Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[S:3]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])=[O:4].[CH3:12][C:13]1[Te:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[F:1][C:2]([F:11])([F:10])[S:3]([O-:6])(=[O:5])=[O:4].[CH3:12][C:13]1[Te:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N+:17]=1[CH2:9][CH:8]=[CH2:7]
Reactant: Cc1nc2ccccc2[te]1
Reactant: C=CCOS(=O)(=O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CC[n+]1c(C)[te]c2ccccc21
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 18 h

Procedure:
The dried solution of 2-propen-1-yl trifluoromethanesulfonate (0.008 mole) in carbon tetrachloride was placed in a dropping funnel and added to a solution of 2-methylbenzotellurazole (Example 18) (1.62 g, 0.0066 mole) in dichloromethane (25 ml) under a nitrogen atmosphere at room temperature. After the addition was complete, stirring was continued for 18 hours. The solid was isolated by filtration, washed with diethyl ether, and dried at room temperature under vacuum. Yield 0.43 g (15%), m.p. 90°-93° C. Infrared, nuclear magnetic resonance, and mass spectra were in agreement with that expected for the structural formula.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].Cl.Cl.Cl.[N:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]([N:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)[CH2:47][NH2:48])[CH:41]=1.C(N(CC)CC)C.CS(C)=O>C(#N)C>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:48][CH2:47][CH:46]([C:42]4[CH:41]=[N:40][CH:45]=[CH:44][CH:43]=4)[N:49]4[CH2:53][CH2:52][CH2:51][CH2:50]4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])=[CH:22][CH:23]=1
Reactant: NCC(c1cccnc1)N1CCCC1
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCC(c4cccnc4)N4CCCC4)n3Cc3ccccc32)cc1

Procedure:
The title compound was prepared according to the procedure Example 6, Step D, from 2,2,2-trichloro-1-{10-[(2′-methoxy-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone (1.21 g, 2.25 mmol), 2-(3-pyridyl)-2-pyrrolidinylethyl amine trihydrochloride (0.450 g, 1.5 mmol), triethylamine (5 equivalents), dimethylsulfoxide (0.540 mL) and acetonitrile (28 mL). The crude material was flash chromatographed over silica gel Merck-60 using a gradient of methanol (1-5%) in dichloromethane containing 0.2% ammonium hydroxide, to provide a brown foam. The material was further purified by preparative HPLC (40:60 acetonitrile:water containing 0.1% formic acid; Primesphere 10 C18, 250×50 mm column; flow 90 mL/min). The solution was brought to pH 8 with concentrated ammonium hydroxide prior to concentration to small volume in vacuo. The residue was redissolved in dichloromethane, dried over anhydrous potassium carbonate and evaporated to dryness to provide an off-white foam (0.560 g). This material was sonicated with hexane (containing a few drops of ethyl acetate). The resulting off-white powder was collected and dried (0.442 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:4][C:3]=1[C:15]1[NH:19][N:18]=[N:17][N:16]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>C(#N)C>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:4][C:3]=2[C:15]2[NH:19][N:18]=[N:17][N:16]=2)=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: CN(C)C(=O)CCc1ccc(N)c(-c2nnn[nH]2)c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CC#N
Product: CN(C)C(=O)CCc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)c(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[4-Amino-3-(1H-tetrazol-5-yl)-phenyl]-N,N-dimethyl-propionamide (90 mg) dissolved in acetonitrile at 65° C. under Ar was treated with 4-chloro-3-trifluoromethylphenylisocyanate (85.6 mg) and the mixture was stirred overnight. Cooling to room temperature and filtration afforded 3-[4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-3-(1H-tetrazol-5-yl)-phenyl]-N,N-dimethyl-propionamide. Mp.=184.5-189.3° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:31]N1C(=O)CCC1=O>O.C(Cl)(Cl)Cl>[Br:31][CH2:9][C:8]([C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(C)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)CBr)cn1
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a chloroform (6.5 mL) solution of 1-(6-methylpyridin-3-yl)ethanone (0.43 g), under ice cooling in a nitrogen atmosphere, 2,6-lutidine (0.63 mL) and trimethylsilyl trifluoromethanesulfonate (0.69 mL) were added, and the resultant was stirred for 30 minutes. Then, N-bromosuccinimide (0.63 g) was added thereto, and the resultant was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the resultant was stirred for 15 minutes, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=90/10→70/30) to obtain the title compound (0.24 g) as a light brown solid.
Reaction SMILES: CCCCCC.[H-].[Na+].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18](=[O:20])[C@@H:17]([CH3:21])[C@@H:16]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:15][C:14]=2[CH:30]=1.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34]Cl>CN(C)C=O.C1(C)C=CC=CC=1>[ClH:9].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])[C:18](=[O:20])[C@@H:17]([CH3:21])[C@@H:16]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH2:15][C:14]=2[CH:30]=1
Reactant: COc1ccc([C@H]2Cc3cc(Cl)ccc3NC(=O)[C@H]2C)cc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ccc([C@H]2Cc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@H]2C)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 161.6 %

Procedure:
To a slurry of hexane washed sodium hydride (132 mg of 50% sodium hydride in mineral oil, 2.74 mmole) in 20 ml of dimethylformamide at 25° C. was added 720 mg of (cis)-7-chloro-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3-methyl-2H-1-benzazepin-2-one (2.28 mmole). After stirring at 25° C. for 1 hour, the solution turned clear, 6.7 ml of a 1.7 M solution of 2-dimethylaminoethyl chloride (11.4 mmole, 5 equiv.) in toluene was added. The reaction mixture was stirred for 3 hours at 80° C., then cooled to 25° C. and quenched with 1N hydrochloric acid, basified with 1N sodium hydroxide, and extracted with ethyl acetate. The organic layer was dried (magnesium sulfate) and concentrated. The residue was diluted with ether and treated with a saturated solution of hydrochloric acid in ether and concentrated. The residue was triturated with ether and filtered. The solid was washed with ether and dried to give 780 mg of the title compound as a white solid, melting point 228°-231° C.
Reaction SMILES: FC(S(O[C:9]1[C:17]2[CH:16]=[CH:15][O:14][C:13]=2[C:12]([C:18]2[C:19](=[O:35])[N:20]([CH3:34])[C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:11][CH:10]=1)(=O)=O)(F)F.[C:36](=[NH:49])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)C>[C:36](=[N:49][C:9]1[C:17]2[CH:16]=[CH:15][O:14][C:13]=2[C:12]([C:18]2[C:19](=[O:35])[N:20]([CH3:34])[C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:11][CH:10]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2ccc(OS(=O)(=O)C(F)(F)F)c3ccoc23)C1=O
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2ccc(N=C(c3ccccc3)c3ccccc3)c3ccoc23)C1=O
Temperature: 25 °C

Procedure:
Heat a mixture of 7-[1-methyl-4-(1-methylindol-3-yl)-2,5-dioxo-3-pyrrolin-3-yl]benzo[b]fur-4-yl (trifluoromethyl)sulfonate (100 mg, 0.2 mmol), benzophenone imine (0.037 ml, 0.22 mmol), tris-(benzylideneacetone)-dipalladium(0)(9 mg, 0.01 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19 mg, 0.03 mmol), and cesium carbonate (91 mg, 0.28 mmol) in anhydrous toluene (1 ml) to 80° C. for 19 hours under a nitrogen atmosphere. Allow the reaction to cool to room temperature, dilute with diethyl ether, and filter through Celite. Wash the filtrate with water, brine, dry over magnesium sulfate, filter and concentrate. Flash chromatography over silica gel (ethyl acetate: hexanes) affords the title compound as a red oil. MS(ES+): 536.1.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].CN([Si](C)(C)C)C(=O)C.CC([O:23][CH2:24][C:25]1[C:38]2[C:33](=CC=CC=2)[C:32](COC(C)=O)=[C:31]2[C:26]=1C=CC=C2)=O>ClCCl>[OH:4][CH2:3][CH:2]([NH:1][C:24](=[O:23])[C:25]1[CH:38]=[CH:33][CH:32]=[CH:31][CH:26]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)N(C)[Si](C)(C)C
Solvent: ClCCl
Product: O=C(NC(CO)c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A slurry of (R)-2-amino-2-phenylethanol (1.0 g, 7.4 mmol) in 50 mL dichloromethane was allowed to stir with N-methyl-N-(trimethylsilyl)acetamide (3.4 mL, 21.1 mmol) until a homogenous solution occured. The solution was cooled to 0° C. to 5° C. and a solution of 2,2'-dithiobis[benzoyl chloride] (1.0 g, 2.9 mmol) in 20 mL dichloromethane was added. The solution was stirred for 2 hours and 1 mL of 50% aqueous acetic was added causing the crude product to precipitate from solution. This solid was collected by filtration, washed with 1N HCl, water, and recrystallized from dimethylformamide/water to afford 1.2 g of the title compound, mp 235°-236° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH2:16]O)=[CH:14][CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[N:32]([CH2:16][C:15]1[N:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[N:12]=[CH:13][CH:14]=1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(-n2nccc2CO)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-n2nccc2CN=[N+]=[N-])cc1
Reaction time: 8 h

Procedure:
To a solution of [2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-methanol (4 mmol) and diphenylphosphoryl azide (0.95 mL, 4.4 mmol, 1.1 equiv) in THF (10 mL) at rt was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL, 4.4 mmol, 1.2 equiv). The resulting solution was stirred overnight, concentrated and chromatographically purified (15% ethyl acetate in hexanes) to give 5-azidomethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole (0.344 g, 31% based on 4-(methylsulfonyl)phenylhydrazine hydrochloride, LCMS: (MH)+=278.0 (rt=1.36 min) and 3-azidomethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole (75 mg, 7% based on 4-(methylsulfonyl)phenylhydrazine hydrochloride, LCMS: (MH)+=278.0 (rt=1.48 min)).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:16])([F:15])[C:5]1[N:6]=[C:7]([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[NH:8][CH:9]=1.[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>CCCCCC>[F:16][C:4]([F:3])([F:15])[C:5]1[N:6]=[C:7]([C:10]2[N:14]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:13]=[CH:12][N:11]=2)[N:8]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: FC(F)(F)c1c[nH]c(-c2ncc[nH]2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1ccnc1-c1nc(C(F)(F)F)cn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To 14.4 g (0.3 mol) 50% NaH (washed 3 times with hexane to remove the mineral oil) and 300 ml DMF, was slowly added 26.3 g (0.13 mol) 4-(trifluoromethyl)-2,2'-bi-1H-imidazole as a solid. The reaction was stirred for 2 hours at room temperature and then heated at 40° C. for 2 hours. Next, 50 g (0.3 mol) SEM-Cl was added dropwise. After 1 hour, the reaction was quenched with water (1 liter) and the product extracted into EtOAc (3×150 ml). After drying (NaSO4) and concentration, 51.2 g crude product was obtained. Purification by preparative HPLC (37% EtOAc/63% hexane) gave 16.7 g (28%) desired product as a tan oil; 1H NMR (CDCl3) δ-0.14 (s, 18), 0.61-1.0 (m, 4), 3.25-3.70 (m, 4), 5.76 (s, 2), 5.81 (s, 2), 0.61-1.0 (m, 4), 3.25-3.70 (m, 4), 5.76 (s, 2), 5.81 (s, 2), 6.91-7.06 (m, 2), 7.36 (s br, 1); MS (CI/CH4) m/z 463 (MH+).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][O:25][C:26]4[CH:30]=[CH:29][O:28][N:27]=4)[O:21][C:20]3=[O:31])=[CH:15][C:14]=2[F:32])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[OH:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][O:25][C:26]4[CH:30]=[CH:29][O:28][N:27]=4)[O:21][C:20]3=[O:31])=[CH:15][C:14]=2[F:32])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CC(O)C2)c(F)c1

Procedure:
3-(4-(3-t-Butyldimethylsilyloxy-1-azetidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxy methyl)oxazolidin-2-one (230 mg, 0.5 mmol) was dissolved in tetrahydrofuran (10 ml), and cooled under nitrogen to 0°. A solution of tetra-n-butylammonium fluoride (1 M, 1 ml, 1 mmol) was added and the mixture allowed to come to ambient temperature. Water (2 ml) was added, and the mixture evaporated to dryness. The residue was purified by chromatography on a 10 g silica Mega Bond Elut(D column, eluting with a gradient increasing in polarity from 0 to 2.5% MeOH in dichloromethane. Relevant fractions were combined and evaporated, then redissolved in EtOAc and the desired product (96 mg) precipitated by addition of isohexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][NH:7]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36]>>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][N:7]1[CH2:27][C:28]([NH:36][CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=1[O:32][CH3:31])=[O:29]
Reactant: COc1ccc(OC)c(CC2NCCc3c(OC)ccc(OC)c32)c1
Reactant: O=C(Br)CBr
Reactant: COc1ccccc1CN
Product: COc1ccc(OC)c(CC2c3c(OC)ccc(OC)c3CCN2CC(=O)NCc2ccccc2OC)c1

Procedure:
prepared by reaction of 1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methoxy-benzyl-amine
Reaction SMILES: [Br:1][C:2]1[CH:33]=[C:32]([OH:34])[C:31]([OH:35])=[CH:30][C:3]=1[C:4]([NH:6][NH:7][S:8]([NH:11][C:12]([N:14]1[CH2:17][C@H:16]([NH:18]C(=O)OCC2C=CC=CC=2)[C:15]1=[O:29])=[O:13])(=[O:10])=[O:9])=[O:5].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].C1(SC)C=CC=CC=1>CCOCC>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH2:18][C@H:16]1[CH2:17][N:14]([C:12]([NH:11][S:8]([NH:7][NH:6][C:4](=[O:5])[C:3]2[CH:30]=[C:31]([OH:35])[C:32]([OH:34])=[CH:33][C:2]=2[Br:1])(=[O:10])=[O:9])=[O:13])[C:15]1=[O:29]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)c2cc(O)c(O)cc2Br)C1=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: CCOCC
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)c2cc(O)c(O)cc2Br)C1=O
Reaction time: 8 h

Procedure:
At room temperature, 2.29 g (4 mmol) of (S)-[1-[[[[2-(2-bromo-4,5-dihydroxybenzoyl)hydrazino]sulfonyl]amino]carbonyl]-2-oxoazetidinyl]carbamic acid, phenylmethyl ester was added to a mixture of 4.5 ml of trifluoroacetic acid and 1.6 g of thioanisole. After stirring overnight, 50 ml of ether was added and the resulting crystals were filtered off by suction, dried and triturated with 40 ml of dichloromethane. The crystals were filtered off again and dried in vacuo; yield: 1.9 g, melting point 157° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([OH:10])[CH:9]=1.CN(C)C=O.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[NH:32][C:31](=[O:38])/[C:30]/2=[CH:39]/OC>CCOCC>[OH:10][C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=1[O:11][CH3:12])[CH2:3][NH:2][CH:39]=[C:30]1[C:29]2[C:34](=[CH:35][CH:36]=[C:27]([O:26][CH3:25])[CH:28]=2)[C:33](=[O:37])[NH:32][C:31]1=[O:38]
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(OC)cc21
Reactant: COc1ccc(CN)cc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc2c(c1)C(=CNCc1ccc(OC)c(O)c1)C(=O)NC2=O
Reaction time: 0.25 h

Procedure:
A mixture of 5-aminomethyl-2-methoxy-phenol hydrochloride (145 mg, 0.50 mmole), 4 mL of N,N-dimethylformamide and triethylamine (75 □L, 0.54 mmole) is stirred for 15 minutes. Then (4E)-6-methoxy-4-methoxymethylene-4H-isoquinoline-1,3-dione (117 mg, 0.50 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is diluted with ether, filtered washed with water, washed with ether and dried to give an light beige solid, 161 mg, (91%), mp 240-2° C. dec; MS (ESI): m/z 355.2 (M−H).
Reaction SMILES: C([Li])(C)(C)C.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH3:18][Si:19]([CH3:28])([CH3:27])[C:20]1[O:24][CH:23]=[C:22]([CH:25]=[O:26])[CH:21]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CCCCC.O1CCCC1>[C:29]([O:26][CH:25]([C:22]1[CH:21]=[C:20]([Si:19]([CH3:28])([CH3:27])[CH3:18])[O:24][CH:23]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)(=[O:31])[CH3:30]
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CC(=O)OC(C)=O
Reactant: BrCCCCCc1ccccn1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(=O)OC(CCCCCc1ccccn1)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl lithium (a 1.7M solution in pentane; 2.4 ml, 4.14 mmol) was added dropwise to a solution of 2-(5-bromopentyl)pyridine (472.3 mg, 2.07 mmol) in tetrahydrofuran (7 ml) at -78° under argon. After 1 hour, a solution of 5-trimethylsilyl-3-furaldehyde (348 mg, 2.07 mmol) in tetrahydrofuran (1 ml) was added, followed by acetic anhydride (0.59 ml, 6.21 mmol) after 2 hours. The mixture was allowed to warm to room temperature and quenched with water (after 22 hours). Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 40% ethyl acetate/hexane. Fractions with Rf of about 0.25 on evaporation gave the title silyfuran as a light brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:24].[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:18])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 3-benzyloxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (300 mg, 0.966 mmol) in DMF (5 mL) was added iodomethane (74 μL, 1.20 mmol). The solution was cooled to 0° C., treated with NaH (36 mg, 1.49 mmol, 95% dispersion in oil), and stirred for 10 minutes. The reaction was removed from the ice bath and allowed to gradually warm to room temperature. The mixture was partitioned between EtOAc and brine, and the organic extract was dried over Na2SO4 and concentrated in vacuo. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product. 1H NMR (400 MHz, CDCl3) δ 7.54-7.53 (m, 2H), 7.37-7.28 (m, 3H), 5.36 (s, 2H), 4.38-4.41 (t, 2H), 3.92 (s, 3H), 3.76-3.72 (t, 2H), 3.16 (s, 3H); ES MS (M+1)=316.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:11][CH:10]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]2)=[CH:4][CH:3]=1.[C:21]([N:28]1[CH:32]=[CH:31]N=[CH:29]1)(N1C=CN=C1)=[O:22].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]2CCNC[CH2:41]2)=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[CH2:41][CH2:29][N:28]([C:21]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:9][CH:10]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:11]4)=[CH:4][CH:3]=3)=[O:22])[CH2:32][CH2:31]2)=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ccc(N)cc2)C1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CC(C)(C)OC(=O)NCC1CN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2)C1

Procedure:
tert-Butyl [1-(4-aminophenyl)azetidin-3-yl]methylcarbamate was reacted with carbonyldiimidazole and 4-(4-chlorophenyl)piperidine by method A. This resulted in the product with the molecular weight of 499.06 (C27H35ClN4O3; MS (ESI): 499 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[N:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][N:34]=2)[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[N:34]=[CH:35][C:36]([C:18]3[N:13]4[C:14]([S:15][C:11]([C:5]5[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:12]4)=[N:16][CH:17]=3)=[CH:37][N:38]=2)[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COc1ccc(-c2nn3c(I)cnc3s2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3c(-c4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc3s2)cc1OC
Temperature: 110 °C
Yield: 102.5 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.3 g, 0.775 mmol, 1 eq), PdCl2(Ph3P)2 (0.11 g, 0.155 mmol, 0.2 eq), 2-(4-boc-piperazin-1-yl)pyrimidine-5-boronic acid pinacol ester (0.454 g, 1.16 mmol, 1.5 eq) and Na2CO3 (2M aqueous solution, 1.5 mL) in dioxane (4.5 mL) was heated at 110° C. for 2.5 h. The reaction was cooled down to it and solvents were removed under reduced pressure. The residue was treated with water, sonicated and filtered. The solid was washed with water, Et2O and dried to give the desired product (416 mg, 100%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=6.48 min, [M+H]+ m/z 524.2; 1H NMR (300 MHz, DMSO) δ 8.99 (s, 2H), 7.70 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.80 (m, 4H), 3.43 (m, 4H), 1.43 (s, 9H).