had been stirred at 105° C. for a further 90 minutes, the solvent was stripped off under reduced pressure, and the residue was crystallized out using petroleum benzine/methyl tert-butyl ether (20:1), giving 83 g (92%) of trans-[4-(6-bromo-hexanoyl)cyclohexyl] 4-allyloxybenzoate, melting point 56° C. 79 g (0.174 mol) of this ester, 25 g (0.21 mol) of potassium methacrylate and 0.2 g of 2,6-di-tert-butyl-4-methylphenol (stabilizer) were dissolved in 400 ml of dimethylformamide, and the mixture was heated at 70-75° C. for 3 hours with stirring. The solvent was then distilled off under reduced pressure, the residue was taken up in 400 ml of methyl tert-butyl ether, and the solution was washed with water, 0.05 N NaOH, and again with water, dried and evaporated. The residue was recrystallized from methanol, yielding 70 g (87.5%) of the title compound, which melts at 50° C. and clears at 55° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]([OH:11])=[S:10])=[C:5]([CH3:8])[S:6][CH:7]=1.[Cl:12]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl.C(O)(=O)C>[Cl:12][C:7]1[S:6][C:5]([CH3:8])=[C:4]([C:9]([OH:11])=[S:10])[C:3]=1[O:2][CH3:1]
Reactant: COc1csc(C)c1C(O)=S
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1c(Cl)sc(C)c1C(O)=S
Reaction time: 2 h

Procedure:
Equimolecular amounts of the thiophene (d) above and N-chlorosuccinimide were dissolved in 1/1 chloroform/acetic acid mixture. The mixture was stirred for two hours and then poured into water. The organic layer was washed with 10% aqueous sodium hydroxide, dried over sodium sulphate and the solvent evaporated. The carboxylic acid was purified by recrystallisation from ethanol, m.p. 193°-194° C.
Reaction SMILES: Br[C:2]1(Br)[CH:6]=[CH:5][S:4][CH:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C(O[Na])(C)(C)C.C1C=CC(P([C:32]2[C:41]([C:42]3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=C[CH:49]=[C:48]4[C:43]=3[CH:44]=[CH:45][CH:46]=[CH:47]4)=C3[C:35]([CH:36]=[CH:37][CH:38]=[CH:39]3)=[CH:34][CH:33]=2)C2C=CC=CC=2)=CC=1.C(CCCCCCCCC[NH2:82])CCCCCCC>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:32]([CH:41]([N:82]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:3]2[S:4][CH:5]=[CH:6][C:2]1=2)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: BrC1(Br)C=CSC1c1cccs1
Reactant: CCCCCCCCCCCCCCCCCN
Reactant: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCC(CCCCCCCC)n1c2ccsc2c2sccc21
Temperature: 110 °C
Reaction time: 7 h
Yield: 813.6 %

Procedure:
To a solution of 3,3-dibromo-2,2′-bithiophene (4.92 g, 15.3 mmol), t-BuONa (3.54 g, 36.8 mmol), Pd2 dba3 (0.35 g, 0.382 mmol) and BINAP (0.95 g, 1.53 mmol) in toluene (38 mL) under an argon atmosphere was added 9-octylnonylamine (4 g, 15.7 mmol). The reaction mixture was subsequently stirred at 110° C. over a period of 7 hours. The reaction mixture was allowed to cool to room temperature followed by the addition of water. The organic layer was removed and the remaining aqueous phase extracted several times with diethyl ether. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. Purification by column chromatography using hexanes as the eluant afforded the title compound as a light green solid (5.2 g, 81% yield): mp: 60° C.; GC-Ms: 417.5; 1H NMR (400 MHz, CDCl3, ppm) δ: 7.11(d, 2H), 7.02-7.01(d, 2H), 4.23-4.19(m, 1H), 2.08(m, 2H), 1.85-1.80(m, 2H), 1.22-1.07(m, 24 H), 0.86-0.82(t, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ: 144.2, 122, 4, 114.9, 59.9, 35.4, 31.9, 29.4, 29.3, 26.7, 22.8, 14.2.