Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[N:17]=1.[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:20])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[N:17]=1
Reactant: CI
Reactant: Cc1ccc2c(n1)Nc1ccccc1NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)Nc1ccccc1N(C)C2=O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
A mixture consisting of 11.3 gm (0.05 mol) of 6,11-dihydro-2-methyl-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one (prepared according to C.A. 74, 53868y, 1971), 150 ml of dimethyl formamide, and 2.8 gm of 50% sodium hydride in mineral oil was stirred at 30° C. in a nitrogen atmosphere for 1 hour. Then, a solution of 10.7 gm (0.075 mol) of methyl iodide in 30 ml of dimethyl formamide was added dropwise while stirring, and the mixture was heated on an oil bath at 100° C. for 3 hours while stirring and then evaporated in vacuo, and an aqueous sodium carbonate solution was stirred into the residue. The mixture was suction-filtered, and the filter cake was washed with water and recrystallized from xylene, yielding 80% of theory of the compound named in the heading, which had a melting point of 192°-194° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C:13]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])[O:12][C@@H:11]([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[C@H:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N-:57]=[N+:58]=[N-:59].[Na+]>CN(C1C=CN=CC=1)C.CN(C=O)C.[Cl-].[Na+].O.ClCCl>[N:57]([C@@H:10]1[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])[O:12][C@H:11]1[N:26]1[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]1=[O:28])=[N+:58]=[N-:59]
Reactant: Cc1cn([C@@H]2OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@@H](OCc3ccccc3)[C@@H]2O)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1cn([C@@H]2OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@@H](OCc3ccccc3)[C@H]2N=[N+]=[N-])c(=O)[nH]c1=O
Yield: 91.1 %

Procedure:
A solution of nucleoside 30 (5.35 g, 10 mmol) in anhyd dichloromethane (300 mL) was cooled to 0° C. Anhyd pyridine (8.08 mL, 100 mmol) and DMAP (4.89 g, 40 mmol) was added followed by the dropwise addition of trifluoromethansulfonic anhydride (3.3 mL, 20 mmol). After 2 h at 0° C. the reaction was quenched by the addition of ice cold sat. aq NaHCO3 (200 mL) and the reaction mixture was transferred to a separatory funnel. The phases were separated and the aq phase was extracted with dichloromethane (200 mL). The combined organic phases were washed with aq HCl (1.0 M, 2×300 mL) and sat. aq NaHCO3 (300 mL), dried (Na2SO4), filtered and concentrated in vacuo to give a white solid. The solid was dissolved in anhyd DMF (300 mL) and NaN3 (1.86 g, 30 mmol) was added. After stirring at rt for 4 h brine (300 mL) was added and the mixture was transferred to a separatory funnel. The aq phase was extracted with dichloromethane (3×200 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo yielding a yellow residue that was purified by DCVC (Ø 5 cm, 25-100% EtOAc in n-heptane v/v, 5% increments, 100 mL fractions) affording nucleoside 32 (5.1 g, 91% from 30) as a white solid. Analytical data were identical to those reported above.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([F:25])[CH:3]=1.OB(O)[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([OH:33])=[O:32].C([O-])([O-])=O.[K+].[K+].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:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:28]5[CH:36]=[CH:35][CH:34]=[C:30]([C:31]([OH:33])=[O:32])[CH:29]=5)=[CH:3][C:4]=4[F:25])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)c(F)c2)c1

Procedure:
A microwave vial was charged with 4-(4-bromo-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.29 mmol), 3-(dihydroxyboranyl)benzoic acid (0.29 mmol), PdCl2(dppf) (0.015 mmol), a solution of K2CO3 (0.733 mmol) in water (1 mL), and 1,4-dioxane (3 mL). The vial was purged with nitrogen, sealed, and irradiated in a microwave reactor for 30 min at 130° C. (pressure ˜3-4 bar). Analysis of the crude reaction by LCMS indicated ˜80% conversion to desired product. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DMSO (3 mL), filtered through a syringe filter, and purified by reverse phase HPLC (10-90% acetonitrile/water+0.1% TFA). The appropriate product fractions were concentrated to remove a majority of the acetonitrile (product did not crash out). The mixture was adjusted to pH˜12 with 1N aq NaOH and partitioned with ethyl acetate. The aqueous layer was separated and adjusted to pH˜2 with 1N aq HCl, causing a gummy precipitate to form which was collected by filtration and dried to constant weight to provide the title product (39 mg, 0.087 mmol, 30% yield) as a tan solid. MS(ES)+ m/e 451.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([CH3:10])[CH:6]=[C:5]([I:11])[C:3]=1[NH2:4].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[F:1][C:2]1[C:8]([F:9])=[C:7]([CH3:10])[CH:6]=[C:5]([I:11])[C:3]=1[N:4]=[C:13]=[O:15]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(I)c(N)c(F)c1F
Solvent: C1COCCO1
Product: Cc1cc(I)c(N=C=O)c(F)c1F
Temperature: 100 °C

Procedure:
A mixture of 2,3-difluoro-6-iodo-4-methylaniline D19 (330 mg, 1.2 mmol), triphosgene (150 mg, 0.5 mmol), and dioxan (5 ml) was heated at 100° C. for 15 min then cooled and evaporated to give the crude title compound used directly in the next step.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N+:8]([O-:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:21]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:22]=[CH2:23]>C1(C)C=CC=CC=1>[N:1]1([CH2:6][C:7]2([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[CH2:23][CH:22]([CH2:21][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:10][N:8]2[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C[N+]([O-])=C(Cn1ccnc1)c1ccc2ccccc2c1
Reactant: C=CCOc1ccccc1
Solvent: Cc1ccccc1
Product: CN1OC(COc2ccccc2)CC1(Cn1ccnc1)c1ccc2ccccc2c1

Procedure:
A mixture of compound 2 (9.0 g, 0.034 mol) and phenyl allyl ether (6.98 ml, 0.051 mol) in 200 ml of toluene is refluxed for 48 hours, cooled and evaporated under vacuum. The semisolid that remained (7.30 g, 54%) is crystallized from ether and recrystallized from ethyl acetate to give tan crystals. Yield: 2.4 g (18%); m.p. 176°-178° C. (Found: C, 74.96; H, 6.41; N, 10.40. C25H25N3O2 requires: C, 75.16; H, 6.31; N, 10.52).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([C@@H:11]3[O:23][C@H:22]([CH3:24])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[C:7]=2[CH:25]=1.[Br:28]C1N([C@@H]2O[C@H](C)[C@@H](OC(=O)C)[C@H]2OC(=O)C)C2C=CC(C(F)(F)F)=CC=2N=1>CCOC(C)=O.CCCCCC>[Br:28][C:9]1[N:8]([C@@H:11]2[O:23][C@H:22]([CH3:24])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])[C:7]2[CH:25]=[C:3]([C:2]([F:1])([F:26])[F:27])[CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2cc(C(F)(F)F)ccc21
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cnc2ccc(C(F)(F)F)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2ccc(C(F)(F)F)cc21
Yield: 52 %

Procedure:
Starting with 6-trifluoromethyl-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole, this compound was prepared in a manner analogous to that described for 2-bromo-5-trifluoromethyl-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole. Following flash column chromatography on silica with EtOAc/hexane (2:3), a 52% yield of the title compound was obtained as an oil. 1H NMR (DMSO-d6) δ1.48 (d, 3H, CH3), 2 (s, 3H, COCH3), 2.1 (s, 3H, COCH3), 4.2-4.3 (m, 1H, CH), 5.2 (t, 1H, CH), 5.63 (t, 1H, CH), 6.22 (d, 1H, CH), 7.6 (d, 1H, aromatic), 7.8 (d, 1H, aromatic), 8.1 (s, 1H, aromatic).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=O)[N:12]([C:20]3[CH:29]=[CH:28][C:23]4[O:24][CH2:25][CH2:26][O:27][C:22]=4[CH:21]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].ON1C2C=CC=CC=2N=N1.Cl.[CH3:41][N:42](C)[CH2:43]CCN=C=NCC.C(N(C(C)C)C(C)C)C.Cl.CNC>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([CH2:15][CH2:16][C:17]([N:42]([CH3:43])[CH3:41])=[O:19])[N:12]([C:20]3[CH:29]=[CH:28][C:23]4[O:24][CH2:25][CH2:26][O:27][C:22]=4[CH:21]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CCc1nc(Nc2ccc(F)c(F)c2)nn1-c1ccc2c(c1)OCCO2
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)CCc1nc(Nc2ccc(F)c(F)c2)nn1-c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound E1 (prepared according to Ex.1) (0.00062 mol) was dissolved in DMF (5 ml). 1-Hydroxy-1H-benzotriazole (0.00186 mol), (3-Dimethylamino-propyl)-ethyl-carbodiimide.hydrochloride (1:1) (0.00186 mol) and N-ethyl-N-(1-methylethyl)-2-propanamine (0.00248 mol) were added, followed by addition of dimethylamine hydrochloride (1:1) (0.00124 mol). The reaction mixture was stirred for 3 hours at r.t. The reaction mixture was poured into water. The mixture was extracted with CHCl3. The organic layer was separated, washed with a 1M HCl solution, then washed with brine and filtered through a hydrophobic frit. The solvents were evaporated under reduced pressure to give a yellow solid residue that was dried further for one hour (in the GeneVac®). The residue was triturated with diethyl ether, filtered off and dried. Yield: 0.245 g of compound E3 (92%).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH2:2][CH3:3].N1C2C(=CC=CC=2)C(=O)[C:16]1=O.BrCC(C)C>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH:2]([CH3:16])[CH3:3]
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Reactant: O=C1Nc2ccccc2C1=O
Solvent: CC(C)CBr
Product: CC(C)CN1C(=O)C(=O)c2ccccc21

Procedure:
Was prepared in an analogous manner to 1-propylindoline-2,3-dione using isatin (purchased from Fisher Scientific) and 1-bromo-2-methyl propane (purchased from Fisher Scientific). 1H NMR δ (dd, 2H), 7.13 (t, 1H), 6.90 (d, 1H), 3.55 (d, 2H), 2.16 (m, 1H), 1.00 (d, 6H).
Reaction SMILES: C([O:8][C:9](=[O:35])[CH2:10][CH2:11][NH:12][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:33])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]=[N+]=[N-])=[CH:25][CH:24]=2)[CH:15]=1)C1C=CC=CC=1.O>C(O)(=O)C.[Pd]>[NH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:13]([NH:12][CH2:11][CH2:10][C:9]([OH:35])=[O:8])=[O:34])=[O:33])=[CH:24][CH:25]=1
Reactant: [N-]=[N+]=NCc1ccc(CC(=O)Nc2cccc(C(=O)NCCC(=O)OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: NCc1ccc(CC(=O)Nc2cccc(C(=O)NCCC(=O)O)c2)cc1
Yield: 56 %

Procedure:
296 mg of N-[m-[2-(α-azido-p-tolyl)acetamido]benzoyl]-β-alanine benzyl ester and 74 mg of Pd/C are stirred in 6 ml of acetic acid for 7 hours under hydrogen. After the addition of 3 ml of water the mixture is filtered and the filtrate is evaporated in a vacuum. The residue is taken up in water and the suspension is evaporated in a vacuum. The residue is triturated in methanol, filtered off under suction and dried. There are obtained 125 mg of N-[m-[2-(α-amino-p-tolyl)acetamido]benzoyl]-β-alanine (3:4 hydrate), m.p. 226° C.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([C:16]([N:18]4[CH2:23][CH2:22][CH:21]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[CH2:20][CH2:19]4)=O)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B.O1CCCC1.[ClH:36]>O1CCCC1>[ClH:36].[ClH:36].[CH:11]1[C:12]2[C:13]3([CH2:16][N:18]4[CH2:23][CH2:22][CH:21]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[CH2:20][CH2:19]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(N1CCC(N2CCOCC2)CC1)C12CC(c3ccccc31)c1ccccc12
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: c1ccc2c(c1)C1CC2(CN2CCC(N3CCOCC3)CC2)c2ccccc21
Temperature: 0 °C
Yield: 68 %

Procedure:
To an ice cooled solution of 1-(9,10-dihydro-9,10-methanoanthracen-9-ylcarbonyl)-4-(4-morpholinyl)piperidine (2.29 g, 5.89 mmol) in tetrahydrofuran (35 mL) was added 1M borane-tetrahydrofuran in tetrahydrofuran (17,7 mL, 17.7 mmol). The reaction was refluxed for 5 h and then was cooled with an ice bath. This mixture was added dropwise a solution of methanolic hydrochloride (25 mL). The ice bath was removed and the solution was refluxed for 0.5 h. The resulting precipitate was filtered with hexane wash (50 mL). The solid was recrystallized from acetonitrile to give the title compound as a white solid (1.62 g, 68%), mp 257.0°-259.0° C.; MS(CI): 375 (M+H); NMR (250 MHz,DMSO-d6): 2.27(m, 6H), 2.75(s, 2H), 3.11(br s, 2H), 3.40(br s, 2H), 3.66(m, 2H), 3.94(m, 4H), 4.38(m, 3H), 4.47(s, 1 H), 7.00(m, 4H), 7.34(m, 4H), 10.46(br s, 1H), 11.91(br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)(=[O:33])=[O:32])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: O=S(=O)(c1ccccc1Br)N1CCCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)pyrrolidine. MS (ESI): mass calcd. for C20H19FN4O2S, 398.12; m/z found, 399.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 8.28 (d, J=1.4, 1H), 8.12-8.08 (m, 1H), 8.0-7.94 (m, 1H), 7.71-7.65 (m, 2H), 7.62-7.56 (m, 1H), 7.42-7.39 (m, 1H), 7.34-7.27 (m, 2H), 2.94 (t, J=6.7, 4H), 1.81-1.69 (m, 4H).
Reaction SMILES: [CH:1]1([C:4](=[C:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][Si](C)(C)C)=[CH:17][C:12]=3[CH2:11][O:10][C:9]3[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:8]2=3)[C:5]#[N:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH:1]1([C:4](=[C:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[CH:19])=[CH:17][C:12]=3[CH2:11][O:10][C:9]3[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:8]2=3)[C:5]#[N:6])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)COc1cc(F)ccc1C2=C(C#N)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc2c(c1)COc1cc(F)ccc1C2=C(C#N)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
[step 2] 2-Cyclopropyl-2-{3-fluoro-8-[(trimethylsilyl)ethynyl]dibenzo[b,e]oxepin-11(6H)-ylidene}acetonitrile (1.0 g, 2.6 mmol) obtained in step 1 was dissolved in methanol (10 mL), potassium carbonate (0.35 g, 2.6 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction was discontinued with water, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether and collected by filtration to give the title compound (600 mg, 74%, E/Z=1/1).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[O:16]1[CH:20]=[CH:19][NH:18][C:17]1=[S:21]>>[O:16]1[CH2:20][CH2:19][N:18]=[C:17]1[S:21][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]1[OH:14]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: S=c1[nH]cco1
Product: CC1(C)Oc2ccc(C#N)cc2C(SC2=NCCO2)C1O

Procedure:
Following the procedure described in the Example 1, using (±) 2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 3H-oxazole-2-thione as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH:27]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:28]3[CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:24])[CH2:26][CH:27]3[CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNC(Cc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc21
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)CCN3C(=O)OC(C)(C)C)C(Cc2ccccc2)C1

Procedure:
Following the procedure of steps 2 and 4 of Example 1, 5-bromo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.48 g, 1.6 mmol) was coupled with 3-benzyl-piperazine-1-carboxylic acid tert-butyl ester to give 5-(2-benzyl-4-tert-butoxycarbonyl-piperazin-1-yl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester, which was then deprotected by reaction with TFA to afford 5-(2-benzyl-piperazin-1-yl)-2,3-dihydro-1H-indole (0.16 g) as a yellow foam; 1H NMR (300, MHz, CDCl3) δ 7.24-7.10 (m, 3H), 7.17-1.01 (m, 2H), 6.96 (d, J=2.2 Hz, 1H), 6.82 (dd, J=8.2, 2.2 Hz, 1H), 3.61-3.46 (m, 3H), 3.20-2.69 (m, 7H), 2.84-2.72 (m, 2H), 2.56 (dd, J=10.5, 13.6 Hz, 1H); MS (M+H)=294.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([C:14]2[N:18]([CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)[N:17]=[C:16]([C:29]3[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=3)[CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:57][C:58]1[NH:62][N:61]=[N:60][N:59]=1.C(Cl)CCl>CN(C=O)C.C(OCC)(=O)C>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([NH:11][C:12]([C:14]2[N:18]([CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH:57][C:58]4[NH:62][N:61]=[N:60][N:59]=4)=[O:26])=[CH:22][CH:21]=3)[N:17]=[C:16]([C:29]3[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=3)[CH:15]=2)=[O:13])[CH2:9][CH2:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)[C@H]1CC[C@H](NC(=O)c2cc(-c3cc(F)c(F)c(F)c3)nn2Cc2ccc(C(=O)O)cc2)CC1
Reactant: Nc1nnn[nH]1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)[C@H]1CC[C@H](NC(=O)c2cc(-c3cc(F)c(F)c(F)c3)nn2Cc2ccc(C(=O)Nc3nnn[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from step F (90 mg, 0.175 mmol) in DMF was added HOAt (36 mg, 0.26 mmol), DIEA (92 μL, 0.52 mmol), amino tetrazole (45 mg, 0.52 mmol) and EDC (50 mg, 0.26 mmol). The reaction was left stirring at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with 1N HCl. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified on the Gilson reverse phase HPLC to give the title compound. 1H NMR (DMSO, 500 MHz): 8.42 (d, J=8.0 Hz, 1H), 8.03 (d, J=8.2 Hz, 2H), 7.68 (dd, J=6.6, 8.7 Hz, 2H), 7.39 (s, 1H), 7.35 (d, J=8.3 Hz, 2H), 5.81 (s, 2H), 3.63 (m, 1H), 1.87 (d, J=10.9 Hz, 2H), 1.76 (d, J=11.7 Hz, 2H), 1.2-1.0 (m, 4H), 0.83 (s, 9H). LC-MS: 2.50 min; (M+H)=581.3.
Reaction SMILES: CO[C:3]1[N:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1.C([O-])(=O)C.[NH4+:33]>O1CCCC1>[NH2:33][C:3]1[N:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1
Reactant: [NH4+]
Reactant: CCOC(=O)C1=C(C)N=C(OC)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N=C(N)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 107.9 %

Procedure:
A solution of 2-methoxy-4-methyl-6-(3-nitrophenyl)-1,5(6H)-pyrimidinedicarboxylic acid, diethyl ester (3.78 g, 9.66 mmoles of crude from previous reaction) in anhydrous tetrahydrofuran (20 ml) was cooled to 0° C. (ice bath) and a slow stream of ammonia gas was bubbled through it for approximately 5 minutes. Solid ammonium acetate (385 mg, 5.0 mmoles) was added and the reaction flask was tightly stoppered and allowed to stir at room temperature for 72 hours. A light yellow solid precipitated out of the reaction. Excess ammonia and tetrahydrofuran were evaporated and the residue was dissolved in methylene chloride. The insoluble material (ammonium acetate) was filtered off and the filtrate was concentrated. The residue was purified by flash chromatography (30% ethyl acetate in dichloromethane). The desired product was crystallized from dichloromethane-isopropyl ether to provide 2.03 g of the title compound as a yellow solid, melting point 166°-168° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[CH2:26]([O:30]C=C)[CH2:27]CC.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC=C)=C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([C:26](=[O:30])[CH3:27])=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: C=COCCCC
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Agent: [Pd+2]
Agent: C=COC=C
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1ccc2c(c1)CCNC2
Temperature: 80 °C
Reaction time: 7 h

Procedure:
To a stirred solution of 6-trifluoromethanesulfonyloxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (3.81 g, 10 mmol) in dry DMF (30 ml) are added n-butylvinyl ether (6.01 g, 60 mmol, 6.0 eq.), TEA (1.67 ml, 12 mmol, 1.2 eq.), 1,3-bis(diphenylphosphino)propane (144 mg, 0.276 mmol, 0.0276 eq.), and palladium acetate (56.1 mg, 0.25 mmol, 0.025 eq.) under nitrogen. The resulting mixture is stirred at 80° C. for 7 hr. Water (100 ml) is added to quench the reaction, and the mixture is extracted with EtOAc (30 ml×3). The combined organic layer is washed with water and brine, dried over sodium sulfate, and concentrated. The crude product is purified through silica gel flash chromatography (hexane/EtOAc 10:1) to give a mixture of the vinyl ether and the ketone product, which is dissolved in EtOAc (50 ml), and then treated with concentrated hydrochloric acid (3.0 ml). The mixture is stirred at rt for 2 hr, and then basified with saturated sodium carbonate solution. The organic phase is collected, and the aqueous phase is extracted with EtOAc twice. The combined organic phase is dried with sodium sulfate and concentrated to give the title compound. MS (+VE) m/z 176.1 (M++1).