Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.Cl[CH2:45][C:46]1[N:50]=[CH:49][O:48][N:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:48]1[CH:49]=[N:50][C:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])=[N:47]1
Reactant: ClCc1ncon1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2ncon2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-(chloromethyl)-1,2,4-oxadiazole to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (36%)) as a colorless solid: mp 160-162° C.; 1H NMR (300 MHz, CDCl3) δ 7.39 (dt, 1H), 7.20-7.13 (m, 3H), 7.05 (d, 1H), 6.50 (s, 1H), 6.12 (s, 1H), 5.86 (dd, 2H), 4.78 (ABq, 2H), 4.68 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 176.7, 156.0, 149.3, 142.5, 139.6, 131.6, 129.4, 124.8, 124.5, 118.4, 113.6, 108.7, 103.0, 101.7, 93.7, 80.3, 58.2, 29.7, 28.0; MS (ES+) m/z 365.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]2[C:12](=[O:28])[N:13]([CH3:27])[C:14](=[O:26])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[CH:17]=2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][O:38]C1CCCCO1>CN(C)C=O.C(OCC)(=O)C>[OH:38][CH2:37][CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:11]2[C:12](=[O:28])[N:13]([CH3:27])[C:14](=[O:26])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[CH:17]=2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cc(O)cc3ccoc23)C1=O
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cc(OCCO)cc3ccoc23)C1=O
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 67.4 %

Procedure:
Add to a mixture of 3-(5-hydroxybenzofur-7-yl)-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (2.5 g, 6.7 mmol) and potassium carbonate (2.78 g, 20.1 mmol) in N,N-dimethylformamide (40 ml), 2-(2-bromoethoxy)tetrahydropyran (3.04 ml, 20.1 mmol). Heat the mixture to 80° C. under nitrogen atmosphere for overnight. Diluted with ethyl acetate, wash with water, brine, dry over magnesium sulfate, filter and concentrate to red solid. Dissolve the solid in methanol (40 ml), add p-toluenesulfonic acid (3 g), stir for 20 minutes. Diluted with ethyl acetate, wash with water, brine, dry over magnesium sulfate, filter and concentrate to afford the title compound (1.88 g, 67%) as a red solid. HRMS: calculated 417.1450 found 417.1462.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:10][NH:11][CH3:12].[H][H]>O.[Pd]>[CH3:10][N:11]([CH2:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH3:12]
Reactant: O=Cc1ccccc1O
Reactant: [H][H]
Reactant: CNC
Agent: [Pd]
Solvent: O
Product: CN(C)Cc1ccccc1O

Procedure:
2-Dimethylaminomethyl phenol was prepared by the method of S. Cavitt, "J. Org. Chem.", 27, 1211 (1962). 61.0 gm salicylaldehyde, 127 gm 25% by wt dimethylamine in water and 1.2 gm 10% by wt palladium on charcoal are placed in a pressure bottle of a Parr hydrogenator and hydrogenated until 41.7 lbs of hydrogen are taken up. The experiment is repeated and reaction mixtures combined. The catalyst is filtered off and the filtrate made acidic (pH 2), extracted with ether, and the ether discarded. The aqueous phase is adjusted to pH 8 with NaOH and extracted with ether. The aqueous phase is adjusted to pH 9 with NaOH and extracted with ether. The ether extracts are combined, dried over MgSO4, filtered, and evaporated on a rotating evaporator. There results 111.7 gm of an orange liquid (Percent crude yield - 75). This is fractionated at reduced pressure. The product is collected at 60°-63° C. at 0.5 mm to provide 99.1 gm of a yellow liquid (Percent yield - 65).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:12])=[C:4]2[C:10]([I:11])=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1c(Br)cnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)c(Br)cnc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
5-Bromo-4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (7.68 g, 21.5 mmol) was dissolved in 100 mL dry DMF and cooled to 0° C. Sodium hydride (60% suspension in mineral oil, 1.03 g, 25.8 mmol) was added cautiously over 5 min. The mixture was cooled to −42° C. and 2-trimethylsilanyl-ethoxymethylchloride (5 mL, 28 mmol) was added slowly over 10 min. The mixture was stirred at −42° C. for 2 h and quenched with 200 mL saturated ammonium chloride solution and 200 mL water. The aqueous mixture was extracted with dichloromethane and the organic phase was washed with water, dried and concentrated to afford 5-Bromo-4-chloro-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (10.1 g, 20.7 mmol, 96% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.07 (s, 1H), 5.57 (s, 2H), 3.49 (t, J=8 Hz, 2H), 0.79 (t, J=8 Hz, 2H), −0.11 (s, 9H). MS: m/z 486.7/488.7 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=[O:24].C([O-])(O)=O.[Na+].[C:31]([O:35][C:36](=[O:39])[CH2:37]Br)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([O:25][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)OCC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.7 %

Procedure:
To a solution of indomethacin (6.388 g, 18 mmol) in anhydrous DMF (45 mL) were successively added NaHCO3 (1.4 g, 16.7 mmol) and tert-butylbromoacetate (2.95 g, 15 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was then poured over ice-cold water, stirred, and the white solid obtained was filtered off, washed with water and dried. The product was recrystallized from EtOAc:hexane (1:4) to give the title compound (7.06 g, 88% yield) as a white solid. Mp 96-97° C. 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.0 (d, J=2.4 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 6.6 (dd, J=9.0 and 2.4 Hz, 1H), 4.52 (s, 2H), 3.83 (s, 3H), 3.77 (s, 2H), 2.37 (s, 3H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 170.1, 168.2, 166.6, 156.2, 139.2, 136.0, 133.8, 131.1 (2×C), 130.7, 130.5, 129.0 (2×C), 114.9, 112.1, 111.9, 101.1, 82.4, 61.5, 55.6, 29.7, 27.9, 13.4; LRMS (APIMS) m/z 472 (MH+)
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:15][C:16]2[CH:21]=[N:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: FC(F)C(F)(F)COc1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)n1ncc(SCc2ccc(OCC(F)(F)C(F)F)nc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
In 40 ml of acetonitrile were dissolved 2.2 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 2.7 g of 5-chloromethyl-2-(2,2,3,3-tetrafluoropropyloxy)-pyridine, and thereto was added 1.5 g of potassium carbonate. The reaction mixture was stirred overnight at room temperature, poured into water and extracted with benzene. The organic layer was washed with a 5% aqueous solution of sodium hydroxide and then with water, and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure and the resulting crystals were washed with n-hexane to obtain 4.0 g of 2-t-butyl-4-chloro-5-[{6-(2,2,3,3-tetrafluoropropyloxy)-3-pyridyl}-methylthio]-3(2H)-pyridazinone, m.p. 113.0°~114.0° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1Cl)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].N12[CH2:25][CH2:24]CN=C1CCCCC2.[N+](CC)([O-])=[O:27].C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:24]([C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:27])[CH3:25]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(C)=O)c([N+](=O)[O-])c1
Reaction time: 5 h

Procedure:
A solution of methyl 3-nitro-4-chlorobenzoate (0.70 g) in ethyl acetate (2 mL) was added to a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.50 mL) and nitroethane (0.70 mL) at 0° C. The mixture was stirred for 5 h and partitioned with ethyl acetate and water. Potassium permanganate (0.57 g) was added to the water layer and resulting solution was stirred for 45 minutes. Toluene (20 mL) was added and mixture was stirred slowly. The toluene layer was separated and washed with saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to afford the crude product. Purification on silica gel with hexane/ethyl acetate 7/3 gave the title compound. NMR (300 MHz, CDCl3) δ 8.74 (1H, s,), 8.36 (1H, d, J=8 Hz), 7.50 (1 H, d, J=8 Hz), 4.00 (3H, s), 2.58 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=O.[Cl:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH2:7][C:15]2[S:14][C:13]([Cl:12])=[CH:17][CH:16]=2)[CH:10]=1
Reactant: Clc1cccs1
Reactant: O=C(O)c1cc(Br)ccc1I
Product: Clc1ccc(Cc2cc(Br)ccc2I)s1

Procedure:
5-Bromo-2-iodobenzoic acid (see Jorg Frahn, A.-Dieter Schluter Synthesis 1997, 1301-1304) and 2-chlorothiophene were treated in a manner similar to Reference Example 5 to give 5-bromo-1-(5-chloro-2-thienylmethyl)-2-iodobenzene as colorless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][NH2:29].Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][NH:29][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: NCc1ccccc1Cl
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1Cl)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (5 ml) at room temperature was sequentially added 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-chlorobenzylamine (54.7 μl, 95%, 0.43 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60.6 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was redissolved in CH2Cl2 (100 ml). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was redissolved in CH2Cl2 (100 ml). The organic layer was washed with aqueous NaHCO3, dried over anhydrous MgSO4, and concentrated to give the crude mixture. Chromatography of the crude (Hex:EtOAc=1:1 to pure EtOAc) afforded desired product as white solid (83 mg, 97%): m.p. 120-121° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.ClCCl.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>O>[CH3:20][S:21]([O:9][CH2:8][CH2:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)(=[O:23])=[O:22]
Reactant: Cn1cccc1CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1cccc1CCOS(C)(=O)=O
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (ice-bath) mixture of 49 g of 1-methyl-1H-pyrrole-2-ethanol, 47.6 g of N,N-diethylethanamine and 500 ml of dichloromethane, there were added portionwise 34 ml of methanesulfonyl chloride. Stirring was continued overnight at room temperature. The reaction mixture was diluted with water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 85.5 g (100%)of 1-methyl-1H-pyrrole-2-ethanol methanesulfonate (ester) (interm. 3);
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH:6]([C:13]1[N:18]=[C:17]([CH2:19][NH:20][CH2:21][CH2:22][OH:23])[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[Br-].[Na+]>C(Cl)Cl>[NH:6]([C:13]1[N:18]=[C:17]([CH2:19][N:20]2[CH2:21][CH2:22][O:23][CH2:2][C:3]2=[O:4])[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCCNCc1ccnc(Nc2ccccc2)n1
Reactant: O=C(Cl)CCl
Agent: [Br-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1COCCN1Cc1ccnc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.7 %

Procedure:
A solution of chloroacetyl chloride (268 mg, 2.38 mmol) in dry DCM (5 ml) was added dropwise over 10 minutes to a stirred solution of 2-anilino-4-(2-hydroxyethylaminomethyl)pyrimidine (Method 19; 582 mg, 2.38 mmol) and triethylamine (332 μl, 2.38 mmol) in dry DCM (20 ml) under nitrogen. The reaction mixture was then stirred for 20 hours at ambient temperature. The mixture was diluted with DCM and washed with water (×2), saturated brine, dried (Na2SO4) and the volatiles removed by evaporation. The residue was dissolved in dry THF (20 ml), sodium bromide (227 mg, 2.2 mmol) added and the mixture stirred at 0° C. under nitrogen sodium hydride (88 mg of a 60% dispersion in oil) was added in one portion and the reaction stirred at 0° C. for 10 minutes and then at ambient temperature for 72 hours. The volatiles were removed by evaporation and the residue partition between EtOAc and water. The layers were separated and the organic layer washed with water, saturated brine, dried (Na2SO4) and the solvent removed by evaporation. The residue was purified by chromatography eluting with EtOAc. The purified product was triturated with diethyl ether, collected by filtration, washed with diethyl ether and dried to give the title compound (438 mg, 70%) as a white solid. NMR: 3.43 (t, 2H), 3.87 (t, 2H), 4.13 (s, 2H),4.52 (s, 2H), 6.72 (d, 1H), 6.93 (t, 1H), 7.25 (t 2H), 7.75 (d, 2H), 8.42 (d, 1H), 9.55 (s, 1H); m/z 285.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.C(O)C.O1CCCC1.[BH4-].[Na+]>O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(-c2nccs2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: OCc1ccc(-c2nccs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
To 4-(thiazol-2-yl)benzaldehyde (see JP 2001-519414A) (1.57 g, 8.30 mmol) were added ethanol (20 ml), tetrahydrofuran (0.46 ml), and then sodium borohydride (157 mg, 4.15 mmol), followed by stirring at room temperature for 1.5 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1→1:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.49 g) as a white solid. (Yield: 94%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[K+].[C:25]([C:27]1[N:28]=[C:29]([C:40]([O-])=[O:41])[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=1)#[N:26]>CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:40]([C:29]3[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[C:27]([C:25]#[N:26])[N:28]=3)=[O:41])=[C:13]([C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=3)[CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(N)c(C3=CCCCC3)c2)CCOCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CCOCC1
Yield: 78 %

Procedure:
The title compound was prepared by the coupling procedure of Example 1, step (f) using 4-(4-amino-3-cyclohex-1-enyl-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in the previous step, 250 mg, 0.793 mmol), and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 266 mg, 0.872 mmol). Silica gel chromatography (20% EtOAc-hexane) afforded the title compound (348 mg, 78%) as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C30H40N4O5Si, 565.3 (M+H). found 565.0.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([F:13])[CH:12]=1)[O:9][CH2:8][C@H:7]([NH2:14])[CH2:6]2.C(OC(=O)[NH:21][CH2:22][C:23](=O)[CH2:24]O[Si](C(C)(C)C)(C)C)(C)(C)C.[S-:35][C:36]#[N:37].[K+].C(O)(=O)C>C(OCC)(=O)C>[ClH:1].[NH2:21][CH2:22][C:23]1[N:14]([C@@H:7]2[CH2:6][C:5]3[C:10](=[C:11]([F:13])[CH:12]=[C:3]([F:2])[CH:4]=3)[O:9][CH2:8]2)[C:36](=[S:35])[NH:37][CH:24]=1
Reactant: N[C@H]1COc2c(F)cc(F)cc2C1
Reactant: N#C[S-]
Reactant: CC(C)(C)OC(=O)NCC(=O)CO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred mixture of (R)-6,8-difluorochroman-3-ylamine hydrochloride (0.22 g, 1.0 mmol), [3-(tert-butyldimethylsilanyloxy)-2-oxopropyl]carbamic acid tert-butyl ester (0.33 g, 1.1 mmol), potassium thiocyanate (0.11 g, 1.1 mmol) and acetic acid (0.3 mL, 5.0 mmol) in ethyl acetate (3 mL) was refluxed for 2 hours, cooled to room temperature, then washed by sodium bicarbonate solution, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by the column chromatography over silica gel using ethyl acetate-petroleum ether mixture as eluent. The resulting oil (0.23 g) was dissolved in ethyl acetate (2 ml), whereupon 2M HCl solution in ethyl acetate was added (2 mL, 4 mmol) and the mixture was stirred for 2 hours at room temperature. The precipitate was removed by filtration and washed with ethyl acetate to give crystals of m.p. 192° C. (decomp.).
Reaction SMILES: C(NC(C)C)(C)C.[Li].[Cl:9][C:10]1[C:11]2[S:18][CH:17]=[CH:16][C:12]=2[N:13]=[CH:14][N:15]=1.[Br:19]C(F)(F)C(Br)(F)F.O>O1CCCC1>[Br:19][C:17]1[S:18][C:11]2[C:10]([Cl:9])=[N:15][CH:14]=[N:13][C:12]=2[CH:16]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Clc1ncnc2ccsc12
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: Clc1ncnc2cc(Br)sc12
Temperature: -78 °C
Yield: 99.5 %

Procedure:
In a 250 mL round-bottomed flask 65 mL of tetrahydrofuran and lithium diisopropylamine (18.5 mL, 37 mmol, 2M in tetrahydrofuran) were cooled to −78° C. 4-chloro-thieno[3,2-d]pyrimidine (5.26 g, 31 mmol) was dissolved in 37 mL of tetrahydrofuran and slowly added to the reaction mixture over 5 minutes, After 20 minutes 1,2-dibromo-1,1,2,2-tetrafluoroethane (4.05 mL, 34 mmol) was added slowly to the solution of the anion. The temperature was maintained at −78° C. for 20 minutes then warmed to room temperature for 2 hours. The reaction mixture was poured into water and extracted with chloroform (3×100 mL), dried over sodium sulfate, and dried in vacuo to afford 7.70 g (99%) of 6-bromo-4-chloro-thieno[3,2-d]pyrimidine. 1H NMR (400 MHz, DMSO) d 8.97 (s, 1H), 8.01 (s, 1H). LC-MS: 249, 251 (MH+); HPLC RT: 4.04 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].C(=O)(O)[O-].[Na+]>ClCCl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:31]([CH:30]=[CH2:29])(=[O:33])=[O:32])[CH:7]=[CH:6][CH:5]=3)[C:16]=12
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)n1nc(-c2cccc(N)c2)c2c(N)ncnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)Nc1cccc(-c2nn(C(C)C)c3ncnc(N)c23)c1
Reaction time: 1 h
Yield: 23 %

Procedure:
A solution of dichloromethane (2 mL), compound 22 (20 mg, 0.075 mmol) and triethylamine (11 μL, 0.079 mmol) was cooled to 0° C. 2-chloro-1-ethane sulfonyl chloride (7 μL, 0.067 mmol) was added and the reaction was allowed to proceed for 1 hour prior to addition of saturated sodium bicarbonate (10 mL) and extraction with dichloromethane (3×10 mL). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The product was purified by preparative RP-HPLC and lyophilized (5.6 mg, 23% yield): 1H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 8.31 (s, 1H), 7.49 (t, J=7.9, 1H), 7.45 (s, 1H), 7.38 (d, J=7.8, 1H), 7.27 (d, J=7.3, 1H), 6.86 (dd, J=16.4, 10.0, 1H), 6.17 (d, J=16.4, 1H), 6.08 (d, J=9.9, 1H), 5.08 (hept, J=6.7, 1H), 1.50 (d, J=6.7, 6H). 13C NMR (100 MHz, DMSO) δ 155.01, 151.96, 151.19, 144.29, 138.50, 136.32, 133.09, 130.22, 127.79, 123.73, 120.09, 119.20, 96.94, 48.85, 21.73; [M+H]+ calculated for C16H18N6O2S 359.1, found 359.4.
Reaction SMILES: [SH:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][N:3]=1.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]\[C:44]([OH:46])=[O:45]>C(O)C.CC(C)=O>[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]\[C:44]([OH:46])=[O:45].[F:33][C:30]([F:31])([F:32])[C:26]1[CH:25]=[C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][S:1][C:2]3[N:6]4[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:13])([F:14])[F:12])[C:5]4=[N:4][N:3]=3)[CH2:23][CH2:22]2)[CH:29]=[CH:28][CH:27]=1
Reactant: FC(F)(F)c1cccn2c(S)nnc12
Reactant: FC(F)(F)c1cccc(N2CCN(CCCl)CC2)c1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc(N2CCN(CCSc3nnc4c(C(F)(F)F)cccn34)CC2)c1
Yield: 44.2 %

Procedure:
A solution of 11 g of 3-mercapto-8-trifluoromethyl-1,2,4-triazolo(4,3-a)pyridine, prepared in Example 18, and 15 g of 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane in 75 ml of ethanol containing 8 ml of triethylamine is heated under reflux for 6 hours. The reaction mixture is then concentrated in vacuo, water and ice are added and the extraction is carried out with ether. The organic phase is washed with water, with a dilute solution of sodium hydroxide and then again with water. The ether phase is dried and then concentrated and the residue obtained (21.5 g) is dissolved in acetone. A solution of 5.1 g of maleic acid in acetone is added to this acetone solution. The crystals which then form are filtered off, washed with acetone and ether and dried to give 11.5 g of 3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethylmercapto]-8-trifluoromethyl-1,2,4-triazolo(4,3-a)pyridine maleate in the form of crystals melting at 144°-5° C.