Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[C:11]2[C:10]([C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=2)=[CH:9]1)=O)(C)(C)C.C(Cl)Cl.B(Br)(Br)Br>CO>[OH:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[C:15]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)[NH:8][CH:9]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(-c4cccs4)cc23)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1c[nH]c2ncc(-c3cccs3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Methoxy-benzoyl)-5-thiophen-2-yl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (118, 100.0 mg, 0.23 mmol) and methylene chloride (15.0 mL) were combined under an atmosphere of nitrogen. Boron tribromide (1.0 M in methylene chloride, 3.0 mL) was added. The reaction was stirred at room temperature overnight. Methanol (2.0 mL) was added into the the reaction mixture. The reaction was concentrated to remove solvents. The residue was extracted with water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with silica gel chromatography. The product was washed with methanol to provide compound (P-0024, 25.0 mg, 34%). MS(ESI) [M+H+]+=321.
Reaction SMILES: I.CS[N:4]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[CH2:7][N:6]=[CH:5]1.[C:15]1([CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(C)C.[ClH:34]>CO>[ClH:34].[C:24]1([CH:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][NH:23][C:5]2[NH:4][CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][N:6]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CSN1C=NCc2ccccc2C1
Agent: Cl
Agent: I
Solvent: CO
Solvent: CC(C)O
Product: c1ccc(C(CNC2=NCc3ccccc3CN2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flask containing 2-methylthio-2,5-dihydro-1H-2,4-benzodiazepine hydroiodide (3.20 g 1.00×10-2 mole) and 2,2-diphenylethylamine (5.91 g, 3.00×10-2 mole) was immersed in an oil bath which had been preheated to ca. 155° C. The reaction was stirred at between 150°-160° C. for ca. 30 minutes. The resulting solid mass was treated with isopropanol and that which did not dissolve was collected by filtration. This guanidine hydroiodide was dissolved in a two phase mixture of 5 molar aqueous NaOH (80 ml) and CH2Cl2 (80 ml). After stirring overnight the CH2Cl2 layer was separated. The aqueous alkaline phase was extracted with CH2Cl2 (2×). The CH2Cl2 layers were combined, washed with H2O (2×), washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving a foam which was dissolved in methanol (35 ml). The solution was cooled to 0° C. before being treated with a methanolic solution of HCl. The solution was concentrated to ca. 10-15 ml at which point crystallization began. After standing ca. 30 minutes, isopropanol was added and the flask was refrigerated. After 1-1.5 hour the product was collected by filtration. Recrystallization from methanol/isopropanol afforded 3-(2,2-diphenylethylamino)-2,5-dihydro-1H-2,4-benzodiazepine hydrochloride as colorless crystals: 2.53 g (67%), m.p. 243°-245° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]3[C:15]([CH:16]=[CH:17][C:7]=2[C:6]=1[OH:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]3[C:15]([CH:16]=[CH:17][C:7]=2[C:6]=1[O:18][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4]
Reactant: COC(=O)c1sc2c(ccc3ccccc32)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1ccc1ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an oven-dried 50 mL round bottom flask under a nitrogen atmosphere was added 3-hydroxy-naphtho[1,2-b]thiophene-2-carboxylic acid methyl ester (0.134 g, 052 mmol), ethyl bromoacetate (0.06 mL, 052 mmol), potassium carbonate (0.072 g, 052 mmol) and 20 mL DMF. The resulting mixture was allowed to stir for 16 hours at room temperature. 30 mL water was added to the mixture, at which point a precipitate formed. The solids were collected by filtration and dried in vacuo. 3-ethoxycarbonylmethoxy-naphtho[1,2-b]thiophene-2-carboxylic acid methyl ester was isolated as a white solid (0.116 g, 65%).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.B(O)(O)[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].C1COCC1>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.B(O)(O)C1C=CC(C)=CC=1.O>[C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([C:2]2[C:3]3[C:8]([CH:9]=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:18][CH:19]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Brc1c2ccccc2cc2ccccc12
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: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2c3ccccc3cc3ccccc23)cc1
Temperature: 85 °C
Yield: 107.5 %

Procedure:
5 g (1 eq, 15.6 mmol) of 9-bromo anthracene, 3.61 g of p-tolylboronic acid (1.7 eq, 26.5 mmol), 2.15 g (1.3 eq, 20.3 mmol) of Na2CO3, and 0.54 g (0.03 eq, 0.47 mmol) of tetrakis(triphenylphosphine)palladium were put into a 500-ml round-bottomed flask in Ar gas condition. 5 ml of THF and 2.2 ml of water, based on 1 mmol of p-tolylboronic acid, were added into the flask and refluxed at 85° C. for 16 hours. After the color of the solution changed to dark brown, water was added to the solution, and the organic phase was extracted using ethyl acetate. The extracted organic phase was dried using anhydrous magnesium sulfate and filtered to remove the solvent. The dried organic phase was dissolved in a small amount of toluene and separated using column chromatography (silica and hexane). A resulting solid was recrystallized using toluene and methanol to obtain 4.5 g (86%) of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:7]=[CH:8][CH:9]=1)([O-])=O.CO.O.[SH-].[Na+]>O>[N:18]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[O:11][C:10]=1[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3cccnc3o2)c1
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CO
Product: Nc1cccc(-c2nc3cccnc3o2)c1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
2-(3-Nitrophenyl)oxazolo[5,4-b]pyridine (600 mg, 2.49 mmol) was mixed with 25 mL of MeOH and 4 mL of water along with 837 mg of sodium hydrosulfide hydrate (14.9 mmol). The reaction mixture was stirred under reflux for 3 hours. It was then cooled to room temperature and concentrated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated to afford 520 mg of 3-(oxazolo[5,4-b]pyridin-2-yl)benzenamine (quantitative crude yield) (MS, M++H=212).
Reaction SMILES: C(N1CC[O:6][CH2:5][CH2:4]1)C.C(OC(=O)C)(=O)C.[CH2:16]([O:23][C:24](=[O:68])[C@H:25]([CH2:64][CH:65]([CH3:67])[CH3:66])[NH:26][C:27](=[O:63])[C@H:28]([C:59]([CH3:62])([CH3:61])[CH3:60])[NH:29][C:30](=[O:58])[C@H:31]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH3:57])[NH:32][C:33](=[O:49])[C@@H:34]([CH:46]([CH3:48])[CH3:47])[NH:35][C:36](=[O:45])[C@H:37]([CH2:39][O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH2:38])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH2:16]([O:23][C:24](=[O:68])[C@H:25]([CH2:64][CH:65]([CH3:67])[CH3:66])[NH:26][C:27](=[O:63])[C@H:28]([C:59]([CH3:62])([CH3:61])[CH3:60])[NH:29][C:30](=[O:58])[C@H:31]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH3:57])[NH:32][C:33](=[O:49])[C@@H:34]([CH:46]([CH3:47])[CH3:48])[NH:35][C:36](=[O:45])[C@H:37]([CH2:39][O:40][C:41]([CH3:42])([CH3:44])[CH3:43])[NH:38][C:5](=[O:6])[CH3:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](NC(=O)[C@@H](N)COC(C)(C)C)C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Reactant: CCN1CCOCC1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](C(=O)N[C@@H](Cc1ccccc1C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 ml of N-ethylmorpholine and 0.37 ml of acetic anhydride were added in sequence to a solution of 1.95 g of N-[N-[N-[N-(O-tert-butyl-L-seryl)-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 70 ml of anhydrous dichloromethane. The mixture was stirred at room temperature for 1 hour and was then washed in sequence with 5% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous magnesium sulphate and evaporated. Chromatography of the residue on silica using 5% methanol in dichloromethane for the elution gave afforded 1.45 g of N-[N-[N-[N-(N-acetyl-O-tert-butyl-L-seryl)-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester; MS: m/e 780.6 [M+H]+.
Reaction SMILES: C([Li])CCC.C([Sn]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(CCCC)CCCC)CCC.[CH3:34][Si:35]([CH3:44])([CH3:43])[C:36]1[O:40][CH:39]=[C:38]([CH:41]=[O:42])[CH:37]=1>CCCCCC.O1CCCC1>[OH:42][CH:41]([C:38]1[CH:37]=[C:36]([Si:35]([CH3:44])([CH3:43])[CH3:34])[O:40][CH:39]=1)[CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CCCC[Sn](CCCC)(CCCC)COCCCc1ccc2ccccc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C(O)COCCCc2ccc3ccccc3c2)co1
Reaction time: 0.08 h

Procedure:
n-Butyl lithium (a 1.6M solution in hexane; 0.56 ml, 0.94 mmol) was added dropwise to a solution of (2-naphthyl)propyl tributylstannylmethyl ether (437 mg, 0.89 mmol), prepared as in Example 3, in tetrahydrofuran (5 ml) at -78° under argon. After 5 minutes, a solution of 5-trimethylsilyl-3-furaldehyde (150 mg, 0.89 mmol) in tetrahydrofuran (1 ml) was added. Stirring was continued at -78° for 2 hours and at room temperature for 1 hour. The mixture was quenched with water and extracted with ethyl ether. Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 30% ethyl ether/hexane. The title alcohol was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[OH:14][C@@H:15]1[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(O)(C)C>[OH:14][C@@H:15]1[C@@H:20]([CH3:21])[CH2:19][N:18]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH2:11][CH2:12][CH2:13][C:3]=23)[CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture containing 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (410 mg, 2.1 mmol), tert-butyl [(3R,4R,5S)-4-hydroxy-5-methylpiperidin-3-yl]carbamate (240 mg, 1.0 mmol) and triethylamine (0.5 mL, 4 mmol) in isopropyl alcohol (3.0 mL) was stirred at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a CombiFlash® apparatus (eluting with 0 to 80% EtOAc in hexanes) to give the sub-title compound as pale yellow powder (200 mg, 50%). LCMS calc. for C19H29N4O5 (M+H)+: m/z=393.2. Found: 393.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:13]([C:24](O)=[O:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:41]=[CH:40][C:31]([O:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:27][C:28]1[CH:41]=[CH:40][C:31]([O:32][C:33]2[CH:39]=[CH:38][C:36]([NH:37][C:24]([C@@H:13]3[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:16][CH2:15][N:14]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:25])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)O
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.4 %

Procedure:
Step (a) A flask was charged with (S)-4-(benzyloxycarbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1 g, 2.74 mmol), obtained commercially, 4-(4-fluorophenoxy)aniline (558 mg, 2.75 mmol), DIEA (3 mL, 17.3 mmol), HATU (1.15 g, 3.03 mmol) and DMF (8 mL). The reaction mixture was stirred at ambient temperature for 20 minutes and then quenched with saturated sodium bicarbonate (aq., 10 mL). The mixture was extracted with ethyl acetate (20 mL) and the extract was washed with deionized water (10 mL) and then brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give (S)-4-benzyl 1-tert-butyl 2-(4-(4-fluorophenoxy)phenylcarbamoyl)piperazine-1,4-dicarboxylate (1.46 g, 2.75 mmol), which was carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[Br:10]Br>C(O)(=O)C>[Br:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccccc1N
Solvent: CC(=O)O
Product: COc1c(N)cccc1Br
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
To a cooled solution of 2-anisidine (2.7 mL, 23.7 mmol) in cetic acid (20 mL) at 10° C. was slowly added a solution of bromine (1.22 mL, 23.7 mmol) in acetic acid (10 mL) over a 10 min period. After stirring for 10 min, the solvents were removed by rotoevaporation and the residue dissolved in ethyl acetate. This solution was successively washed with saturated sodium bicarbonate solution and dried over anhydrous magnesium sulfate. After filtering, the solvents were removed by rotoevaporation and the product purified by flash column chromatography on silica gel eluted with 45% methylene chloride in hexanes to yield 3.44 g (72% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH2:6][NH:5]2.[N+:14]([O-])([OH:16])=[O:15]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2
Reactant: O=C1CNc2cc(Br)c(Cl)cc2N1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: O=c1cnc2c([N+](=O)[O-])c(Br)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a stirred suspension of 6-bromo-7-chloro-3,4-dihydroquinoxaline-2(1H)-one (0.06 g, 0.23 mmol) in CF3COOH (0.5 mL) was added fuming HNO3 (0.02 mL, 0.46 mmol) and the resulting reddish yellow suspension was stirred at r.t. overnight. The cream colored suspension so obtained was poured into ice (2.5 mL) and the precipitated solid was filtered, washed with water (1.0 mL) and dried under vacuum to afford 0.049 g (70%) of title compound as a cream colored powder which contained ~10% impurity (1H NMR integration); 1H NMR (DMSO-d6): δ7.577 (s, 1H), 8.251 (s, 1H), 12.879 (s, 1H). The crude product was used for the next reaction.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[CH:22]=[CH:21][C:16]4[O:17][CH2:18][CH2:19][O:20][C:15]=4[CH:14]=3)=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(OP([CH2:31][C:32]#[N:33])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[CH:22]=[CH:21][C:16]4[O:17][CH2:18][CH2:19][O:20][C:15]=4[CH:14]=3)=[CH:31][C:32]#[N:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C(c1ccc2c(c1)OCCO2)c1ccc2c(c1)OCCO2
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC=C(c1ccc2c(c1)OCCO2)c1ccc2c(c1)OCCO2
Yield: 74.7 %

Procedure:
Bis-(2,3-dihydrobenzo[1,4]dioxin-6-yl)methanone (1.12 g, 3.75 mmol), cyanomethylphosphonic acid diethyl ester (1.18 ml, 7.51 mmol) in anhydrous THF (10 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 7.51 ml, 7.51 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give a foam, which was lyophilized to give 3,3-bis-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-acrylonitrile as an light yellow solid (0.90 g, 75%): mp, 138-140° C.; 1HNMR (DMSO-d6) δ 6.98 (d, J=8 Hz, 1H, Ar), 6.91-6.77 (m, 5H, Ar), 6.08 (s, 1H, double bond proton), 4.33-4.24 (m, 4H, 2CH2CH2); 13C NMR (DMSO-d6) δ 160.4, 145.6, 144.7, 143.2, 143.1, 131.2, 130.0, 122.5, 121.9, 118.6, 117.9, 117.2, 117.1, 116.9, 93.3, 64.3, 64.2, 64.0, 64.0. Anal. Calcd. For C19H15NO4: C, 70.62; H, 4.74; N, 4.33. Found: C, 70.45; H, 4.67; N, 4.20.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1B(O)O.[O:21]=[S:22]1(=[O:39])[CH2:27][CH2:26][N:25]2[CH2:28][CH2:29][CH2:30][C@@H:31]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[C:24]2=[N:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[O:38][C:35]1[CH:34]=[CH:33][C:32]([C@H:31]2[C:24]3=[N:23][S:22](=[O:39])(=[O:21])[CH2:27][CH2:26][N:25]3[CH2:28][CH2:29][CH2:30]2)=[CH:37][CH:36]=1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4cc(C(F)(F)F)ccc4Cl)cc3)C2=N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.6 %

Procedure:
Diacetoxycopper (907 mg) was added to a mixture of pyridine (0.606 mL), 2-chloro-5-(trifluoromethyl)phenylboronic acid (459 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (700 mg) and cesium carbonate (814 mg) in MeCN (25 mL). The mixture was stirred at room temperature under a dry atmosphere with anhydrous calcium chloride tube for 2 days. The insoluble material was removed by filtration, and the filtrate was diluted with water, and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo to give the title compound (5.9 mg) as pale yellow gum.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=O)(C)(C)C.[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1O>C1COCC1>[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Oc1cccc(F)c1F
Solvent: C1CCOC1
Product: Fc1cccc(OC[C@@H]2CCCN2)c1F
Reaction time: 40 h

Procedure:
A 4.03 g (20 mmol) sample of (S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (from Example 3a above) and 3.90 g (30 mmol) of 2,3-difluorophenol (Aldrich) were added to a complex of TPP and TBAD, (prepared as in Example 5b above, 30 mmol of each) in 150 mL of THF. The reaction was stirred for 40 hr, and the solvents were removed under vacuum. Hexane was added to the residue, and the crude product was collected by filtration. The product was washed with hexane and 10% NaOH, then purified by flash chromatography on silica gel, eluting with CHCl3. Removal of the solvent gave 7.5 g of the title compound.
Reaction SMILES: [ClH:1].C([NH:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)(OC(C)(C)C)=O>O1CCOCC1.C(Cl)Cl>[ClH:1].[ClH:1].[NH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ccccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCNc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4 N HCl in dioxane (3.2 mL) was added in a stream to a solution of 2-[[2-(Boc-amino)ethyl]amino]pyridine (148.4 mg, 0.63 mmole) in anhydrous CH2Cl2 (3.2 mL) at 0° C., then the reaction was warmed to RT. After 2 hr, the mixture was suction filtered to collect the precipitated solid, which was washed with anhydrous Et2O and dried to afford the title compound (132.8 mg, quantitative) as a yellow solid: 1H NMR (400, CD3OD) δ 7.99-8.07 (m, 1 H), 7.92-7.98 (m, 1 H), 7.19 (d, J=9.1 Hz, 1 H), 6.98-7.04 (m, 1 H), 3.76 (t, J=6.2 Hz, 2 H), 3.27 (t, J=6.2 Hz, 2 H, partially obscured by residual solvent signal); MS (ES) m/e 138 (M+H)+.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7](Cl)([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:8]>O1CCCC1>[C:7]([NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:8]
Reactant: C=C(C)C(N)=O
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Product: C=C(C)C(=O)NC(=O)C(=O)OCC
Reaction time: 4 h
Yield: 70.2 %

Procedure:
Into the same reaction vessel as used in Example 1, tetrahydrofuran (50 ml), methacrylamide (4.26 g; 50 mmol) and ethoxalyl chloride (6.83 g; 50 mmol) were charged, and refluxing was continued for 4 hours. Removal of the organic solvent by distillation under reduced pressure gave N-ethoxalylmethacrylamide (6.5 g). Yield, 70.6%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([O:18][C:19]1[CH:27]=[C:22]2[CH2:23][NH:24][CH2:25][CH2:26][N:21]2[N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:11]([O:18][C:19]1[CH:27]=[C:22]2[CH2:23][N:24]([C:6]([C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)=[O:7])[CH2:25][CH2:26][N:21]2[N:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: c1ccc(COc2cc3n(n2)CCNC3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCn2nc(OCc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
4-Fluorobenzoyl chloride (0.36 mL, 3.04 mmol) was added to a stirred solution of 2-(benzyloxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.71 g, 2.53 mmol) and triethylamine (0.65 mL, 3.8 mmol) in DCM (25 mL) under nitrogen at 0° C. The mixture was stirred at room temperature for 16 hours, diluted with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected, the solvents evaporated in vacuo and the residue triturated with DIPE to yield 2-(benzyloxy)-5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.73 g, 83% yield) as a white solid. C20H18FN3O2. 1H NMR (400 MHz, CDCl3) δ ppm 4.10 (br. s., 4H), 4.73 (br. s., 2 H), 5.18 (s, 2 H), 5.50 (br. s., 1 H), 7.10-7.19 (m, 2 H), 7.29-7.35 (m, 1 H), 7.35-7.41 (m, 2 H), 7.41-7.46 (m, 2 H), 7.46-7.51 (m, 2 H).