Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]12[CH2:23][C@H:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[N:13]1[C@@H:8]([CH2:9][C@H:10]([OH:26])[CH2:11][CH2:12]1)[C:7](=[O:27])[NH:6]2)=[O:4].[CH3:28][O:29][C:30]1[C:39]([CH3:40])=[C:38]2[C:33]([C:34](O)=[CH:35][C:36]([C:41]3[S:42][CH:43]=[C:44]([C:46]#[CH:47])[N:45]=3)=[N:37]2)=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C@@:5]12[CH2:23][C@H:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[N:13]1[C@@H:8]([CH2:9][C@H:10]([O:26][C:34]3[C:33]4[C:38](=[C:39]([CH3:40])[C:30]([O:29][CH3:28])=[CH:31][CH:32]=4)[N:37]=[C:36]([C:41]4[S:42][CH:43]=[C:44]([C:46]#[CH:47])[N:45]=4)[CH:35]=3)[CH2:11][CH2:12]1)[C:7](=[O:27])[NH:6]2)=[O:4]
Reactant: C#Cc1csc(-c2cc(O)c3ccc(OC)c(C)c3n2)n1
Reactant: COC(=O)[C@@]12C[C@H]1C=CCCCCN(C)C(=O)N1CC[C@@H](O)C[C@H]1C(=O)N2
Agent: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCC/C=C\[C@@H]5C[C@@]5(C(=O)OC)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: COC(=O)[C@@]12C[C@H]1/C=C\CCCCN(C)C(=O)N1CC[C@@H](O)C[C@H]1C(=O)N2
Solvent: C1CCOC1
Product: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)OC)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of compound 36 (0.143 g, 1 eq.), compound 209b (0.112 g, 1 eq.), and polystyrene supported triphenylphosphine (0.411 g, 2 eq.) in anhydrous THF (8 mL) was added dropwise DIAD (150 μL, 2 eq.) at 0° C. The reaction mixture was stirred at room temperature overnight. The mixture was filtered on autocup, washed with dichloromethane, and concentrated. The crude residue was purified by chromatography on a silica gel to give compound 37 in 42% yield. MS (ESI, EI+) m/z=658 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Cl)=[CH:9][CH:8]=1)[CH:4]=[CH2:5].[N:15]1[N:16]([CH2:20][CH2:21][OH:22])[N:17]=[CH:18][CH:19]=1.O>CN(C=O)C>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:22][CH2:21][CH2:20][N:16]2[N:17]=[CH:18][CH:19]=[N:15]2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5]
Reactant: OCCn1nccn1
Reactant: C=CCOc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(COCCn2nccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
207 mg (8.21 mmol) 95% Sodium hydride were given at −50° C. to a solution of 1.00 g (5.47 mmol) 1-allyloxy-4-chloromethyl-benzene and 619 mg (5.47 mmol) 2-(2H-[1,2,3]-triazol-2-yl)-ethanol in 10.0 ml DMF. The mixture was allowed to warm slowly to r.t., stirred overnight and 6 ml water added. The formed oil was collected with 10 ml dichloromethane, the aqueous phase extracted with 10 ml dichloromethane and the combined organic phases dried over Na2SO4.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:11][CH2:10]1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:10][CH2:11][CH:12]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:13][CH2:14]1
Reactant: COc1cnccc1C1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccncc3O)CC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-({1-[4-(3-Methoxy-pyridin-4-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (0.101 g, 0.206 mmol, as prepared in Example 8) was dissolved in anhydrous dichloromethane (10 mL) under Ar, treated with 0.83 N boron tribromide in dichloromethane (Aldrich, 2.00 mL, 1.66 mmol), and stirred at ambient temperature for 24 h. After quenching with saturated aqueous NaHCO3, the reaction was stirred at ambient temperature for 30 mins and extracted thrice with 3:1 EtOAc/2-propanol. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo giving a gold gum that was purified by preparative thin layer chromatography on silica gel (15% MeOH in CH2Cl2, 0.6N in ammonia), giving the title compound as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]([OH:14])=[O:13])[C:6]=2[C:15]=1[CH3:16].[C:19](OC(=O)C)(=[O:21])[CH3:20].O.Cl>N1C=CC=CC=1>[C:19]([O:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]([OH:14])=[O:13])[C:6]=2[C:15]=1[CH3:16])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)C(C(=O)O)C(C)(C)O2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(C(=O)O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of 25.03 g (0.1M) of 2,3-dihydro-5-hydroxy-2,2,4,6,7-pentamethyl-1-benzofuran-3-carboxylic acid (described in Example 1) in 200 ml of pyridine is added 100 ml of acetic anhydride and the mixture is stirred at room temperature for 24 hours. Water and ice is added and the mixture is stirred at about 30° C. for 30 minutes. More ice and 450 ml of 6N hydrochloric acid is added and the resulting solid is collected, washed with water, and taken up in ethyl acetate. The solution is washed with 2N hydrochloric acid and water and is dried over anhydrous sodium sulfate. The residue obtained after filtration and evaporation of solvent is recrystallized from ethyl acetate to give 23.6 g (81%) of the title compound as racemate, m.p. 187°-8° C. Elemental analysis, UV, and 1H-NMR spectra confirm the structure.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH:8]([CH2:11][C:12]([O:14]C)=[O:13])[C:7]=2[CH:16]=1)#[N:2].[OH-].[Na+].Cl>C1COCC1.CO.C(OCC)(=O)C>[C:12]([CH2:11][CH:8]1[C:7]2[CH:16]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:10][CH2:9]1)([OH:14])=[O:13]
Reactant: COC(=O)CC1COc2ccc(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)C(CC(=O)O)CO2
Reaction time: 0.17 h

Procedure:
To a solution of methyl [5-cyano-2,3-dihydro-benzofuran-3-yl]-acetate (3.73 g, 17.2 mmol) (reference example 10a) in THF:MeOH (2:1, 60 mL) was added aqueous NaOH (16 mL, 2M). The resulting mixture was stirred for 10 min then acidified to pH 1 with 2M aqueous HCl. This mixture was diluted with ethyl acetate and washed, sequentially, with water and brine, dried over MgSO4 and concentrated. The crude solid product was used without further purification. 1H NMR (CDCO3) d 2.70 (dd, 16, 8 Hz, 1H), 2.85 (dd, J=16, 5 Hz, 1H), 3.91 (m, 1H), 4.38 (dd, J=8, 6 Hz, 1H), 4.85 (t, J=8 Hz, 1H), 6.84 (d, J=8 Hz, 1H), 7.47 (m, 2H). MS (EI) m/z 203 (M)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[N:8].O.[NH2:10][NH2:11]>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:10][NH2:11])[NH2:8]
Reactant: NN
Reactant: N#Cc1ccccn1
Solvent: O
Solvent: CCO
Product: NN=C(N)c1ccccn1

Procedure:
A solution of pyridine-2-carbonitrile 20 g (192 mmol) and hydrazine hydrate (3 Eq.) in ethanol (50 mL) was stirred at room temperature for 18 hrs. The reaction mass was then diluted with water, extracted with ethyl acetate, and the organic portion dried (Na2SO4) and concentrated in vacuo to yield the desired compound.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C:19]2[C:24]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)=[N:23][C:22]([C:35]3[CH:40]=[CH:39][C:38]([O:41][Si](C(C)(C)C)(C)C)=[CH:37][CH:36]=3)=[CH:21][N:20]=2)=[O:17])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH4+].[Cl-]>C1COCC1>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C:19]2[C:24]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)=[N:23][C:22]([C:35]3[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=3)=[CH:21][N:20]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2cccc3ccccc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(O)cc1)Nc1ncc(-c2ccc(O)cc2)nc1-c1cccc2ccccc12
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 2-[4-(tert-butyldimethylsilyloxy)phenyl]-N-[5-{4-(tert-butyldimethylsilyloxy)phenyl}-3-(naphthalen-1-yl)pyrazin-2-yl]acetamide (11d) (291 mg, 430 μmol) in THF (5 mL) was added tetrabutylammonium fluoride (1.0 M THF solution) (2.20 mL, 2.20 mmol) at 0° C. and the mixture was stirred for 30 minutes while elevating to room temperature. To the mixture was added saturated NH4Cl aqueous solution (50 mL) and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with saturated NH4Cl aqueous solution (200 mL), water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was recrystallized (n-hexane/ethanol) to give Compound 4d (TMD-338) (181 mg, 404 μmol, 93.8%) as a brown solid. Rf=0.56 (dichloromethane/methanol=9/1); HPLC retention time 9.1 min; 1H NMR (400 MHz, DMSO-d6) δ 3.17 (s, 2H), 6.45-6.53 (AA′BB′, 2H), 6.56-6.64 (AA′BB′, 2H), 6.80-6.88 (AA′BB′, 2H), 7.35-7.56 (m, 4H), 7.61-7.68 (m, 1H), 7.88-8.04 (m, 4H, includes AA′BB′), 9.03 (s, 1l), 9.15 (s, 1H), 9.85 (s, 1H), 10.14 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ 41.2, 115.0 (2C), 115.9 (2C), 125.1, 125.3, 125.4, 125.8, 126.3, 126.5, 126.9, 128.25, 128.27 (2C), 128.7, 129.8 (2C), 130.7, 133.4, 134.9, 138.0, 144.0, 148.38, 148.44, 155.9, 159.2, 169.8; IR (KBr, cm−1) 492, 540, 623, 777, 802, 839, 982, 1078, 1171, 1231, 1317, 1364, 1447, 1477, 1516, 1609, 1670, 3055, 3246; HRMS (ESI+) m/z 470.1483 ([M+Na]+, C28H21N3NaO3+ requires 470.1475).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([O:27]C)=[O:26])[CH:11]3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH:11]3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)CN1C(=O)CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C1c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1C1N(CC(=O)O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(methoxycarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.21 g, 0.4 mmol) prepared in 29b in the mixture of methanol (10 mL) and tetrahydrofuran (20 mL) was added aqueous NaOH solution (1N, 10 mL, 10 mmol). The reaction mixture was stirred at room temperature for overnight and then concentrated. The residue was neutralized to “pH” ˜7, then extracted with ethyl acetate. The organic layer was separated, washed with H2O, brine, dried over MgSO4 and concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(hydroxycarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white foam.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=2I)[CH2:3][CH2:2]1.C([SnH](CCCC)CCCC)CCC.[C]=O.C[CH2:33][O:34]CC>C1(C)C=CC=CC=1.[F-].[K+]>[CH:1]1([O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=2[CH:33]=[O:34])[CH2:3][CH2:2]1
Reactant: FC(F)(F)Oc1ccc(OC2CC2)c(I)c1
Reactant: CCOCC
Agent: CCCC[SnH](CCCC)CCCC
Agent: [C]=O
Agent: [F-]
Solvent: Cc1ccccc1
Product: O=Cc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 2-cyclopropoxy-5-(trifluoromethoxy)iodobenzene (Description 8, 0.344 g, 1 mmol) in toluene (2.5 mL) was degassed wtih bubbling nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium (0) (15 mg) was added, the mixture was degassed with bubbling nitrogen for a further 5 min., then carbon monoxide was bubbled through the mixture for 10 min. The mixture was warmed to 50° C. and a solution of tributyl tin hydride (0.3 mL, 1.1 mmol) in toluene (5 mL) was added at a rate of 2 mL/h. via a syringe pump, maintaining carbon monoxide bubbling throughout. The mixture was cooled, diluted with ether (20 mL) and aqueous potassium fluoride solution (50%) was added. The mixture was stirred at room temperature overnight, filtered and the layers were separated. The organic layer was dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2O (80:20), to give the title compound as a colourless oil. 1H NMR (360 MHz, CDCl3) δ0.86 (4 H, m), 3.82-3.9 (1 H, m), 7.42 (2 H, m), 7.62 (1 H, d, J 2.5 Hz), and 10.36 (1 H, s).
Reaction SMILES: CC(C)([O-])C.[K+].F[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=1.[OH:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1.O>CS(C)=O.[Cl-].[Na+].O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([O:15][CH:16]2[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19]2)=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Fc1ccc(F)nc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)cn2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
Potassium tert-butoxide (1M in THF, 14.4 ml, 14.4 mmol, 5 eq) and 2,5-difluoropyridine (498.3 mg, 4.33 mmol, 1.5 eq) are added to a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate a1-47 (500 mg, 2.89 mmol, 1 eq) in DMSO (50 ml). The reaction is stirred for 4 h at room temperature. Brine (70 ml) and water (10 ml) are added. The resulting mixture is extracted with ethyl acetate (3×50 ml). The combined organic phases are dried over MgSO4, filtered and concentrated in vacuo. The residue of evaporation is purified by flash chromatography over silicagel (eluent: EtOAc/Heptane 10/90) to afford 240 mg of tert-butyl 3-[(5-fluoropyridin-2-yl)oxy]azetidine-1-carboxylate a1-48.
Reaction SMILES: [CH3:1][C@@:2]12C(=O)CC[C@H:15]1[C@H:14]1[C@@H:5](C3C(CC1)=CC(O)=C(OC)C=3)[CH2:4][CH2:3]2.[C:23]([O-:26])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:26][CH2:23][C:2]1[CH:15]=[CH:14][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:14][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 379.6 %

Procedure:
The 2-Methoxy estrone (0.521 g, 0.00173 mol) was dissolved in anhydrous DMF under nitrogen atmosphere, added K2CO3 (0.718 g, 0.00225 mol) and stirred at r.t. for approximately 40 h. The crude mixture was diluted with EtOAc, washed with water and brine. The organics were dried (MgSO4) and concentrated. The crude product was pre-absorbed onto silica gel, purified using Flash Master-2 system to give the benzylated compound 32 (0.651 g, 96%) as a chalky white solid: TLC (Rt, 0.4, EtOAc:Hexane, 3:7); 1H NMR (270 MHz, CDCl3) δ 0.90 (s, 3H, 18-CH3 diastereomeric methyl signals), 1.24-1.27 (t, J=3.4 Hz, 3H, CH2—CH3), 1.24-1.29 (t, J=7.1 Hz, 3H, CH2—CH3), 1.39-2.44 (broad m, 12H), 2.44-2.54 (dd, J=18.8 and 8.6 Hz, 1H), 2.77-2.83 (m, 2H), 3.84-3.87 (s, 3H, OMe), 5.0 (s, 2H, PhCH2), 6.6 (s, 1H, aromatic), 6.77 (s, 1H, aromatic), 3.87-3.84 (s, 3H, OMe), 4.10-4.16 (q, J=7.0 Hz, 2H, CH3—CH2—O), 5.09 (s, 2H, CH2-phenyl), 6.61 (s, 1H, 4-CH), 6.82 (s, 1H, aromatic 1-CH), 7.41-7.43 (m, 5H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[S:26][C:25]4[CH:27]=[CH:28][S:29][C:24]=4[CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17]([C:22]3[S:26][C:25]4[CH:27]=[CH:28][S:29][C:24]=4[CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cc4sccc4s3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2cc3sccc3s2)cc1
Temperature: 50 °C
Reaction time: 13 h
Yield: 58.2 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(thieno[3,2-b]thiophen-2-yl)pyrazin-2-amine (7k) (250 mg, 569 μmol) and 4-(dimethylamino)pyridine (12.3 mg, 101 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 13 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 30 g, n-hexane/ethyl acetate=3/1) to give Compound 11k (228 mg, 331 μmol, 58.2%) as a yellow solid. Rf=0.26 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.17 (s, 6H), 0.22 (s, 6H), 0.93 (s, 9H), 0.95 (s, 9H), 3.67 (s, 2H), 6.78-6.86 (AA′BB′, 2H), 6.96-7.04 (AA′BB′, 2H), 7.20-7.30 (AA′BB′, 2H), 7.41 (d, 1H, J=5.2 Hz), 7.57 (s, 1H), 7.73 (d, 1H, J=5.2 Hz), 8.04-8.13 (AA′BB′, 2H), 8.92 (s, 1H), 10.69 (s, 1H); IR (KBr, cm−1) 527, 635, 702, 779, 837, 918, 1007, 1074, 1169, 1256, 1362, 1445, 1508, 1603, 1655, 2857, 2886, 2928, 2955, 3211.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(OC)cc1I
Reactant: Nc1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OC)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 30 mL suspension of methyl 2-iodo-4-methoxybenzoate 2.7 g, rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 58 mg, palladium acetate 20 mg and cesium carbonate 6.0 g was added 4-fluoroaniline 1.3 mL, and it was heated and refluxed under nitrogen atmosphere for 5 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=10:1] to give methyl 2-(4-fluoroanilino)-4-methoxybenzoate 2.2 g of white solid.
Reaction SMILES: C[Si](C)(C)[O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:13])[CH:11]=[CH2:12].CO.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>C(O)(=O)C>[OH:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:13])[CH:11]=[CH2:12]
Reactant: C=CC(=O)NCCOCCO[Si](C)(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CC(=O)O
Solvent: CO
Product: C=CC(=O)NCCOCCO
Reaction time: 8 h

Procedure:
N-[2-(2-trimethylsiloxyethoxy)ethyl]acrylamide (73.5 g), methanol (400 g) and acetic acid (50 g) were introduced into a 1 L eggplant type flask and were mixed to a homogeneous state, after which the mixture was allowed to stand at room temperature overnight. 2,6-di-t-butyl-4-methylphenol (0.2 g) was added, after which the solvent was removed by means of a rotary vacuum evaporator (using a vacuum pump; bath temperature, 60 to 70° C.). The volatile components were removed by means of a vacuum pump under decreased pressure over a two-hour period at 70° C. and N-[2-(2-hydroxyethoxy)ethyl]acrylamide was obtained as a yellow transparent, viscous liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:14]=[C:13]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)=[CH:8][CH:7]=1.[CH:36]1([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][O:2][C:3](=[O:35])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:14]=[C:13]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:39]3[CH:38]=[CH:37][C:36]([CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:41][CH:40]=3)=[CH:30][CH:29]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(C(F)(F)F)cc3)nc2Cc2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(C(F)(F)F)cc3)nc2Cc2ccc(-c3ccc(C4CCCCC4)cc3)cc2)cc1

Procedure:
{4-[2-(4-Bromo-benzyl)-4-(4-trifluoromethyl-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (1.3 g, 2.4 m mol) was coupled with 4-cyclohexyl-phenylboronic acid (615 mg, 3.0 mmol) according to general procedure G to give {4-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(4-trifluoromethyl-phenyl)-imidazol-1-yl]phenylamino}-acetic acid methyl ester.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH:39]=O)=[C:22]2[C:26]=1[N:25]=[C:24]1[N:27]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[Cl:38])[CH2:28][CH2:29][CH2:30][N:23]21.O>O1CCCC1>[Cl:17][C:18]1[C:26]2[N:25]=[C:24]3[N:27]([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])[CH2:28][CH2:29][CH2:30][N:23]3[C:22]=2[C:21](/[CH:39]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (0.78 mL, 3.93 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (60% dispersion in mineral oil, 0.157 g, 3.93 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (500 mg, 1.31 mmol) at 0° C. The mixture was stirred at room temperature for 4 hr and at 40° C. for 18 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound (489 mg, 1.08 mmol, 83%) as a colorless solid.