Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]2)C1C=CC=CC=1>CO.[Pd].C(OCC)(=O)C>[OH:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]2
Reactant: COc1ccc2c(c1OCc1ccccc1)CCN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(c1O)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed a solution of tert-butyl 5-(benzyloxy)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (5.5 g, 14.89 mmol, 1.00 equiv) in MeOH (20 mL) and Pd/C (0.55 g). To the above H2 (enough, gas) was introduced in. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 3.6 g (87%) of tert-butyl 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylate as a light yellow solid. MS (ESI) m/z 224 ([M+H-t-butyl]+); Rf: 0.15 (starting material) and 0.32 (product) in ethyl acetate:petroleum ether=1:5.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][C:17](=O)[CH2:18][CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:17]([C:18]1([CH3:19])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1)[CH3:16]
Reactant: CCC(C)=O
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 2-butanone (1.0 mL), p-toluenesulfonic acid monohydrate (0.0096 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 1 h at 70° C. The reaction mixture was poured into aqueous sodium hydrogen carbonate (200 mL). Extraction with ethyl acetate (200 mL, 100 mL), washing with aqueous sodium hydrogen carbonate, drying over magnesium sulfate, filtration and concentration at reduced pressure gave a residue, which was triturated with dichloromethane/ethyl acetate (1:1, 6 mL), and the precipitate was collected by filtration to afford the title compound (0.095 g, 69%) as a yellow solid:
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:26]=1)C1C=CC=CC=1.C.[H][H]>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:26]=1
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)n2cc(C=CCCCCCCCCCCCCCCOCc3ccccc3)c3ccccc32)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)n2cc(CCCCCCCCCCCCCCCCO)c3ccccc32)cc1
Yield: 91.9 %

Procedure:
3-(16-benzyloxyhexadecenyl)-1-(4-methoxybenzensulfonyl)indole (530 mg, 0.86 mmol) was dissolved in 25 mL of ethanol and added to palladium supported on activated charcoal (5%, 50 mg). The resulting mixture was allowed to stand at room temperature for 3 hours under 1 atmospheric pressure of hydrogen. After filtration, the reaction mixture was extracted with ethyl ether. The organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography to give 3-(16-hydroxyhexadecyl)-1-(4-methoxybenzenesulfonyl)indole as a white solid (417 mg, 92%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[OH:12])[CH3:2].[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[O:12][CH3:14])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(F)cc1O
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)c1ccc(F)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a solution of compound 4 (19.9 g, 0.109 mol) in acetonitrile (200 mL) was added cesium carbonate (42.0 g, 0.129 mol). The resulting mixture was stirred at rt for 30 min. followed by addition of methyl iodide (13.5 mL, 0.218 mol). The resulting mixture was stirred at rt O/N and filtered through Celite. The solvent was removed under reduced pressure to give crude product 5 (20.0 g, 93%) and used in the next step without further purification. 1H NMR 400 MHz (CDCl3) δ: 7.81-7.78 (m, 1H), 6.60-6.58 (m, 2H), 4.38 (q, J=7.0 Hz, 2H), 3.82 (s, 3H), 1.39 (t, J=7.0 Hz, 3H); MS (ES) m/z: 199 (M+1)′.
Reaction SMILES: BrCC1C=CC(C(OC(C)(C)C)=O)=C(Cl)C=1.FC(F)(F)CN.[Cl:23][C:24]1[CH:36]=[C:35]([CH2:37][NH:38][CH2:39][C:40]([F:43])([F:42])[F:41])[CH:34]=[CH:33][C:25]=1[C:26]([O:28]C(C)(C)C)=[O:27].Cl>CS(C)=O.O1CCOCC1>[Cl:23][C:24]1[CH:36]=[C:35]([CH2:37][NH:38][CH2:39][C:40]([F:41])([F:42])[F:43])[CH:34]=[CH:33][C:25]=1[C:26]([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)c1ccc(CNCC(F)(F)F)cc1Cl
Agent: CC(C)(C)OC(=O)c1ccc(CBr)cc1Cl
Agent: Cl
Agent: NCC(F)(F)F
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CNCC(F)(F)F)cc1Cl

Procedure:
To 24.9 g of 2-chloro-4-(methoxycarbonyl)benzoic acid and 2 mL of Sulfuric Acid in 350 mL of DCM was added isobutylene gas at −78° C. until the solvent was saturated and capped off securely. Let go several days at room temperature and re-cool to −78° C. before removing cap. Concentrate solvent, extract with Ethyl Acetate and bicarbonate, dry with Magnesium Sulfate, filter and concentrate to give 31.4 g of 1-tert-butyl 4-methyl 2-chloroterephthalate. 3.35 g of 1-tert-butyl 4-methyl 2-chloroterephthalate was hydrolyzed via Procedure M. 2.5 g of 4-(tert-butoxycarbonyl)-3-chlorobenzoic acid was was cooled to 0° C. in 25 mL of THF before a solution of 19.5 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at ˜50% complete by TLC. The reaction is re-cooled to 0° C. and another 19.5 mL of BH3-THF is added dropwise before the ice bath is removed. Upon completion, the reaction is re-cooled to 0° C. and quenched with 3N HCl dropwise. The aqueous layer was extracted two times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 564 mg of tert-butyl 2-chloro-4-(hydroxymethyl)benzoate was cooled to 0° C. in 5 mL of DCM before adding 665 mg of Triphenylphosphine and 417 mg of NBS. Reaction was concentrated and directly purified via ISCO Combi-Flash to give pure tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 147 mg of tert-butyl 4-(bromomethyl)-2-chlorobenzoate was reacted with 2,2,2-trifluoroethanamine in DMSO via Procedure P. 141 mg of tert-butyl 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoate was treated with 4N HCl in Dioxane at 45° C. and concentrated to give 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 75 mg of 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to give pure 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,2,2-trifluoroethylamino)methyl)benzamide. MS (Q1) 454.6 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[O:35]=[S:36]1(=[O:54])[CH2:41][CH2:40][C:39]([CH2:43][O:44][C:45]2[CH:50]=[C:49]([CH3:51])[C:48](Br)=[C:47]([CH3:53])[CH:46]=2)([OH:42])[CH2:38][CH2:37]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:48]2[C:49]([CH3:51])=[CH:50][C:45]([O:44][CH2:43][C:39]3([OH:42])[CH2:40][CH2:41][S:36](=[O:35])(=[O:54])[CH2:37][CH2:38]3)=[CH:46][C:47]=2[CH3:53])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: Cc1cc(OCC2(O)CCS(=O)(=O)CC2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC6(O)CCS(=O)(=O)CC6)cc5C)ccc(F)c43)ccc21
Temperature: 110 °C
Reaction time: 3 h

Procedure:
In a microwave vial methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (190 mg), 1,1-dioxo-4-((4-bromo-3,5-dimethylphenoxy)methyl)tetrahydro-2H-thiopyran-4-ol (150 mg), K3PO4 (250 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (21 mg) are suspended in N,N-dimethylformamide (2 mL) and water (100 μL). The mixture is purged for 10 minutes with argon. Palladium-(II)-acetate (6 mg) is added, the vial is sealed and the mixture is stirred at 110° C. for 3 hours. After cooling to room temperature the mixture is partitioned between diethylether and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (petrole ether/ethyl acetate 50:50→0:100) to give the title compound. Yield: 90 mg; LC (method 8): tR=0.53 min; Mass spectrum (ESI+): m/z=625 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH:11]([O:12][C:13](=[O:15])[CH3:14])[CH:10]([O:16][C:17](=[O:19])[CH3:18])[CH:9]([O:20][C:21](=[O:23])[CH3:22])[CH:8]([O:24][C:25]2[CH:29]=[CH:28][S:27][C:26]=2[CH:30]=O)[O:7]1)(=[O:3])[CH3:2].[C:32](=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH:6]1[CH:11]([O:12][C:13](=[O:15])[CH3:14])[CH:10]([O:16][C:17](=[O:19])[CH3:18])[CH:9]([O:20][C:21](=[O:23])[CH3:22])[CH:8]([O:24][C:25]2[CH:29]=[CH:28][S:27][C:26]=2[CH:30]=[CH2:32])[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1OC(Oc2ccsc2C=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Reactant: O=C([O-])[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1sccc1OC1OC(COC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O

Procedure:
3.30 g of 3,4,5-triacetoxy-6-(2-formyl-thiophen-3-yloxy)-tetrahydropyran-2-ylmethyl actate were dissolved in 60 ml of dioxane. 6.43 g of methyltriphenylphosphonium bromide, 5.37 g of potassium carbonate and 0.25 ml of water were added, and the solution was refluxed for 4 h. The solution was concentrated and purified by column filtration. 2.89 g of the product with the molecular weight: 456.47 (C20H24O10S), MS (ESI): 479.10 (M+Na+); 474.10 (M+NH4+) were obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH3:18].[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH2:17][CH3:18])=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 76.6 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-propoxypiperidine-1-carboxylate obtained in Example (113d) (0.73 g, 2.8 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.61 g, 2.98 mmol), WSC hydrochloride (1.15 g, 6 mmol), HOBt (0.61 g, 4.5 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.89 g of the title compound as a colorless solid (77%).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:20]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>ClCCl.C(O)(C)C>[NH2:20][CH:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]2[CH:16]=[C:15]([C:18]#[N:19])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(C#N)cc2C1Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: N#Cc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Tert-butyl 1-benzyl-7-cyano-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (1.1 g, 3.03 mmol) was dissolved in dichloromethane (20 mL) and 5 M hydrochloric acid in isopropanol (2 mL) was added. The reaction mixture was stirred at room temperature for 12 h followed by 4 h at 35° C. The solvent was evaporated in vacuo. Water (30 mL) was added and the pH was adjusted to pH 9 using aqueous saturated sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane. The combined extracts were dried (MgSO4) and the solvent was evaporated in vacuo. Yield: 790 mg (3.03 mmol, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C1COCC1>[NH2:1][C:2]1[C:3]([C:9]([N:12]2[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)O)n1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1ccc(N)c(C(=O)N2CCC2)n1
Temperature: 70 °C
Yield: 65.5 %

Procedure:
To a stirred mixture of 3-amino-6-methylpicolinic acid (525 mg, 2.17 mmol) and azetidine (124 mg, 146 μl, 2.17 mmol) at r.t. in THF (15 ml) under an argon atmosphere were added HATU (1.65 g, 4.35 mmol) and 4-methylmorpholine (719 μl, 6.52 mmol). The mixture was heated to 70° C. overnight, then cooled to r.t. and concentrated. The crude product was purified by silica gel chromatography using a n-heptane/EtOAc gradient to give the title compound (272 mg, 65%) as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>O1CCCC1>[CH:29]1([C:32]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([C@H:12]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=2)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:7]3)=[O:33])[CH2:31][CH2:30]1
Reactant: CCOc1cc([C@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Product: CCOc1cc([C@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Yield: 58.7 %

Procedure:
A stirred mixture of 7-amino-2-[(1R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one (0.91 g, 2.2 mmol) and cyclopropane carbonyl chloride (0.25 mL, 2.8 mmol) in tetrahydrofuran (10 mL) was heated to reflux for 15 min. The solvent was removed in vacuo to give a solid. The solid was recrystallized from ethanol (10 mL) to give cyclopropyl-N-{2-[(1R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide as an off-white solid (0.61 g, 56% yield); mp, 173-175° C.; 1H NMR (CDCl3) δ 0.86-0.93 (m, 2H, 2CHH), 1.07-1.14 (m, 2H, 2CHH), 1.46 (t, J=6.9 Hz, 3H, CH3), 1.63-1.73 (m, 1H, CH), 2.95 (s, 3H, CH3), 3.68 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.20 (d, J=16.7 Hz, 1H, CHH), 4.21 (dd, J=9.9, 14.3 Hz, 1H, CHH), 4.44 (d, J=16.7 Hz, 1H, CHH), 5.73 (dd, J=4.3, 9.9 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.44 (t, J=7.8 Hz, 1H, Ar), 8.43 (d, J=8.3 Hz, 1H, Ar), 10.46 (s, 1H, NH); 13C NMR (CDCl3) δ 8.24, 14.61, 16.10, 41.43, 47.81, 51.55, 55.75, 55.88, 64.56, 111.46, 112.09, 116.69, 116.99, 117.76, 119.17, 129.27, 133.54, 138.06, 141.22, 148.84, 149.67, 169.96, 172.59; Anal Calcd for C24H28N2O6S: C, 61.00; H, 5.97; N, 5.93. Found: C, 60.73; H, 5.91; N, 5.69.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[CH:9]1[C:17]2[C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[O:14][C:13]=2[CH:12]=[CH:11][C:10]=1[NH2:22]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:7][CH3:8])[C:4]([NH:22][C:10]1[CH:11]=[CH:12][C:13]2[O:14][C:15]3[CH2:21][CH2:20][CH2:19][CH2:18][C:16]=3[C:17]=2[CH:9]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc2oc3c(c2c1)CCCC3
Reactant: CCN(CC)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)Nc1ccc2oc3c(c2c1)CCCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
Diethylcarbamoyl chloride (0.72 mL, 5.5 mmol) was added to a solution of 6,7,8,9-tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol) in pyridine (15 mL). The reaction mixture was stirred overnight at room temperature. The crude material was diluted in chloroform and washed with 1 N HCl, water, and brine, dried (Na2SO4) and concentrated. The crude material was recrystallized from acetonitrile to provide 1,1-diethyl-3-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-urea (0.78 g). Mp 179-180° C.; Anal. Calcd. for C17H22N2O2: C, 71.30; H, 7.74; N, 9.78; Found: C, 71.29; H, 7.66; N, 9.72.
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].[C:5](OCC)(=[O:13])[C:6]#[C:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C>C(#N)C>[OH:13][C:5]1[N:4]=[CH:2][N:3]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=1
Reactant: N=CN
Reactant: CCOC(=O)C#CC(=O)OCC
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(O)ncn1
Temperature: 25 °C

Procedure:
Formamidine hydrochloride (2.0 g, 45.4 mmol) and diethyl 2-butynedioate (7.23 mL, 45.4 mmol) were added together in acetonitrile (85 mL) and the resulting mixture was treated dropwise with triethylamine (6.33 mL, 45.4 mmol). The resulting mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool to room temperature, further cooled in an ice bath and the resulting solid was collected by filtration and discarded. The filtrate was evaporated under reduced pressure and the residue purified by column chromatography (Biotage SP4) eluting with a gradient of 0-100% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as an off white solid (0.995 g);
Reaction SMILES: O1CCCC1.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C([Li])CCC.[F:17][C:18]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=1[CH:20]=[O:21]>CCCCCC>[F:17][C:18]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=1[CH:20]([OH:21])[C:7]1[S:8][CH:9]=[CH:10][N:11]=1
Reactant: Brc1nccs1
Reactant: O=Cc1cc(F)ccc1F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1nccs1)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a tetrahydrofuran (10 ml) solution of 2-bromothiazole (180 μg, 2 mmol) was added dropwise a hexane solution of n-butyl lithium (1.57M, 1.40 ml, 2.2 mmol) at −78° C. After stirring for 10 minutes, 2,5-difluorobenzaldehyde (238 μl, 2.2 mmol) was added and while stirring, the temperature of the mixture was gradually raised to 0° C. The reaction was then quenched by the addition of an aqueous solution of ammonium chloride, followed by the addition of ether. The ether layer was washed with water and brine, and then, dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1), whereby the title compound (358 mg, 79%) was obtained as an oil.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH2:20][O:21][C:22]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=4[CH:24]=3)(=[O:18])=[O:17])[CH2:12][C:11]2=[O:30])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[C:33]([O:36][CH:37]([O:39][C:40](OC1C=CC([N+]([O-])=O)=CC=1)=[O:41])[CH3:38])(=[O:35])[CH3:34].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:33]([O:36][CH:37]([O:39][C:40]([NH:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH2:20][O:21][C:22]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=4[CH:24]=3)(=[O:18])=[O:17])[CH2:12][C:11]2=[O:30])=[CH:31][CH:32]=1)=[NH:3])=[O:41])[CH3:38])(=[O:35])[CH3:34]
Reactant: N=C(N)c1ccc(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)cc1
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC(C)OC(=O)NC(=N)c1ccc(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)cc1
Yield: 41.7 %

Procedure:
A solution of 1-(4-amidinobenzyl)-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone hydrochloride (99 mg), O-(1-acetoxyethoxycarbonyl)-4-nitrophenol (54 mg), diisopropylethylamine (39 mg) in DMF (5 ml) was stirred at 80° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated. Precipitated crystals were washed with ether to give colorless crystals of the title compound (49 mg).
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.F[C:27]1[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=1.[C:38]([O:42][C:43]([C:45]1[CH:55]=[C:54]([OH:56])[C:48]2[CH2:49][CH:50]([CH2:52][OH:53])[O:51][C:47]=2[CH:46]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([C:45]1[CH:55]=[C:54]([O:56][C:27]2[CH:37]=[CH:36][C:30]([C:31](=[O:32])[N:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[C:48]2[CH2:49][CH:50]([CH2:52][OH:53])[O:51][C:47]=2[CH:46]=1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CN(C)C(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(CO)C2
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: CN(C)C(=O)c1ccc(Oc2cc(C(=O)OC(C)(C)C)cc3c2CC(CO)O3)cc1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-fluoro-N,N-dimethylbenzamide (989 mg, 5.91 mmol) and 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) (1.500 g, 5.633 mmol) to give a white solid (154 mg, 7% yield). 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=8.59 Hz, 2 H) 7.20 (d, J=16.17 Hz, 2 H) 6.96 (d, J=8.59 Hz, 2 H) 4.87-5.03 (m, 1 H) 3.77-3.87 (m, 1 H) 3.71 (br. s., 1 H) 2.99-3.13 (m, 7 H) 2.90 (dd, J=16.55, 7.20 Hz, 1 H) 1.54 (s, 9 H); LCMS for C23H27NO6 m/z 358.20 (M-tBu+H)+.