Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:1]1([C:7]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([S:16]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)(=[O:18])=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (3.36 g, 9 mmol) was dissolved in methylene chloride (135 ml). Piperidine (1.33 ml, 13.5 mmol) and ethyldiisopropyl amine (2.3 ml, 13.5 mmol) were added at room temperature. The reaction was stirred at room temperature overnight and washed twice with 1N aqueous HCl solution, twice with 1N aqueous NaOH solution and once with brine. The organic layer was dried over sodium sulfate and filtered. The solvent was evaporated and the residue was purified by column chromatography (4/1 hexane/ethyl acetate eluant). The product was suspended in diethyl ether and filtered to yield a white crystalline solid (1.98 g, 52%). m.p.: 163-164° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].CCCCCC>C(#N)C>[Cl:8][C:7]1[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13][CH2:14]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: CC(C)N1CCNCC1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Product: CC(C)N1CCN(c2nccnc2Cl)CC1
Yield: 79.4 %

Procedure:
A mixture 2,3-dichloro-pyrazine (5.0 g, 34 mmol), 1-isopropylpiperazine (6.5 g, 51 mmol) and potassium carbonate (7.0 g, 51 mmol) in acetonitrile (100 mL) was stirred at ambient temperature for 2 h. Addition of hexane, followed by filtration and concentration of the filtrate gave 9.5 g of crude material as an orange liquid. Purification by filtration through silica using heptane/EtOAc (3:1), followed by EtOAc/acetone (1:1), provided 6.5 g (79%) of the title compound as a yellow oil which solidified upon cooling. HPLC purity: 98%. MS m/z 241 (M+H)+. HRMS m/z calcd for C11H17ClN4 (M)+ 240.1142, found 240.1138.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[C:6]([NH:8][CH2:9][C:10]1[S:11][C:12]([S:15]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:13][CH:14]=1)=[O:7].[CH3:39]CN(C(C)C)C(C)C.C=O.C([BH3-])#N.[Na+]>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[C:6]([NH:8][CH2:9][C:10]1[S:11][C:12]([S:15]([N:18]2[CH2:19][CH2:20][CH:21]([N:24]([CH3:39])[CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:30][CH:31]=3)[CH2:22][CH2:23]2)(=[O:17])=[O:16])=[CH:13][CH:14]=1)=[O:7]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cccc(C(=O)NCc2ccc(S(=O)(=O)N3CCC(NCc4ccc(C(F)(F)F)cc4)CC3)s2)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NCc2ccc(S(=O)(=O)N3CCC(N(C)Cc4ccc(C(F)(F)F)cc4)CC3)s2)c1

Procedure:
A solution of the hydrochloride salt of 1 (50 mg, 0.08 mmol), DIEA (12 ul, 0.08 mmol), formaldehyde solution 37% aq. (32 ul, 0.4 mmol) and Sodiumcyanoborohydride (10 mg, 0.16 mmol) in THF were heated under reflux for 15 h, whereupon complete alkylation took place. The reaction was diluted with DCM and the inorganic salts were extracted with water. The crude was dried over MgSO4, and the solution was evaporated to dryness. The oily residue was taken up in THF, 1N HCl in ether was added slowly upon which colourless crystalls of compound 205 were formed (yield: 51 mg, 97%). Anal. HPLC: R.t=4.39 min (method b). M/Z APCI: 582.1 (M+1), 580.4 (M−1). The following compound was prepared in a similar fashion according to the example 205 described above:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH:17]1([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH2:21])[CH2:19][CH2:18]1.C(N(CC)CC)C.C>C1(C)C=CC=CC=1>[CH:17]1([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:21][C:6]([C:5]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[O:7])[CH2:19][CH2:18]1
Reactant: C=C(C1CC1)N(CC)CC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN(CC)C(=CC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-])C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
2-nitro-4-trifluoromethylbenzoyl chloride (9.4 g) was added dropwise to a cooled mixture of 1-cyclopropyl-1-diethylaminoethene (5.1 g) and triethylamine (3.7 g) in toluene (100 ml) whilst maintaining the temperature below 10° C. The mixture was then stirred at room temperature for 1 hour. The suspension was treated with decolourising charcoal and filtered. The filtrate was evaporated and the residue was purified by chromatography on silica gel eluted with a mixture of ethyl acetate and dichloromethane (1:9) to give 3-cyclopropyl-3-diethylamino-1-(2-nitro-4-trifluoromethylphenyl)prop-2-en-1-one (4.1 g) as a red oil with its 1H NMR (in CDCl3) giving peaks at d=0.7-1.8(m, 11H), 3.5(q, 4H), 5.0(s, 1H), 7.5(d, 1H), 7.7(d, 1H),and 7.95(s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH2:29][C:30]1([CH2:35][OH:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:29][C:30]2([CH2:35][OH:36])[CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: NC1(CO)CCCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC3(CO)CCCC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with (1-aminocyclopentyl)methanol via General Procedure E to give 10.2 mg of 274 following reverse phase purification. MS (Q1) 477.2 (M)+
Reaction SMILES: C(N1C=[C:15]2[C:10]([CH:11]=[C:12]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)[CH:13]=[CH:14]2)=N1)C1C=CC=CC=1.BrC1C=C([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([OH:41])=[O:40])[CH2:35][CH2:34]2)C=CC=1>>[C:19]([O:41][C:39]([N:36]1[CH2:35][CH2:34][CH:33]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([B:17]3[O:18][C:19]([CH3:24])([CH3:25])[C:20]([CH3:22])([CH3:23])[O:21]3)[CH:11]=2)[CH2:38][CH2:37]1)=[O:40])([CH3:25])([CH3:24])[CH3:20]
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: O=C(O)N1CCC(c2cccc(Br)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1

Procedure:
Using the procedure described for the preparation of Intermediate C, 4-(3-bromo-phenyl)-piperidine-1-carboxylic acid Pert-butyl ester was converted to the title compound. 1H NMR (CD3OD) δ 7.63 (bs, 1H), 7.60 (m, 1H), 7.32 (m, 1H), 7.31 (m, 1H), 4.23 (m, 2H), 2.83-2.62 (m, 3H), 1.80 (m, 2H), 1.62 (ddd, 2H), 1.47 (s, 6H), 1.33 (s, 3H), 1.24 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:8][C@H:7]([O:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]2[C:19]3[C:26]([CH3:27])=[C:25]([C:28]([OH:30])=O)[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:6]1)(=[O:3])[CH3:2].[CH3:31][N:32]([CH3:38])[CH2:33][C:34]#[C:35][CH2:36][NH2:37]>>[CH3:31][N:32]([CH3:38])[CH2:33][C:34]#[C:35][CH2:36][NH:37][C:28]([C:25]1[S:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([NH:17][C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[O:9][C@H:7]3[CH2:8][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6]3)[C:19]=2[C:26]=1[CH3:27])=[O:30]
Reactant: CN(C)CC#CCN
Reactant: CC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)C1
Product: CC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NCC#CCN(C)C)c(C)c23)C1

Procedure:
Prepared analogously to 35.3 from 0.080 g 4-[2-(trans-3-acetylamino-cyclobutoxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (cpd. 35.2) and 0.045 g 4-(dimethylamino)-but-2-ynylamin*2HCl.
Reaction SMILES: [C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38][CH3:39])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([CH:26]=O)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38][CH3:39])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([CH2:26][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1C=O)O2
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1CN1CCOCC1)O2
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step 2 (34 mg, 0.060 mmol) in CH2Cl2 (3 ml) was added morpholine (0.016 ml, 0.180 mmol) and acetic acid (10.32 μl, 0.180 mmol) followed by sodium triacetoxyborohydride (38.2 mg, 0.180 mmol). The reaction was complete in 30 minutes at which stage it was quenched with water and extracted with dichloromethane. Purification by PTLC (40% EtOAc/hexane) provided the desired compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[OH-].[Na+].CO>[C:19]1([CH:18]=[CH:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH:10]=[C:11]3[S:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])=[CH:8][CH:9]=2)=[O:3])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1NC(=O)C(=Cc2ccc(C(=O)C=Cc3ccccc3)cc2)S1
Reaction time: 72 h
Yield: 29.8 %

Procedure:
A solution of 5-(4-acetylphenylmethylene)thiazolidine-2,4-dione (1.0 g, 4.0 mmol) and benzaldehyde (0.62 ml, 6.1 mmol) in 1N NaOH (14 ml) and methanol (25 ml) was stirred for 1 hour at 0° C. and then at room temperature for 3 days, the precipitate was collected and dissolved in water, and this solution was acidified with 2N HCl and extracted with ethyl acetate (2×30 ml). The combined extracts were washed with brine (30 ml), dried over sodium sulfate and concentrated in vacuo, leaving the free acid form of title product (0.4 g, 29%) as a yellow solid. The latter was converted to sodium salt according to the method of Example 42.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.CO[CH:17]([O:20][CH3:21])[O:18][CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH3:21][O:20][CH:17]([O:18][CH3:19])[C:6]1[CH:9]=[C:2]([F:1])[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]=1[O:10][CH3:11]
Reactant: COC(OC)OC
Reactant: COc1cc([N+](=O)[O-])c(F)cc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc([N+](=O)[O-])c(F)cc1C(OC)OC

Procedure:
A mixture of 0.210 g (1.06 mmole) of 5-fluoro-2-methoxy-4-nitro-benzaldehyde (IV.46c), 1 mL of trimethylorthoformate, 0.025 g of p-toluenesulfonic acid monohydrate and 5 mL of methanol was heated at reflux for one hour. The mixture was cooled, neutralized by addition of saturated sodium bicarbonate solution and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.243 g of 1-dimethoxymethyl-5-fluoro-2-methoxy-4-nitro-benzene (IV.46d) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[N:12]=[C:11]([NH2:13])[N:10]=[C:9]([NH2:14])[C:8]=2[NH2:15])=[CH:4][CH:3]=1.[N:16](OCCC(C)C)=O>O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[NH:15][N:16]=[N:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nc(N)nc(N)c2N)o1
Reactant: CC(C)CCON=O
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc(N)nc3nn[nH]c23)o1
Temperature: 80 °C
Yield: 72.2 %

Procedure:
A solution of 6-(5-methyl-2-furyl)pyrimidine-2,4,5-triamine (5.8 g, 30.1 mmol) in dioxane (116 mL) was treated with isoamyl nitrite (4.1 mL, 30.5 mmol), heated at 80° C. for 3.5 h, cooled to room temperature and the resulting precipitate was filtered, washed with dioxane (10 mL) and heptane (2×15 mL) then triturated with heptane and filtered to give the title compound (4.7 g, 77%) as a sandy solid.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:17][Si](C(C)(C)C)(C)C)=[C:6]2[C:10](=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14])[CH2:9][O:8][C:7]2=[O:16])[CH:2]=[CH2:3].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(O)(=O)C>[C:25]([O:17][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[C:12]([O:13][CH3:14])[C:11]([CH3:15])=[C:10]2[C:6]=1[C:7](=[O:16])[O:8][CH2:9]2)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Solvent: CC(=O)O
Product: C=CCc1c(OC)c(C)c2c(c1OC(C)=O)C(=O)OC2
Temperature: 0 °C

Procedure:
A solution of 5-allyl-4-tert-butyldimethylsilyloxy-1,3-dihydro -6-methoxy-7-methyl-3-oxoisobenzofuran [(J. W. Patterson and G. Huang, Chemical Communications, 1579 (1991)] (7.5 g) in acetic acid (95 ml) and acetic anhydride (95 ml) was refluxed for 18 hours, then cooled and poured into ice water. The solution was extracted with ethyl acetate, and the extract washed with dilute aqueous sodium bicarbonate, followed by water, then dried and evaporated. The residue was chromatographed on silica gel, eluting with 7:3 hexane:ethyl acetate, to give 4-acetoxy-5-allyl -1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran, mp 101°-102° C.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH3:16].C(O)C>>[NH2:16][CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N
Solvent: CCO
Product: CCOC(=O)C(=CN)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To diethyl ethoxymethylenemalonate (50.13 g, 0.232 mmol), cooled to −20° C. under nitrogen, was added a 2.0 M solution of ammonia in ethanol (232 ml, 0.464 mmol) and the resulting solution was stirred at room temperature overnight. The solution was then evaporated in vacuo to give a quantitative yield of the title compound as a cream solid; 1H NMR (360 MHz, CDCl3) 5 1.28 (3H, t, J 7.1 Hz), 1.35 (3H, t, J 7.1 Hz), 4.19 (2H, q, J 7.1 Hz), 4.26 (2H, q, J 7.1 Hz), 5.68 (1H, br s), 8.11 (1H, dd), 8.69 (1H, br s).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17](Br)=[C:16]([CH3:21])[N:15]([CH:22]([CH3:24])[CH3:23])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([C:33]3[CH:32]=[CH:31][N:30]=[C:29]([C:28]([F:39])([F:38])[F:27])[CH:34]=3)=[C:16]([CH3:21])[N:15]([CH:22]([CH3:24])[CH3:23])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1C(C)C
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(-c2ccnc(C(F)(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1C(C)C
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (preparation 5, 24 mg, 0.054 mmol), 2-(trifluoromethyl)pyridine-4-boronic acid (13 mg, 0.068 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5 mg, 0.007 mmol) in acetonitrile (0.15 mL) is added 2 M aqueous K2CO3 solution (0.055 mL, 0.11 mmol). After stirring for 18 h at 75° C., the reaction mixture is filtered and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 4 mg (15% of theory); ESI mass spectrum: [M+H]+=508; Retention time HPLC: 0.88 min (Z003_001).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][C:27]1[C:35]([CH3:36])=[CH:34][C:30]2[N:31]=[CH:32][NH:33][C:29]=2[CH:28]=1.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Cu+2].C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:13])[O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:31]3[C:30]4[CH:34]=[C:35]([CH3:36])[C:27]([CH3:26])=[CH:28][C:29]=4[N:33]=[CH:32]3)=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(B(O)O)cc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3cnc4cc(C)c(C)cc43)cc2)cc1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A mixture of 4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenylboronic acid (100 mg, 0.28 mmol), 5,6-dimethylbenzimidazole (40 mg, 0.28 mmol), Cu(OAc)2 (60 mg, 0.33 mmol), triethylamine (115 μl, 0.83 mmol), MS4A (100 mg), and CH2Cl2 (4 ml) was stirred at room temperature for 1 week. After filtration through a bed of celite, the filtrate was diluted with CH2Cl2, and washed with water. The organic fraction was dried over MgSO4 and filtered. After concentration under reduced pressure, the residue was purified by preparative TLC (CH2Cl2/MeOH=10/1) to afford 28 mg (22%) of the title compound.
Reaction SMILES: C(O[C:6](=[O:31])[NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]1[O:25][C@H:24]2[C@:19]([CH3:29])([C@H:20]3[CH2:26][C@@H:22]([CH2:23]2)[C:21]3([CH3:28])[CH3:27])[O:18]1)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])(C)(C)C.[C:32]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C@@H:39]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[C:45]=2[O:54][CH3:55])C(O)=O)[CH:33]=1>>[C:32]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C@@H:39]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[C:45]=2[O:54][CH3:55])[C:6]([NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]2[O:25][C@H:24]3[C@:19]([CH3:29])([C@H:20]4[CH2:26][C@@H:22]([CH2:23]3)[C:21]4([CH3:28])[CH3:27])[O:18]2)[CH2:13][CH:14]([CH3:15])[CH3:16])[CH3:9])=[O:31])[CH:33]=1
Reactant: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)c(OC)c1OC
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)c(OC)c1OC

Procedure:
The title compound is prepared as described in example 1 but using {(S)-1-[(R)-3-Methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester and (S)-2-(Biphenyl-3-ylamino)-3-(2,3,4-trimethoxyphenyl)-propionic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH:15]1[C:28]2[C:19](=[CH:20][C:21]3[C:26]([C:27]=2[CH:29]=O)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+].O>C(O)C>[CH:15]1[C:28]2[C:19](=[CH:20][C:21]3[C:26]([C:27]=2[CH2:29][NH:14][CH2:13][CH2:12][CH2:11][N:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:29][C:27]4[C:28]5[C:19]([CH:20]=[C:21]6[C:26]=4[CH:25]=[CH:24][CH:23]=[CH:22]6)=[CH:18][CH:17]=[CH:16][CH:15]=5)[CH2:10][CH2:9]2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1c2ccccc2cc2ccccc12
Reactant: NCCCN1CCN(CCCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc2c(CNCCCN3CCN(CCCNCc4c5ccccc5cc5ccccc45)CC3)c3ccccc3cc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and 9-anthracenaldehyde (1.080 g, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: [Si]([O:8][CH:9]([CH2:38][CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C)[CH:10]=[CH:11][CH:12]([CH:14]1[C:18](=[O:19])[C:17]([S:20][CH3:21])=[CH:16][C:15]1([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:22][Si](C)(C)C)[OH:13])(C(C)(C)C)(C)C.N1C=CC=CC=1.N1C=CC=CC=1.F.C(=O)([O-])O.[Na+]>C(#N)C>[OH:13][CH:12]([CH:14]1[C:18](=[O:19])[C:17]([S:20][CH3:21])=[CH:16][C:15]1([OH:22])[CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH:11]=[CH:10][CH:9]([OH:8])[CH2:38][CH2:39][CH2:40][OH:41]
Reactant: CSC1=CC(CCCCOc2ccccc2)(O[Si](C)(C)C)C(C(O)C=CC(CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C1=O
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: CSC1=CC(O)(CCCCOc2ccccc2)C(C(O)C=CC(O)CCCO)C1=O
Yield: 71.3 %

Procedure:
To a solution of 270 mg of 5-[4,7-bis(t-butyldimethylsilyloxy)-1-hydroxy-2-heptenyl]-2-methylthio-4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone obtained in Example 62 dissolved in 15 ml of acetonitrile, 2 ml of pyridine was added. While stirring the mixture under ice-cooling, 1 ml of a hydrogen fluoride-pyridine solution was added and the mixture was stirred at 0° C.-room temperature for 16 hours. The mixture was poured onto saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtration and concentration, the concentrate was subjected to silica gel chromatography to give 114 mg (yield 71%) of 5-(1,4,7-trihydroxy-2-heptenyl)-4-hydroxy-2-methylthio-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: C[Si]([CH2:5][C:6]([NH2:8])=[O:7])(C)C.Cl[Si:10]1(Cl)[CH2:13][CH2:12][CH2:11]1>C(Cl)Cl>[C:6]([NH:8][Si:10]1([NH:8][C:6](=[O:7])[CH3:5])[CH2:13][CH2:12][CH2:11]1)(=[O:7])[CH3:5]
Reactant: C[Si](C)(C)CC(N)=O
Reactant: Cl[Si]1(Cl)CCC1
Solvent: ClCCl
Product: CC(=O)N[Si]1(NC(C)=O)CCC1

Procedure:
When 1.72g of trimethylsilylacetamide was mixed with 0.92 g of 1,1-dichlorosilacyclobutane in 5 g of methylene chloride, a white precipitate formed. The precipitate dissolved upon shaking and slowly recrystallized as .white needles. There was no trimethylchlorosilane detected in the residual fluid, indicating that the expected reaction to form 1,1-diacetamidosilacyclobutane did not occur.