Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[Br:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]#[N:17])[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.Cl.[OH-].[Na+]>C(OCC)(=O)C.CO>[Br:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][NH2:17])[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1
Reactant: COc1cc(Br)cc(CC#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Br)cc(CCN)c1
Temperature: 80 °C

Procedure:
A borane-tetrahydrofuran complex (1 M, 73.6 mL) was added to a THF (36.8 mL) solution of Intermediate 3 at room temperature and the resulting mixture was stirred to reflux at 80° C. for 2 hours. Methanol (26 mL) and 1 N hydrochloric acid (26 mL) were added to the reaction mixture solution and the resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was neutralized with 1 N aqueous sodium hydroxide solution followed by the addition of ethyl acetate (100 mL) to extract the reaction mixture, the organic layer was dried, and then the solvent was evaporated under reduced pressure to give the title compound (8.76 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[C:6]([N:14]([CH2:27][CH:28]=[CH2:29])[S:15]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])(=[O:17])=[O:16])[CH:5]=1>C1(C)C=CC=CC=1.[H-].[C-]#[O+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Ru+2]>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]=[CH:12][CH3:13])=[C:6]([N:14]([S:15]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])(=[O:17])=[O:16])[CH:27]=[CH:28][CH3:29])[CH:5]=1
Reactant: C=CCOc1ccc(C(=O)OC)cc1N(CC=C)S(=O)(=O)c1cc(Cl)ccc1OC
Agent: [Ru+2]
Agent: [C-]#[O+]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC=COc1ccc(C(=O)OC)cc1N(C=CC)S(=O)(=O)c1cc(Cl)ccc1OC
Reaction time: 48 h
Yield: 72.9 %

Procedure:
A solution of 3-[allyl-(5-chloro-2-methoxy-benzenesulfonyl)-amino]-4-allyloxy-benzoic acid methyl ester (243 mg, 0.537 mmol) and carbonylchlorohydrotris(triphenylphosphine)ruthenium (15 mg, 16 mmol) in toluene (2.6 mL) was stirred at 95° C. for 16 h, then another portion of carbonylchlorohydrotris(triphenylphosphine)ruthenium (27 mg, 25 mmol) was added, and stirring was continued over 48 h, then the solvent was evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) furnished 3-[(5-chloro-2-methoxy-benzenesulfonyl)-propenyl-amino]-4-[(propenyl)oxy]-benzoic acid methyl ester (177 mg, 73%). Light red oil, MS (ISP)=452.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])[C:8]([NH:10][C:11]([NH2:13])=[NH:12])=[O:9])(=[O:4])=[O:3].[C:20]([O-:23])([O-])=O.[K+].[K+].C(Cl)Cl.CO>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])[C:8]([NH:10][C:11](=[NH:13])[NH:12][C:20](=[O:23])[C:7]1[CH:14]=[CH:15][C:16]([CH:17]([CH3:18])[CH3:19])=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=1)=[O:9])(=[O:3])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1ccc(C(=O)NC(=N)N)cc1S(C)(=O)=O
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)NC(=N)NC(=O)c2ccc(C(C)C)c(S(C)(=O)=O)c2)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The acid chloride 1 a) and 3.9 g of 3-methylsulfonyl-4-i-propylbenzoylguanidine are dissolved in 50 ml of DMF, and 3.4 g of K2CO3 are then added. The mixture is stirred at RT for 4 h and then left to stand overnight. The solution is subsequently concentrated and the residue stirred up in 200 ml of water. The solid is filtered off and washed with 100 ml of water. This solid is then dissolved in 100 ml of EA and washed 1× with 10 ml of 1N HCl and then 1× with 50 ml of NaCl solution. Drying takes place over Na2SO4 and the solvent is removed in vacuo. A yellow solid is obtained which is purified by being titurated twice with 20 ml of diethyl ether and subsequently being filtered off. The product is dried in vacuo and 1.9 g are obtained of a white solid, mp 218-221° C. Rf (CH2Cl2/MeOH 20:1)=0.57 MS (ES):508 (M+1)
Reaction SMILES: [CH2:1]([N:4]([CH2:29][CH2:30][CH3:31])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:11][C:12]1[CH:20]=[CH:19][C:18]([CH2:21][O:22]CC(OC)OC)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])[CH3:10])[CH2:2][CH3:3].[CH3:32]CN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(O)C>[CH3:32][O:16][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([CH2:21][OH:22])[CH:19]=[CH:20][C:12]=1[CH2:11][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:29][CH2:30][CH3:31])[CH2:1][CH2:2][CH3:3])[CH3:10]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCN(CCC)CCCCN(C)Cc1ccc(COCC(OC)OC)cc1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Product: CCCN(CCC)CCCCN(C)Cc1ccc(CO)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.2 %

Procedure:
The compound (263.3 mg) obtained in Example 102-3 was dissolved in ethanol (6 ml). The reaction solution was added with WSCI hydrochloride (147.5 mg) and HOBt (104.9 mg) and the whole was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and added with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After the drying agent was filtrated out, the filtrate was concentrated under reduced pressure. The resultant residue was dissolved in 2-methyl-2-propanol (6 ml). The reaction solution was added with pyridinium p-toluenesulfonate (35.2 mg) and the whole was refluxed under heating for 2 days. After that, the solution was added with 1 mol/l hydrochloric acid (4 ml) and stirred at 90° C. for 30 minutes. After having been cooled to room temperature, the reaction solution was subjected to extraction with chloroform. The aqueous layer was added with a 1 mol/l sodium hydroxide aqueous solution to thereby adjust to pH 13, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After the drying agent was filtrated out, the filtrate was concentrated under reduced pressure. The resultant residue was purified through silica gel column chromatography (hexane/ethyl acetate) thereby obtaining the subject compound (83.5 mg) as a colorless oily substance.
Reaction SMILES: [O:1]=[S:2]1(=[O:22])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.Cl>CCO>[C:9]1([N:8]2[CH2:7][CH2:6][CH2:5][CH2:4][NH:3][S:2]2(=[O:22])=[O:1])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCCN(c2ccccc2)S1(=O)=O
Agent: Cl
Solvent: CCO
Product: O=S1(=O)NCCCCN1c1ccccc1
Yield: 83.7 %

Procedure:
A solution of tert-butyl 1,1-dioxo-7-phenyl-1λ6,2,7-thiadiazepane-2-carboxylate (860 mg, 2.64 mmol) in a 4 M solution of HCl in EtOH (30 mL) was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to afford 2-phenyl-1λ6,2,7-thiadiazepane-1,1-dione as a yellow oil (500 mg, 85%). LCMS (ESI): m/z=227.2 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[C@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[C@:18]2([CH3:25])[C@H:4]([C@H:5]3[C@:15]([F:27])([C@@H:16]([OH:26])[CH2:17]2)[C@:14]2([CH3:28])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1.[H][H]>CCOC(C)=O.C(O)C.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[F:27][C@@:15]12[C@:14]3([CH3:28])[C:8](=[CH:9][C:10](=[O:11])[CH2:12][CH2:13]3)[CH2:7][CH2:6][C@H:5]1[C@H:4]1[C@@:18]([CH3:25])([C@@:19]([OH:24])([C:20](=[O:21])[CH2:22][OH:23])[C@H:2]([CH3:1])[CH2:3]1)[CH2:17][C@@H:16]2[OH:26]
Reactant: [H][H]
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Yield: 95.5 %

Procedure:
In a 1000 mL round-bottomed flask was suspended dexamethasone (10 g, 25.48 mmol) in EtOAc (400 mL) and ethanol (100 mL) and tris(triphenylphosphine)rhodium(I)chloride (Wilkinson's catalyst, 2.5 g, 2.70 mmol) was added together with a magnetic stirrer bar. The mixture was vigorously stirred in a hydrogen atmosphere (1 atm) at room temperature for 1 week and another 1.0 g of the catalyst was added. The reaction was allowed to proceed for another week and the resulting mixture was concentrated in vacuo to obtain a solid that was suspended in DCM (100 ml) and the suspension was filtered. The obtained solid was washed with 3 portions of DCM (50 ml) and dried on the sinter in air, yielding 9.6 g of the target compound as an off white solid. APCI-MS m/z: 395 [MH+].
Reaction SMILES: Br[C:2]1[C:3]2[CH:12]=[CH:11][O:10][C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[CH:20][C:19]=2B2OC(C)(C)C(C)(C)O2)[CH2:15][CH2:14]1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[CH:20][C:19]=2[C:2]2[C:3]3[CH:12]=[CH:11][O:10][C:4]=3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH2:14][CH2:15]1
Reactant: Cn1cc(Br)c2ccoc2c1=O
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cn(C)c(=O)c3occc23)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
A mixture of the title compound of step 2 (150 mg, 0.66 mmol), 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (336 mg, 1.0 mmol), NaHCO3 (167 mg, 1.99 mmol), Pd(dppf)Cl2 (35 mg, 0.048 mmol) in dioxane/H2O (10 mL/2.5 mL) was bubbled with argon for 5 min. The sealed vial was stirred at 80° C. for 18 h. The reaction mixture was concentrated, treated with DCM (30 mL), washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by prep-HPLC to give the title compound (63 mg, 25%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.90-7.86 (m, 2H), 7.75 (d, J=1.6 Hz, 1H), 7.31 (s, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.57 (d, J=1.6 Hz, 1H), 3.95 (d, J=6.8 Hz, 2H), 3.74 (s, 3H), 3.18-3.12 (q, J=7.6 Hz, 2H), 1.34 (t, J=7.6 Hz, 3H), 1.16-1.15 (m, 1H), 0.61-0.55 (m, 2H), 0.31-0.27 (m, 2H). LCMS (M+H)+=388.
Reaction SMILES: C([N:8]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([CH:17]([NH2:33])[CH2:18][C:19]([NH:21][CH2:22][C:23]2([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:25][CH2:24]2)=[O:20])[CH2:13][CH2:12]1)=[O:10])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:33][CH:17]([C@H:14]1[CH2:15][CH2:16][C@H:11]([C:9]([NH:8][C:34]2[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=2)=[O:10])[CH2:12][CH2:13]1)[CH2:18][C:19]([NH:21][CH2:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)=[O:20]
Reactant: CC(C)(C)OC(=O)N(c1ccncc1)C(=O)[C@H]1CC[C@H](C(N)CC(=O)NCC2(c3ccc(Cl)cc3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(CC(=O)NCC1(c2ccc(Cl)cc2)CC1)[C@H]1CC[C@H](C(=O)Nc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Boc-trans-4-[1-Amino-2-[[[1-(4-chlorophenyl)cyclopropyl]methylamino]carbonyl]ethyl]-N-4-pyridinyl-cyclohexylcarboxamide (2-4) (0.51 g) was dissolved in anhydrous DCM (10 mL). A 20% TFA/CH2Cl2 (10 mL, 2 mL of TFA in 8 mL of anhydrous CH2Cl2) solution was added. The reaction mixture was stirred at RT and monitored by LC/MS. After 60 minutes, the reaction mixture was poured into 20% Na2CO3 (100 mL). The white solid was collected by filtration, and washed with H2O (2×20 mL). The solid was dried under vacuum at <50° C. to give 260 mg (62.6%) of trans-4-[1-Amino-2-[[[1-(4-chlorophenyl)cyclopropyl]methylamino]-carbonyl]ethyl]-N-4-pyridinyl-cyclohexylcarboxamide (2). 99% pure by HPLC (254 nm); MS (ESI) m/z=441.27 [M+H]+ 1H NMR (DMSO-d6) data is depicted in FIG. 21.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:36][CH2:37][C:38](N(OC)C)=[O:39]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:38](=[O:39])[CH2:37][Cl:36])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)CCl
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)CCl)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3) and 2-chloro-N-methoxy-N-methylacetamide.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(Br)oc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2cccc(OC)c2)oc1C
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 3-methoxyphenylboronic acid (1.8 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.3 g, 92%) as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:9][N:10]([C:29]([O:31]C(Cl)(Cl)Cl)=O)[C@H:11]1[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C>>[CH2:2]([O:9][N:10]1[C@H:11]2[CH2:15][N:14]([C@H:13]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:12]2)[C:29]1=[O:31])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CCOC(=O)[C@@H]1C[C@@H](N(OCc2ccccc2)C(=O)OC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)[C@@H]1C[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrochloric acid (4.2 M solution in dioxane, 16 mL, 70.4 mmol) was added to 2-allyl 1-tert-butyl (2S,4R)-4-{(benzyloxy)[(trichloromethoxy)carbonyl]amino}-pyrrolidine-1,2-dicarboxylate (80 mg, 1.49 mmol). The resulting mixture was stirred at room temperature overnight then the solvent was removed under vacuum. Dichloromethane (82 mL) was added to the residue followed by triethylamine (0.62 mL, 4.45 mmol). The resulting mixture was stirred at room temperature overnight then the solvent was removed under vacuum. The residue was chromatographed on silica gel (ISCO chromatography system) using a gradient from hexane for 2 minutes to 7:3 hexane:ethyl acetate over 6 minutes, hold for 3 minutes and go to 100% EtOAc over 8 minutes to afford the title compound as a clear oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:41])[CH2:29][O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH:26]=1)[C:21](O)=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:66][C:67]1[CH:71]=[CH:70][N:69]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[N:68]=1>CN(C=O)C.O>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:41])[CH2:29][O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:32]([CH3:34])[CH3:33])[CH:35]([CH3:37])[CH3:36])[CH:26]=1)[C:21]([NH:66][C:67]1[CH:71]=[CH:70][N:69]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[N:68]=1)=[O:22])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1)(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
DIPEA (0.21 mL, 1.2 mmol) was added to a solution of 3-(benzyloxy)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoic acid (220 mg, 0.48 mmol), HATU (228 mg, 0.6 mmol), and tert-butyl 3-amino-1H-pyrazole-1-carboxylate (110 mg, 0.66 mmol) in DMF (2 mL) and the reaction mixture stirred at ambient temperature overnight. Water was added to the reaction mixture and extracted with ethyl acetate (3×25 mL). The combined organic extracts were separated and washed with 1M hydrochloric acid, saturated sodium hydrogen carbonate solution, saturated brine solution, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica, eluting with 0% to 50% ethyl acetate in hexanes, to give a clear oil (90 mg)
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH:12]([C:16]([NH2:18])=[O:17])[C:13]([NH2:15])=[O:14].O.[C:20]1(S(O)(=O)=O)C=CC=CC=1.C(OC)(OC)OC>C(O)C>[C:1]1([S:7]([OH:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]1[NH:11][C:12]([C:13]([NH2:15])=[O:14])=[C:16]([OH:17])[N:18]=1
Reactant: NC(=O)C(N)C(N)=O
Agent: O=S(=O)(O)c1ccccc1
Solvent: COC(OC)OC
Solvent: CCO
Solvent: O
Product: NC(=O)c1[nH]cnc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Into a suspension of benzenesulfonic acid salt of 2-aminomalonamide [4] (1.20 g; 4.37 mmol) prepared above and benzenesulfonic acid monohydrate (81 mg; 0.46 mmol) in dry ethanol (100 ml) was added trimethyl orthoformate (1.9 ml; 17.4 mmol), and was refluxed for 2 hours under an argon atmosphere. The resulting white suspension was stirred overnight at room temperature and the precipitates were collected by filtration to give colorless benzenesulfonic acid salt of SM-108 (1.02 g; 3.58 mmol; yield 82%), which was identical with that obtained in Example 2.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:6][C:5]([C:12]([O:14]CC)=[O:13])([C:7]([O:9]CC)=[O:8])[CH2:4]1)[CH3:2].[OH-].[K+]>C(O)C>[CH2:1]([CH:3]1[CH2:4][C:5]([C:12]([OH:14])=[O:13])([C:7]([OH:9])=[O:8])[CH2:6]1)[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(CC)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCC1CC(C(=O)O)(C(=O)O)C1
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
A solution of 7.0 g (0.031 mole) of 3-ethyl-1,1-dicarbethoxycyclobutane (prepared in 1C) dissolved in 7 ml of absolute ethanol was prepared. To this solution there was added 6.87 g (0.123 mole) of potassium hydroxide dissolved in 76 ml of absolute ethanol and the mixture was heated to reflux with stirring for 1.5 hr. The mixture was then filtered and the filter cake was washed with 10 ml of absolute ethanol and 75 ml of ether. The resulting filter cake was dissolved in 30 ml of ice water and acidified with 36 ml of 50% aqueous sulfuric acid. The resulting mixture was cooled, filtered and dried to yield 4.5 g of the title compound having the following physical characteristics:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[O:23][C:24]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)=[CH:34][CH:33]=4)=[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:41]1([CH2:40][CH2:39][O:38][C:35]2[CH:36]=[CH:37][C:32]([C:24]3[O:23][C:19]4[N:20]=[CH:21][CH:22]=[C:17]([NH:16][CH2:15][CH2:14][N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[C:18]=4[C:25]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:33][CH:34]=2)[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCNc2ccnc3oc(-c4ccc(OCCN5CCOCC5)cc4)c(-c4ccccc4)c23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2c(-c3ccc(OCCN4CCOCC4)cc3)oc3nccc(NCCN4CCNCC4)c23)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(2-{2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-phenyl-furo[2,3-b]pyridin-4-ylamino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester 10d (0.062 g, 0.099 mmol) in dichloromethane (1.0 mL) was cooled to 0° C. Trifluoroacetic acid (0.5 mL) was added and the solution stirred under a nitrogen atmosphere at 0° C. for 15 min and then at room temperature for 2.5 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford 2-(4-((2-(4-morpholinyl)ethyl)oxy)phenyl)-3-phenyl-N-(2-(1-piperazinyl)ethyl)furo[2,3-b]pyridin-4-amine 10e as an off-white solid. MS (MH+) 528.3; Calculated 527 for C31H37N5O3.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[O:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7]
Reactant: CC(C)(C)OC(=O)COC(=O)c1cccs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 2-tert-butoxy-2-oxoethyl thiophene-2-carboxylate (945 mg, 3.90 mmol) in DCM (6 ml) kept at 0° C., TFA (6.00 ml, 78 mmol) was added dropwise. The solution was stirred at room temperature overnight, then volatiles were evaporated obtaining 2-(thiophene-2-carbonyloxy)acetic acid as a white solid (710 mg, 3.81 mmol, 98% yield, MS/ESI+ 186.7 [MH]+) that was used in the following reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[N:13]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[CH2:27])=[CH:24][CH:23]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:27]=[CH:26][C:25]3[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(I)cc2)CO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: Fc1ccc(C=Cc2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cc1
Reaction time: 3 h
Yield: 41 %

Procedure:
The compound of Example 2 (0.7 g, 1.8 mmol), 4-fluorostyrene (1 g, 2.6 mmol), palladium acetate (0.03 g, 0.013 mmol) and tri-o-tolyphosphine (0.03 g, 0.01 mmol) were heated to 100°-120° C. in dimethylformamide (20 mL). After 3 h, palladium acetate (0.03 g, 0.013 mmol) was added and heating was continued for 2 h. The cooled reaction mixture was extracted with diethylether (50 mL) and water (100 mL). The diethylether solution was dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to chromatography on silica gel using hexanes/ethyl acetate (6:1) as eluent. The product was isolated as a solid (0.28 g): m.p.: 154°-156° C. 1H NMR (CDCl3, 200 MHz) δ 7.5-7.0 (m, 13H), 5.5 (m, 1H), 4.8 (m, 1H), 4.3 (m, 1H).