Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:15][S:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])(=[O:18])=[O:17])=[O:4].CN1CCO[CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:46]2[N:47]=[CH:48][CH:49]=C[C:45]=2[N:44]=N1.C(N(CCCN)CC)C>CN(C)C=O.O>[CH2:30]([N:47]([CH2:48][CH3:49])[CH2:46][CH2:45][NH:44][C:21]([C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[S:16]([NH:15][C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4])(=[O:18])=[O:17])=[O:22])[CH3:31]
Reactant: CN1CCOCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2C(=O)O)ccc2ccccc12
Agent: CCN(CC)CCCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1ccccc1S(=O)(=O)Nc1ccc2ccccc2c1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of Example 149B (228 mg, 0.592 mmol) in dimethylformamide (3.0 mL) was treated with 4-methylmorpholine (230 μL, 2.07 mmol), cooled to 0° C., treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (450 mg, 1.18 mmol), stirred for 1 hour, treated with 3-(N,N-diethylamino)propylamine (166 μL, 1.18 mmol), warmed to room temperature, stirred overnight, treated with distilled water, and extracted with ethyl acetate three times. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 484 (M+H)+; (ESI(−)) m/e 482 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.36 (s, 1H), 9.21 (br s, 1H), 9.11 (t, 1H), 8.04 (d, 1H), 7.94 (dd, 1H), 7.79-7.68 (m, 4H), 7.62 (d, 1H), 7.60-7.53 (m, 3H), 3.81 (s, 3H), 3.67 (m, 2H), 3.26 (m, 6H), 1.26 (t, 6H).
Reaction SMILES: [S:1]1[CH2:5][CH:4]=[CH:3][C:2]1=[O:6].Br[CH2:8][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][CH3:23].[H-].[Na+]>C1C=CC=CC=1>[CH2:23]([O:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: O=C1C=CCS1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOc1cccs1
Reaction time: 24 h

Procedure:
A mixture of 20 g (0.2 mole) of 3-thiolen-2-one[R. T. Hawkins, J. Heterocyclic Chemistry 11, 291-4 (1974)], 61.1 g (0.2 mole) of 1-bromohexadecane, and 9.6 g (0.2 mole) of sodium hydride (50% in oil) in dry benzene is refluxed with stirring for 24 hours after which the solvent is removed and the product is distilled to give 2-hexadecyloxythiophene.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:36]I>C1(C)C=CC=CC=1.C(#N)C.O>[I:36][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1
Reactant: OCC1Cc2ccccc2N1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: ICC1Cc2ccccc2N1
Reaction time: 0.17 h

Procedure:
To a mixture of 2-hydroxymethylindoline (7.77 g, 52.08 mmol), imidazole (8.86g, 130.2 mmol), triphenylphosphine (34.15 g, 130.2 mmol)in toluene (500 mL) was added iodine (26.44 g, 104.16 mmol) in acetonitrile (100 mL) at 0° C. The mixture was stirred for 10 min and water was added. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated. The residue was triturated with diethyl ether and insoluble solids were removed by filtration. The filtrate was concentrated to give crude 2-iodomethylindoline. The crude 2-iodomethylindoline was dissolved in DMF (130 mL) and KCN (4.07 g, 62.5 mmol) was added. The mixture was heated at 80° C. for 12 h and after addition of KCN (4.07 g), the heating was further continued for 5 h. The mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 3:1 to 2:1 hexane/ethyl acetate to give 3.04 g of 2-cyanomethylindoline (37%): 1H NMR (270 MHz, CDCl3) δ7.03 (m, 2 H), 6.77 (t, 1H, J=7 Hz), 6.54 (t, 1H, J=7 Hz), 4.42 (m, 1H), 4.13 (bs, 1H), 3.07 (m, 1H), 2.81 (dt, 1H, J=16, 4 Hz), 2.22 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([C@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([OH:12])=[O:11])[CH:8]=1)([O-:3])=[O:2].[CH3:19]C1C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[CH3:19][O:11][C:10](=[O:12])[C@H:9]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCC[C@H](C(=O)O)n1cnc([N+](=O)[O-])c1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCC[C@H](C(=O)OC)n1cnc([N+](=O)[O-])c1
Yield: 2813.6 %

Procedure:
(R)-2-(4-Nitro-1H-imidazol-1-yl)-octanoic acid (16.0 g, 63.0 mmol) was dissolved in 1 L of anhydrous methanol. To this solution was added pTsOH (300 mg). The reaction was then heated to reflux for 16 hours. Upon cooling, the solvent was removed in vacuo, to give an oil that was dissolved in 300 mL of ethyl acetate. The solution was washed (2×250 mL) with saturated NaHCO3 solution. The organic was then dried (Na2SO4) and concentrated in vacuo to provide 13.2 g (78%) of (R)-methyl-2-(4-nitro-1H-imidazol-1-yl)-octanoate as an amber oil.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:22]3[C:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)[O:25][C:21]=3[CH:20]=2)=[CH:14][C:13]=1[Cl:43].[CH3:44][S:45](Cl)(=[O:47])=[O:46].O>C1COCC1.CCOC(C)=O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([C:19]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:22]3[C:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)[O:25][C:21]=3[CH:20]=2)[S:45]([CH3:44])(=[O:47])=[O:46])=[CH:14][C:13]=1[Cl:43]
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(Nc3ccc(Br)c(Cl)c3)c(C3CC3)cc12
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(Br)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 48.9 %

Procedure:
A 1M solution of LiHMDS in THF (1.049 mL, 1.049 mmol) was added dropwise to a solution of ethyl 6-((4-bromo-3-chlorophenyl)amino)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate (440 mg, 0.807 mmol) in THF (15 mL) at −78° C. After stirring for 45 min, the red solution was added dropwise via cannula to a solution of MsCl (0.252 mL, 3.23 mmol) in THF (1 mL) at −78° C. Upon complete addition the yellow solution was allowed to warm to RT and stirred overnight. Water (150 mL) and EtOAc (150 mL) were added. The organic layer was separated and washed with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified on silica gel (hex/EtOAc) to give ethyl 6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate (259 mg, 0.395 mmol, 49% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (s, 1H), 8.05 (d, 2H), 7.78 (d, 1H), 7.64-7.71 (m, 3H), 7.62 (s, 1H), 7.31 (dd, 1H), 4.35 (q, 2H), 3.46 (s, 3H), 2.10-2.22 (m, 1H), 1.34 (t, 3H), 0.69-1.13 (m, 3H), 0.42 (br. s., 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[CH2:15])[CH:5]=[CH:4][C:3]1=2.[H][H]>[Pd].C(O)C>[CH3:25][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH3:15])[CH:5]=[CH:4][C:3]1=2
Reactant: [H][H]
Reactant: C=C(c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 73.8 %

Procedure:
The olefin 48 (0.0105 g, 0.0314 mmol) was hydrogenated over 5% palladium on charcoal (1 mg) in 0.5 mL of ethanol at room temperature and atmospheric pressure. After one equivalent (0.7 mL) of hydrogen was taken up, the catalyst was removed by filtration through a small Celite pad. The solvent was removed in vacuo to give the crude acid as a white solid (0.019 g). Recrystallization from benzene-hexane afforded the desired acid 49 as a white crystalline solid (0.0078 g, 74%): m.p. 186°-188° C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].ClC1C([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)=CC=CC=1N>>[Cl:9][C:7]1[CH:6]=[C:4]([CH:3]=[C:2]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)[CH:8]=1)[NH2:5]
Reactant: CC1(C)OB(c2cccc(N)c2Cl)OC1(C)C
Reactant: Nc1cc(Cl)cc(Br)c1
Product: CC1(C)OB(c2cc(N)cc(Cl)c2)OC1(C)C
Yield: 48 %

Procedure:
This material was prepared from 3-bromo-5-chloroaniline following a similar procedure used for SM-9, step 3. The crude product was purified by flash chromatography (RediSep Cyano®, Teledyne ISCO, 0-50% EtOAc in hexanes) to afford 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (48%) as a pale orange solid: LCMS (m/z) 172.1 (MH+), tR=0.33 minute.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl-].C[Al+]C.[F:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH2:17][C:16]3[CH:22]=[C:23]([C:25]([O-])=[O:26])[S:24][C:15]=3[C:14]=2[CH:13]=1>ClCCCl>[F:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH2:17][C:16]3[CH:22]=[C:23]([C:25]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:26])[S:24][C:15]=3[C:14]=2[CH:13]=1
Reactant: O=C([O-])c1cc2c(s1)-c1cc(F)ccc1OC2
Reactant: C1COCCN1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1cc2c(s1)-c1cc(F)ccc1OC2)N1CCOCC1
Yield: 40 %

Procedure:
To a cooled solution (ice/H20) of morpholine in DCE was added slowly dropwise 2 equiv. of dimethylaluminum chloride. This reaction was stirred for greater than 30 minutes until reaching ambient temperature. Next the reaction was again cooled (ice/H20) and 8-fluoro-4H-thieno[3,2-c]chromene-2-carboxylate was added as a solid portion wise. The reaction was allowed to equilibrate to ambient temp and monitored by LC/MS. The completed reaction was quenched with an aqueous solution of Na, K-tartrate (20% wt/wt). This mixture was extracted with EtOAc and the organic was washed with saline and dried (MgSO4). The dried org. was concentrated in vacuo to a residue. This residue was not soluble in DMF and 170bp as a white solid was collected by vacuum filtration, Yield=40% of theoretical. MS: (ESI+)=320.5
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[CH:22][C:17]3[NH:18][C:19](=[S:21])[NH:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCN([C:38]2[C:47]([Cl:48])=[CH:46]C3NC(=S)N[C:40]=3[CH:39]=2)CC1)=O)(C)(C)C>>[ClH:48].[ClH:48].[CH2:39]([CH:38]([S:21][C:19]1[NH:18][C:17]2[CH:22]=[C:23]([F:24])[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:15][C:16]=2[N:20]=1)[CH2:47][CH3:46])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(=S)[nH]c3cc2Cl)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(=S)[nH]c3cc2F)CC1
Product: CCC(CC)Sc1nc2cc(N3CCNCC3)c(F)cc2[nH]1
Product: Cl

Procedure:
Reactions were conducted following Example 1 except that 5-(4-tert-butoxycarbonylpiperazin-1-yl)-6-fluoro-1,3-dihydro-2H-benzimidazol-2-thione (which was prepared by the method as described in U.S. Pat. No. 6,051,570) was used in place of the 5-(4-tert-butoxycarbonyl-piperazin-1-yl)-6-chloro-1,3-dihydro-2H-benzimidazol-2-thione as obtained in Production Example 1, to provide the title compound as a colorless powder.
Reaction SMILES: [F:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][O:12]CCO>>[F:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH2:9][O:12][CH3:11])=[O:6]
Reactant: CCOC(=O)CC(=O)CF
Reactant: COCCO
Product: COCCOC(=O)CC(=O)CF

Procedure:
Ethyl 4-fluoro-3-oxobutanoate (2.1 g) was heated at reflux in 2-methoxyethanol (10 ml) for 3 hours. The solvent was removed in vacuo and the residue distilled to give the title compound as a colourless oil (1.75 g). Nmr (CDCl3)δ4.9 (d,2H,J-48 Hz), 3.4 (s,3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([NH2:24])=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C@H:26]1[C:30](=[O:31])[NH:29][CH2:28][C@@H:27]1[C:32](O)=[O:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:21])[F:23])[CH:14]=3)=[CH:11][C:10]([NH:24][C:32]([C@@H:27]3[C@@H:26]([CH3:25])[C:30](=[O:31])[NH:29][CH2:28]3)=[O:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H]1C(=O)NC[C@@H]1C(=O)O
Reactant: Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1C(=O)NC[C@@H]1C(=O)Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Yield: 64.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine (90 mg) in N,N-dimethylformamide (0.9 ml) were added (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (50 mg) prepared in Preparation 1, HOBt.H2O (61 mg) and WSC.HCl (77 mg), and the mixture was stirred at room temperature for 2 hours. To this mixture were added water and a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (80 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1.[OH2:44]>CN(C=O)C>[Cl:43][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][C:39]=1[Cl:42])[CH2:35][O:44][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:28][C:27]([CH3:29])=[N:26][CH:25]=4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[N:16][N:17]=[C:10]12
Reactant: O
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3n2CCCC3(OCc2ccc(Cl)c(Cl)c2)c2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3,4-difluorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (100 mg) in DMF (2 mL) was added sodium hydride (60%, 14.2 mg), and the mixture was stirred at room temperature for 30 min in the air. Sodium hydride (60%, 14.2 mg) was added, and the mixture was further stirred at room temperature for 30 min in the air. 4-(Bromomethyl)-1,2-dichlorobenzene (85.2 mg) was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and further recrystallized from ethyl acetate/hexane to give the title compound (64.8 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([NH2:24])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:25]1(O)OC2OC(O)C(O)OC2O[CH:26]1O>O.C(O)C.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[N:23]=[CH:26][CH:25]=[N:24]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Reactant: OC1OC2OC(O)C(O)OC2OC1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nccnc4c3O2)cc1
Temperature: 60 °C

Procedure:
To a solution of [(2R)-7,8-diamino-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (2.226 g, 5.258 mmole) in water (50 mL) was added a solution of glyoxal trimeric dihydrate (1.104 g, 5.258 mmole) in ethyl alcohol (50 mL) and the reaction mixture was heated at 60° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and was diluted with aqueous sodium hydrogen carbonate (250 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 7:3) gave 1.135 g (58%) of the (R)-enantiomer of the title compound as a brown crystalline solid. Rf=0.27 (silica, ethyl acetate:hexanes 3:2); mp 124-127° C.
Reaction SMILES: Cl.N[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:10].N([O-])=O.[Na+].[I:22]I>CC(O)=O.O.CCOC(C)=O>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[I:22])=[O:10]
Reactant: II
Reactant: Nc1ccccc1C(=O)c1ccccc1Cl
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1Cl)c1ccccc1I
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 116.3 %

Procedure:
Add concentrated HCl (0.5 mL) to a solution of (2-amino-phenyl)-(2-chloro-phenyl)-methanone (495 mg, 2.14 mmol) in glacial AcOH (1.1 mL). Cool solution to 10° C.; add a solution of sodium nitrite (156 mg, 2.26 mmol) in water (1 mL) dropwise over 30 min. After an additional 30 min., add water (4° C., 2 mL) and EtOAc (4° C., 4 mL). Add a solution of KI (425 mg, 2.56 mmol) and I2 (319 mg, 1.25 mmol) in water (2 mL) dropwise over 25 min. Stir at 5-15° C. for 2.5 hours under N2. Extract with EtOAc (×3), wash with 1N aqueous Na2S2O3 solution (×3), saturated aqueous NaHCO3 solution (×3) and brine. Dry the combined organic layers over Na2SO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-10% EtOAc/hexanes to afford the title compound (498 mg, 68%): MS(IS) 343 (M+1); TLC (10% EtOAc/hexanes) Rf=0.39.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:6]=1.C(O[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1)(C)C.C([Li])CCC.CCCCCC>C1COCC1>[CH3:35][C:30]1([CH3:36])[C:31]([CH3:34])([CH3:33])[O:32][B:28]([C:2]2[CH:3]=[C:4]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:6]=2)[O:29]1
Reactant: CC(C)(C)OC(=O)n1cc(I)cc1C(=O)OCc1ccccc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCc1ccccc1

Procedure:
At −78° C. to a solution of 2-benzyl 1-tert-butyl 4-iodo-1H-pyrrole-1,2-dicarboxylate (10.0 g, 23.4 mmol), and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.6 mL, 47 mmol) in THF (120 mL) was added dropwise a solution of 2.5 M n-butyllithium in hexane (11.2 mL, 28.1 mmol) with stirring. After completion of addition the mixture was stirred at this temperature for 35 min and then 2.5 M n-butyllithium in hexane (1.87 mL, 4.68 mmol) was added and stirred for another 30 minutes. The reaction was quenched with sat. NH4Cl solution and then diluted with EtOAc. The organic layer was separated, washed with water twice, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The product was isolated by chromatography eluting with 0 to 10% EtOAc in hexanes. LCMS calculated for C19H23BNO6 (M−[tBu+1]+1)+: m/z=372.2. found: 372.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]2=[O:25].[H][H]>CO.[Pd]>[O:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:7]2[O:8][C:9]3[C:4]([C:5](=[O:25])[C:6]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:3][CH:2]=[CH:11][CH:10]=3)[CH2:14][CH2:15]1
Reactant: O=c1c(-c2ccccc2)c(CN2CCOCC2)oc2ccc(Br)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1c(-c2ccccc2)c(CN2CCOCC2)oc2ccccc12
Yield: 100 %

Procedure:
To a solution of Example 2 (0.1 g, 0.249 mmoles) in methanol (10 ml), palladium on carbon 20 mg) was added and the solution was hydrogenated at RT under 5 kg/cm2 pressure of hydrogen for 4 h. The solution was filtered through celite and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as brown solid (0.080 g, 87% yield). 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 8.08(d, J=7.8Hz, 1H), 7.90(t, J=7.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.55(t, J=7.4 Hz, 1H), 7.49(m, 3H), 7.31(d, J=6.5 Hz, 2H), 3.72(br s,4H), 3.42(br s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:22]2C(=O)C3=CC=CC=C3C2=O)=[N:19][N:18]=[C:17]1[CH2:33][N:34]([CH3:36])[CH3:35].O.NN>C(O)C>[F:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]3[C:17]([CH2:33][N:34]([CH3:35])[CH3:36])=[N:18][N:19]=[C:20]3[CH2:21][N:22]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: CN(C)Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(F)cc1C(=O)c1ccccc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)Cc1nnc2n1-c1ccc(F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 27, 2'-chloro-5-fluoro-2-[3[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-fluoro-1[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[F:21][C:19]1[CH:18]=[CH:17][C:15]2=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=[C:14]2[CH:20]=1
Reactant: C#CCCn1nc2ccc(F)cc2n1
Reactant: Brc1ccccn1
Product: Fc1ccc2nn(CCC#Cc3ccccn3)nc2c1
Yield: 20000 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (20 mg, 0.13 mmol) and 2-(but-3-ynyl)-5-fluoro-2H-benzo[d][1,2,3]triazole (24 mg, 0.13 mmol). Reaction time: 1 day. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM, DCM/MeOH 98:2 to DCM/MeOH/NH4OH 95:4:1) to yield 7.6 mg (26 mmol, 21%) of 5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.