Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Ni+2:5].C([O-])(=O)C.CCOCCO.[CH3:16][NH:17][C:18]1[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:20]([OH:22])=[O:21]>O>[Ni:5].[CH3:16][NH:17][C:18]1[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:20]([OH:22])=[O:21]
Reactant: [Ni+2]
Agent: CC(=O)[O-]
Agent: CNc1ccccc1C(=O)O
Solvent: CCOCCO
Solvent: O
Product: [Ni]
Temperature: 50 °C
Reaction time: 1 h

Procedure:
23.8 g (0.1 mol) of nickel acetate was added to 500 ml of ethyl cellosolve and stirred. The mixture was heated to 50° C., and 30.2 g (0.2 mol) of N-methyl-anthranilic acid was gradually added. The mixture was subjected to reaction for 2 hours at about 130° C. under refluxing and then dispersed in 2 liters of water. After 1 hour, the dispersion was subjected to filtration and the precipitate was washed with water until neutrality. The precipitate was then dried at 90° C. to obtain about 29 g of pale blue powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.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>[CH2:20]([N:13]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:4]1[C:5]([CH3:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[C:2]([C:32]2[CH:31]=[CH:30][C:29]([CH2:28][N:25]3[CH2:26][CH2:27][O:22][CH2:23][CH2:24]3)=[CH:34][CH:33]=2)[CH:3]=1)[CH3:21]
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
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: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 58.8 %

Procedure:
To a stirred solution of methyl 5-bromo-3-(ethyl-(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (1 g, 2.82 mmol) and 4-((morpholino)methyl)phenylboronic acid pinacol ester (1.03 g, 3.38 mmol) in dioxane/water mixture (10 mL+2 mL), Na2CO3 (1.08 g, 10.14 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.325 g, 0.28 mmol) was added and argon was purged again for 10 min. Reaction mass was heated at 100° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.75 g, 59%).
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[C:13]([SH:20])=[N:14][C:15]([Br:19])=[C:16]([Br:18])[N:17]=1>>[Br:18][C:16]1[N:17]=[C:12]2[N:11]=[CH:1][S:20][C:13]2=[N:14][C:15]=1[Br:19]
Reactant: Nc1nc(Br)c(Br)nc1S
Reactant: CCOC(OCC)OCC
Product: Brc1nc2ncsc2nc1Br
Yield: 73 %

Procedure:
Fifty ml. of triethylorthoformate and 8.6 g. of 3-amino-5,6-dibromopyrazinethiol were mixed and heated to boiling under reflux for 22 hours. The reaction mixture was then concentrated under reduced pressure and diluted with petroleum-ether. The resulting precipitate of yellowish brown crystalline material weighed 6.7 g. (73% yield), m.p. 142°-4° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([F:9])[C:6]=1[CH2:7][OH:8].C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[N:3]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:5]([F:9])[C:6]=1[CH:7]=[O:8]
Reactant: O=S(=O)(c1ccccc1)n1c(Cl)c(CO)c(F)c1-c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1c(F)c(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
To a solution (15 mL) of [2-chloro-4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (210 mg) in acetonitrile were added tetra-n-propylammonium perruthenate (31 mg), N-methylmorpholine N-oxide (156 mg) and molecular sieves 4A powder (500 mg), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=90:10→85:15) to give the title compound as a colorless oil (yield 140 mg, 67%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH:9]([OH:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>ClC(Cl)C.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][O:11][CH:9]([CH3:10])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:12])[CH3:20]
Reactant: CC(O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)COC(C)CNC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 50.9 %

Procedure:
500 mg (2.85 mmol) of (2-hydroxy-propyl)-carbamic acid t-butyl ester was dissolved in 10 mL of dichloroethane, then 0.44 mL (4.24 mmol) of ethyl diazoacetate was added thereto. 38 mg (0.085 mmol) of rhodium acetate was added to the reaction and then heated to 80° C. for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 381 mg (1.45 mmol) of the title compound in a yield of 50%.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]([CH2:12][OH:13])[C:9]([CH3:14])=[C:8]2[C:4]=1[C:5]1[CH2:18][CH2:17][O:16][C:15]([CH2:22][C:23]([OH:25])=[O:24])([CH2:19][CH2:20][CH3:21])[C:6]=1[NH:7]2)#[N:2].Cl[CH:27](Cl)[CH3:28].C1C=CC=CC=1>CCOC(C)=O.O=[Mn]=O>[CH2:27]([O:24][C:23](=[O:25])[CH2:22][C:15]1([CH2:19][CH2:20][CH3:21])[C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH2:18][CH2:17][O:16]1)=[C:3]([C:1]#[N:2])[CH:11]=[C:10]([CH:12]=[O:13])[C:9]=3[CH3:14])[CH3:28]
Reactant: CC(Cl)Cl
Reactant: CCCC1(CC(=O)O)OCCc2c1[nH]c1c(C)c(CO)cc(C#N)c21
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)c(C=O)cc(C#N)c21
Temperature: 40 °C
Reaction time: 1.3 h
Yield: 96 %

Procedure:
To a solution of (5-cyano-7-hydroxymethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (8.28 g, 22 mmol) in dichloroethane/benzene (85 mL/85 mL) was added a homogeneous mixture of activated MnO2 (19.4 g, 223 mmol) and Celite (19.4 g). The solution was heated to 40° C. and agitated vigorously for 1.3 hours. The reaction was cooled, diluted with EtOAc and filtered through Celite. Concentration of the filtrate in vacuo afforded 7.88 g (96%) of a pale yellow foam. 1H NMR (CDCl3) δ 10.31 (bs, 1 H), 10.27 (s, 1H), 7.90 (s, 1H), 4.27 (m, 2H), 4.11 (m, 1H), 3.95 (m, 1H), 3.09 (m, 2H), 3.04 (d, J=17.0 Hz, 1H), 2.95 (d, J=7.6 Hz, 1H), 2.57 (s, 3H), 2.00 (m, 2H), 1.30 (m, 4H), 0.90 (t, J=7.62 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14].Cl>CC(O)C>[CH2:11]([NH:15][C:2]1[N:3]=[CH:4][C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN
Reactant: Clc1ncc2[nH]ccc2n1
Agent: Cl
Solvent: CC(C)O
Product: CCCCNc1ncc2[nH]ccc2n1
Temperature: 170 °C
Yield: 95.9 %

Procedure:
A suspension of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.62 g, 4 mmol) in 5 mL iPrOH was added nBuNH2 (2.5 mL, 25.3 mmol) and followed by HCl (2.0 mL, 4.0 M in dioxanes, 8 mmol). The resulting solution was heated at 170° C. for 1 h under microwave irradiation. The reaction was monitored by LC-MS. The reaction time should be extended whenever it is necessary. After evaporation of solvents, the crude product was washed with minimal amount of MeOH. The solid was collected. And the MeOH filtrate was purified by ISCO to provide the desired product (0.73 g, 96%). 1H NMR (400 MHz, CD3OD) δ 8.42 (d, J=0.8 Hz, 1H), 7.53 (d, J=3.1 Hz, 1H), 6.27 (dd, J=3.0, 0.8 Hz, 1H), 3.37 (t, J=7.1 Hz, 2H), 1.68-1.57 (m, 2H), 1.52-1.36 (m, 2H), 0.97 (t, J=7.4 Hz, 3H); MS m/z 191.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:17])[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN1CCOCC1>C1(C)C=CC=CC=1>[NH2:17][C:10]1[C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])=[CH:7][CH:6]=2)[N:9]=1
Reactant: Nc1ccc(-c2cn3ccnc3c(N)n2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Product: Nc1nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)cn2ccnc12

Procedure:
(FIG. 1) Procedure: A mixture of 1.00 eq. of 6-(4-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamine, 1.50 eq. of phenylisocyanate, and 2.00 eq. of N-methylmorpholine, in toluene is mixed at room temperature for 2 hr. The mixture is partitioned between 1 N NaOH and ethyl acetate and extracted three times. The organic extracts are combined and dried over MgSO4. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (50% ethyl acetate/hexanes) to yield 8.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:18][OH:19])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]1([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I:35]N1C(=O)CCC1=O.C(OCC)(=O)C>C(#N)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:18][O:19][C:27]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:28][I:35])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N[C@H](CO)COCc1ccccc1
Reactant: C=C(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)COC(CI)(c1ccccc1)c1ccccc1

Procedure:
Dissolve ((R)-2-benzyloxy-1-hydroxymethylethyl)-carbamic acid tert-butyl ester (1.0 g, 3.55 mmol) and 1,1-diphenylethylene (0.534 g, 2.96 mmol) in acetonitrile (20 mL). Add N-iodosuccinimide (0.800 g, 3.55 mmol) and stir at room temperature 72 hours. Pour into ethyl acetate and wash with saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate. Purify on silica gel, eluting with 0:100 to 30:70 ethyl acetate:hexanes to give the desired compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]12[CH2:15][CH:14]1[CH2:13][NH:12][CH2:11]2.C=O.[C:18](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[Cl:34]CCCl>>[ClH:34].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]12[CH2:15][CH:14]1[CH2:13][N:12]([CH3:18])[CH2:11]2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1ccc2sc(C34CNCC3C4)cc2c1
Reactant: ClCCCl
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CN1CC2CC2(c2cc3ccccc3s2)C1
Product: Cl

Procedure:
A stirred solution of 1-(benzothiophen-2-yl)-3-azabicyclo[3.1.0]hexane (72 mg, 0.348 mmol) in 1,2-dichloroethane (7 ml) was treated with 37% formaldehyde (0.21 mL, 2.8 mmol), then with sodium triacetoxyborohydride (294.5 mg, 1.39 mmol) and this reaction mixture was stirred at room temperature for 3 h. 1N sodium hydroxide (7 mL) was then added, stirring continued for a few minutes, and the organic layer was separated. The aqueous layer was washed with methylene chloride, and the organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was chromatographed on a silica gel column (eluted with 90:9:1 methylene chloride/ethanol/ammonia). The oily 1-(benzothiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane (71.6 mg, 90%) was converted to the hydrochloride salt by treating with 2N HCl/ether (49 mg, 53%). MS (M+1) 229.79. 1H NMR (MeOD-d4) δ 7.84-7.66 (m, 2H), 7.39-7.23 (m, 3H), 4.11-4.02 (m, 1H), 3.85-3.71 (m, 2H), 3.68-3.60 (m, 1H), 3.07-2.97 (s, 3H), 2.31-2.21 (m, 1H), 1.56-1.44 (m, 2H). 13C NMR (METHANOL-d4) δ 142.20, 140.06, 138.95, 124.56, 124.41, 123.18, 121.96, 121.92, 59.69, 57.19, 40.00, 27.81, 25.6, 16.21.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:11][S@:12]([C:14]2[NH:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[O:13])=[N:4][CH:5]=[CH:6][C:7]=1[N+]([O-])=[O:9].[OH-:23].[K+].O.C1(C)C=CC=CC=1.[F:33][C:34]([F:38])([F:37])[CH2:35][OH:36]>>[CH3:1][C:2]1[C:3]([CH2:11][S@:12]([C:14]2[NH:15][C:16]3[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:18]=2)=[O:13])=[N:4][CH:5]=[CH:6][C:7]=1[O:36][CH2:35][C:34]([F:38])([F:37])[F:33].[CH3:1][C:2]1[C:3]([CH2:11][S@:12]([C:14]2[NH:15][C:16]3[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:18]=2)=[O:13])=[N:4][CH:5]=[CH:6][C:7]=1[O:36][CH2:35][C:34]([F:38])([F:37])[F:33].[OH2:9].[OH2:23].[OH2:9]
Reactant: OCC(F)(F)F
Reactant: Cc1c([N+](=O)[O-])ccnc1C[S@@](=O)c1nc2ccccc2[nH]1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(OCC(F)(F)F)ccnc1C[S@@](=O)c1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of compound (II) (1.42 Kg) in 2,2,2-trifluoroethanol (6.40 L) is treated with potassium hydroxide (1.31 Kg). The reaction mixture is left to react at 90° C. for 1.5 hours and then cooled to 25° C. Water and toluene are added to the reaction mixture and the two newly formed phases are separated. Pure crystalline Dexlansoprazole sesquihydrate (1.56 Kg, 90% yield) can be isolated from the organic phase following the procedure reported in Example 2.
Reaction SMILES: [Na].[CH3:2][N:3]1[C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:6]([CH3:14])[C:4]1=[O:5].Cl[CH2:16][CH2:17][CH2:18][CH2:19][P:20](=[O:23])([CH3:22])[CH3:21]>>[CH3:2][N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH2:16][CH2:17][CH2:18][CH2:19][P:20](=[O:23])([CH3:22])[CH3:21])[CH:9]=[N:8][C:7]=2[N:6]([CH3:14])[C:4]1=[O:5]
Reactant: CP(C)(=O)CCCCCl
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: [Na]
Product: Cn1c(=O)c2c(ncn2CCCCP(C)(C)=O)n(C)c1=O

Procedure:
The title substance was prepared from 10.1 g (0.05 mol) of 1,3-dimethyl-xanthine sodium salt and 4-chlorobutyldimethylphosphine oxide analogously to Example 63.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][N:3]=1.[Br:11]C1(Br)C(=O)NC(=O)NC1=O>C1COCC1.C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][Br:11])=[CH:4][N:3]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cl
Product: O=C(CBr)c1ccc(Cl)nc1
Reaction time: 2 h
Yield: 126 %

Procedure:
A solution of 784 mg of 2-chloro-5-acetylpyridine in 10 mL of THF was added via canula to a solution of 1.44 g of dibromobarbituric acid (DBBA) in 10 mL of THF. The resultant solution was heated at 50°-55° C. for 12 h, and then an additional 0.72 g DBBA was added. After stirring at 50°-55° C. for 2.5 more hours, 0.36 g DBBA was added. The mixture was allowed to stir for 2 h at which point NMR analysis of an aliquot indicated 87% conversion. The reaction mixture was cooled, diluted with ethyl acetate, washed with two portions of saturated aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate and concentrated. Purification by flash chromatography (silica gel, 15% ethyl acetate/hexane) provided 0.86 g (73%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ8.96 (d, 1H, J=2.6 Hz), 8.21 (dd, 1H, J=2.5, 8.3 Hz), 7.46 (d, 1H, J=8.4 Hz), 4.37 (s, 2H). The NMR also indicated the presence of the corresponding 2-bromo derivative. The ~4:1 mixture was carried on through the synthesis.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33]OC3C=CC(C4C(C#N)=CSC=4)=CC=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[OH:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[C:56]([C:61]#[N:62])=[N:57][CH:58]=[CH:59][CH:60]=2)=[CH:51][CH:50]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:48][C:49]3[CH:54]=[CH:53][C:52]([C:55]4[C:56]([C:61]#[N:62])=[N:57][CH:58]=[CH:59][CH:60]=4)=[CH:51][CH:50]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: N#Cc1ncccc1-c1ccc(O)cc1
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Product: N#Cc1ncccc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1

Procedure:
The title compound 58 was prepared in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 58A in step 2 of Example 51: 1H NMR (DMSO-d6): δ 8.84 (dd, J=4.6, 1.53 Hz, 1H), 7.98 (dd, J=7.98, 1.53 Hz, 1H), 7.95 (d, J=7.67 Hz, 1H), 7.27-7.7 (m, 9H), 7.01-7.03 (m, 2H), 4.77 (s, 2H), 4.01 (t, J=6.29 Hz, 2H), 3.66 (t, J=5.98 Hz, 2H), 3.12-3.16 (m, 2H), 2.97 (t, J=5.98 Hz, 2H), 1.95-2.02 (m, 2H). ESI (+)/MS: 673 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:43])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33])=[C:28]([NH:39][CH:40]([CH3:42])[CH3:41])[CH:27]=3)=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.O.[Pd].C(Cl)(Cl)Cl>[OH:43][C@H:8]([C:5]1[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=1)[CH2:9][N:10]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])=[O:33])=[C:28]([NH:39][CH:40]([CH3:42])[CH3:41])[CH:27]=2)=[CH:24][CH:25]=1)[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)Nc1cc(-c2ccc(CCN(C[C@H](O)c3ccc(Cl)nc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(C)(=O)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)Nc1cc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(C)(=O)=O
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To a solution of tert-butyl [(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl][2-[3′-(isopropylamino)-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]-carbamate (132 mg) in methanol (3.0 ml) and water (0.30 ml) were added ammonium formate (66 mg) and palladium on carbon (66 mg) at room temperature. The mixture was stirred under reflux for 1 hour. The suspension was cooled to room temperature, diluted with chloroform and filtrated. The filtrate was concentrated in vacuo and the residue was dissolved with chloroform, methanol and water. The organic layer was separated, and the aqueous layer was extracted with chloroform and methanol twice. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give tert-butyl [(2R)-2-hydroxy-2-(3-pyridyl)ethyl][2-[3′-(isopropylamino)-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]-carbamate (123 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:43][C:44]1[CH:48]=[C:47]([CH3:49])[O:46][N:45]=1.Cl[C:51]([O:53][CH:54]([CH3:56])[CH3:55])=[O:52]>>[CH:54]([O:53][C:51](=[O:52])[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:35][C:36](=[O:41])[NH:37][S:38]5(=[O:40])=[O:39])=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:43][C:44]1[CH:48]=[C:47]([CH3:49])[O:46][N:45]=1)([CH3:56])[CH3:55]
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1
Reactant: Cc1cc(CBr)no1
Product: Cc1cc(CN(C(=O)OC(C)C)c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)no1

Procedure:
5-{4-[2-(4′-Amino-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (61 mg, 0.1 mmol) was treated subsequently according to general procedure K using 3-(bromomethyl)-5-methylisoxazole (27 mg, 0.15 mmol) and general procedure U using isopropyl chloroformate (1M solution in toluene) (0.2 mL, 0.2 mmol) to give (4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-(5-methyl-isoxazol-3-ylmethyl)-carbamic acid isopropyl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C=O>[F:22][C:20]1[CH:19]=[CH:18][C:17]2[N:11]3[CH:10]=[N:9][C:8]([C:5]4[N:4]=[C:3]([CH2:2][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[O:7][N:6]=4)=[C:12]3[CH2:13][N:14]([CH3:24])[C:15](=[O:23])[C:16]=2[CH:21]=1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CN4CCCC4)n3)ncn2-c2ccc(F)cc2C1=O
Temperature: 25 °C
Reaction time: 65 h
Yield: 82.1 %

Procedure:
A suspension of 1.50 g (0.0043 mol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl) -8-fluoro-5-methyl-5,6-dihydro-4H-imidazo [1,5-a][1,4]benzodiazepin-6-one in 15 ml of dimethylformamide was treated with 1.5 g (0.022 mol) of pyrrolidine. After stirring at room temperature for 65 hrs. the yellow-orange solution obtained was freed completely from solvent. The residue was chromatographed over silica gel with dichloromethane/methanol 19:1 as the eluent. The product was recrystallized from methanol/ether. There were obtained 1.35 g (82%) of 8-fluoro-5-methyl-3-(5-pyrrolidin-1-ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 158°-160°.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11]C)=O)[CH:5]=1.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Li]>>[C:20]([O:19][C:16](=[O:18])[CH2:17][C:9](=[O:11])[C:8]1[CH:13]=[CH:14][CH:15]=[C:6]([N:4]2[CH:5]=[N:1][N:2]=[CH:3]2)[CH:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1cccc(-n2cnnc2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cnnc2)c1

Procedure:
Prepared from methyl 3-[1,2,4]triazol-4-yl-benzoate [prepared by reaction of 3-aminobenzoic acid with hydrazine hydrate and triethyl orthoformate in acetic acid at 120° C., followed by esterification with conc. H2SO4 in refluxing MeOH] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a light yellow gum (870 mg).
Reaction SMILES: OS(O)(=O)=O.[CH2:6]1[CH:11]2[CH2:12][C:13]3(O)[CH2:15][CH:9]([CH2:10]2)[CH2:8][CH:7]1[CH2:14]3.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[C:22]([C:13]23[CH2:14][CH:7]4[CH2:8][CH:9]([CH2:10][CH:11]([CH2:6]4)[CH2:12]2)[CH2:15]3)[CH:23]=1
Reactant: COc1ccc(Br)cc1
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.2 %

Procedure:
Reagent grade concentrated H2SO4 (11 mL) was added dropwise to a solution of 1-adamantol (30.25 g, 200 mmol) and 4-bromoanisole (37.21 g, 200 mmol) in 130 mL of CH2Cl2. The light pink solution was stirred at ambient temperature for 20 hours. The solvent was decanted, water (100 mL) and hexane (100 mL) were added and the solid was filtered and washed with hexane and dried to give 31 g of the product as a white powder. The supernatant was diluted with hexane, washed with water and brine, dried over MgSO4 and filtered thru a silica gel pad. The solvent was removed and the solid was recrystallized from hexane to yield 17 g of the product as a white powder.