Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].B(F)(F)F.[CH3:33]COCC.C(O)(=O)CC>C1COCC1>[CH3:33][O:25][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:12]1[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:11]=1
Reactant: O=C(O)CCCCCc1nn(-c2ccc([N+](=O)[O-])cc2)c2c1CCCC2
Reactant: CCOCC
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCC(=O)O
Product: COC(=O)CCCCCc1nn(-c2ccc([N+](=O)[O-])cc2)c2c1CCCC2
Temperature: 70 °C
Yield: 40.4 %

Procedure:
A solution of 6-[4,5,6,7-tetrahydro-1-(4-nitrophenyl)-1H-inda-zol-3-yl]hexanoic acid (1.11 g, 3 mmol) in THF (10 ml) was treated with sodium borohydride (0.175 g) and boron trifluoride etherate (4.7 mmol) in THF (11 ml) during 0.5 hour. The solution was reacted for 18 hours at ambient temperature, treated with propionic acid (2 ml), and heated at 70° C. for 2 hours. The solution was cooled, dilution with water and the precipitate was extracted into ethyl acetate. Drying and evaporation of solvent gave crude title compound (1.69 g) as a viscous residue. Polar impurities were removed by filtration through silica gel (100 g) to yield pure title compound (0.45 g), m.p. 60°-61° C., after methanol crystallization.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10]Br)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1CBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1CN1CCOCC1

Procedure:
A mixture of 5-bromo-2-bromomethyl-benzonitrile (2.0 g, 7.3 mmol), morpholine (0.76 g, 8.7 mmol) and K2CO3 (1.0 g, 7.3 mmol) is stirred in 50 DMF at room temperature for 72 hours. The reaction mixture is filtered and the filtrate is dried under vacuum to yield the title compound. 1H-NMR (400 MHz; DMSO-d6): 8.11 (d, 1H), 7.90 (dd, 1H), 7.53 (d, 1H), 3.60 (s, 2H), 3.56 (t, 4H), 2.39 (t, 4H). LC-MS (m/z, ES+): 281 (MH+), Retention time: 1.79 mins (LC-MS method 2)
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]([OH:10])=O)(=[O:5])[C:2]([CH3:4])=[CH2:3].CN(C)C=O.S(Cl)([Cl:18])=O>>[C:1]([O:6][CH2:7][C:8]([Cl:18])=[O:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=C(C)C(=O)OCC(=O)O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCC(=O)Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Into a 100-mL reaction vessel with a condenser were added 30 g (purity: 46%, 95.1 mmol) of methacryloyloxyacetic acid (prepared in a method described in International Publication No. 96/41841 and the like), 347 mg (4.8 mmol/0.05 eq) of dimethylformamide and 47.6 g (380.5 mmol/4.0 eq) of thionyl chloride. The resulting solution was stirred at 70° C. for 1 hour and subjected to distillation purification, thereby obtaining 10.0 g of target methacryloyloxyacetyl chloride. The purity of the target product was 70%; and the yield of the target product was 45%.
Reaction SMILES: [I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([O-:18])=O)=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[K+].[N:20]1(C([O-])=O)C2C=CC=CC=2N=N1.[NH4+]>CN(C)C=O.O>[I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH2:20])=[O:18])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1
Reactant: O=C([O-])n1nnc2ccccc21
Reactant: Cn1nc(C(=O)[O-])c2c1-c1nc(I)ncc1CC2
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(N)=O)c2c1-c1nc(I)ncc1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A suspension of potassium 8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (394 mg, 1.0 mmol) in anhydrous dimethylformamide (10 mL) was treated with N-ethyl-N′,N′-diisopropyl carbodiimide hydrochloride (EDCI) (287 mg, 1.5 mmol) and with ammonium 1H-1,2,3-benzotriazol-1-ate (304 mg, 2 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water and the resulting precipitate was collected by filtration to afford the title compound (320 mg, 90% yield).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([O:38]CC6C=CC=CC=6)[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:46])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>[Pd].CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([OH:38])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:46])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(OCc4ccccc4)cccc32)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(O)cccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To 15 mL of a methanol solution containing 309 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-benzyloxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 31 mg of 5% palladium on carbon was added, and stirred at room temperature under hydrogen atmosphere overnight. The insoluble material was filtered off, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=20:1], to give 239 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-hydroxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale brown foam.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1)=[O:15].[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:28]=1[CH2:29]Br>C1COCC1.CS(C)=O>[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[C:28]=1[CH2:29][N:19]1[CH:20]=[CH:21][C:17]([NH:16][C:14](=[O:15])[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[CH3:11])=[N:18]1
Reactant: Fc1cccc(C(F)(F)F)c1CBr
Reactant: Cc1ccccc1C(=O)Nc1cc[nH]n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccn(Cc2c(F)cccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 M lithium bis(trimethylsilyl)amide (100 μl, 0.1 mmol, Aldrich) was slowly added to a solution of 2-methyl-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 46)(22 mg, 0.1 mmol) in THF (400 μl). The resulting solution was then transferred to a solution of 2-fluoro-6-(trifluoromethyl)benzyl bromide (26 mg, 0.1 mmol, Aldrich) in THF (200 μl) and stirred for 1 h under nitrogen at ambient temperature. The mixture was diluted with DMSO (0.6 ml) and purified by MDAP using a Sunfire C18 (Method D) column using Acetonitrile-Water with a TFA modifier. The solvent was removed under a stream of nitrogen to give the title compound (27 mg); LCMS (System 3) MH+=378, tRET=1.13 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31]1[O:41][C:40]2[C:33](=[CH:34][C:35]([N+:42]([O-:44])=[O:43])=[C:36]([CH:39]=2)[CH:37]=O)[O:32]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH2:37][C:36]2[CH:39]=[C:40]3[O:41][CH2:31][O:32][C:33]3=[CH:34][C:35]=2[N+:42]([O-:44])=[O:43])[CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2cc3c(cc2[N+](=O)[O-])OCO3)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (0.150 mmol), 4,5-methylenedioxy-2-nitrobenzaldehyde (0.45 mmol), methanol (4.5 mL), and acetic acid (0.048 mL) was added NaBH3CN (0.75 mmol) in methanol (1.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated to afford (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4,5-methylenedioxy-2-nitrobenzyl)pyrrolidine.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.I[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu](I)I>[CH3:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[C:1]1=[O:11]
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2cnccc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2cnccc2C1=O
Yield: 15.1 %

Procedure:
3,4-Dihydro-2,6-naphthyridin-1(2H)-one (I-67h: 45 mg, 0.304 mmol) was reacted with 3-iodo-4-methylpyridine (100 mg, 0.456 mmol), copper iodide (5.7 mg, 0.0304 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (12.95 mg, 0.0912 mmol) and potassium phosphate (193.3 mg, 0.912 mmol) in 1,4-dioxane (5 mL) to afford the crude product. Purification by column chromatography on silica gel (4% methanol in CHCl3), followed by preparative HPLC afforded 11 mg of the product (15.27% yield).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=4)[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COc1cccc(Nc2nc3c(Br)cccn3n2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1cccc(Nc2nc3c(-c4ccc(S(C)(=O)=O)cc4)cccn3n2)c1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-methoxy-phenyl)-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(3-methoxy-phenyl)-amine (200.0 mg, 0.6266 mmol) and (4-methylsulfonylphenyl)boronic acid (150.0 mg, 0.7499 mmol) with Pd(dppf)Cl2 (50.0 mg) as the catalyst in a manner analogous to
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nccc(Nc2ccccc2)n1

Procedure:
2,4-Dichloropyrimidine (3.75 g, 25 mmol) was dissolved in EtOH (12 ml) and treated with aniline (2.27 ml, 25 mmol) and triethylamine (3.82 ml, 27.2 mmol). The reaction mixture was heated to reflux for 6 hours, partitioned between EtOAc and water. The organic phase was washed with 1M HCl, dried over MgSO4 and evaporated to obtain a cream coloured solid. This material was purified by chromatography (25–50% EtOAc in isohexane) to give the title product as an off white solid. NMR (300 MHz) 6.73 (d, 1H), 7.08 (t, 1H), 7.35 (t, 2H), 7.57 (d, 2H), 8.12 (d, 1H), 9.95 (brs, 1H); m/z: (ES+) 206 (MH+).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17]C)=O.[O-]CC.[Na+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:37][C:38]([NH2:40])=[NH:39])[CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1>C(O)C>[OH:17][C:15]1[C:3]2[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7][C:2]=2[N:40]=[C:38]([NH:37][C:27]2[CH:28]=[CH:29][C:30]([N:31]3[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]3)=[C:25]([O:24][CH3:23])[CH:26]=2)[N:39]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Nc2nc(O)c3c(n2)CCN(C(=O)OC(C)(C)C)C3)ccc1-n1cnc(C)c1
Temperature: 100 °C
Yield: 39.5 %

Procedure:
In a microwave vial was 1-tert-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (0.577 g, 2.24 mmol, Example 7c), Sodium ethoxide (0.153 g, 2.24 mmol), and 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (0.55 g, 2.24 mmol) added in ethanol (10 mL) to give a suspension. The reaction was heated in the microwave oven for 20 min at 100° C. Solvent was evaporated under reduced pressure. The crude was dissolved in minimal volume of EtOH and few drops of water added to allow the product to precipitate. The precipitated product was filtered and dried to give tert-butyl 4-hydroxy-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.400 g, 39.4%). MS (ESI+)/(ESI−) m/z 453/450
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:13][S:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=2[O-:22])=[O:15])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].C(OO)(=[O:25])C>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:13][S:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=2[O-:22])(=[O:25])=[O:15])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)OO
Reactant: O=[N+]([O-])c1cc(CS(=O)c2cccc[n+]2[O-])cc([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(CS(=O)(=O)c2cccc[n+]2[O-])cc([N+](=O)[O-])c1
Temperature: 70 °C

Procedure:
To 14.0 g (0.043 mole) of 2-[[(3,5-dinitrophenyl)methyl]sulfinyl]-pyridine-N-oxide in 35 ml of glacial acetic acid was added, dropwise over 0.5 hours with stirring, 8.2 g of 40% peracetic acid in acetic acid. After addition was complete, the mixture was heated to 70° C. for 4.5 hours. The mixture was cooled to room temperature, and then an additional 2.0 g of 40% peracetic acid was added, and the mixture heated to 45-50° C. for three hours while stirring. The mixture became quite thick, so 20 ml of glacial acetic acid was added to enable better stirring and heating was continued at 70° C. for one more hour, followed by stirring at 30° C. overnight. Workup of a small aliquot indicated some sulfoxide to still be present, so heating was continued at 65-70° C. for 4 more hours. The excess peracetic acid was then destroyed by adding 100 ml of water and sodium bisulfite. After neutralizing the mixture to pH 4 with potassium carbonate, the white solid was filtered off, and then dried under vacuum. Yield was 11.5 g or 79%, having a melting point of 198-201° C. This material was recrystallized from ethanol to give a white solid, melting point 202-204° C. Infrared and NMR spectra were consistent with the proposed structure.
Reaction SMILES: [CH:1]1([C:4]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[CH:7]=[C:6]3[O:22][CH2:23][CH2:24][N:25]([CH2:26][CH:27]([OH:31])[CH2:28][O:29][CH3:30])[C:5]=23)[CH2:3][CH2:2]1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1O.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[CH:7]=[C:6]3[O:22][CH2:23][CH2:24][N:25]([CH2:26][CH:27]([O:31][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[F:32])[CH2:28][O:29][CH3:30])[C:5]=23)[CH2:2][CH2:3]1
Reactant: COCC(O)CN1CCOc2cc3c(c(C4CC4)c21)CCN(C(=O)OC(C)(C)C)CC3
Reactant: Oc1ccccc1F
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COCC(CN1CCOc2cc3c(c(C4CC4)c21)CCN(C(=O)OC(C)(C)C)CC3)Oc1ccccc1F
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 300 mg of t-butyl 5-cyclopropyl-4-(2-hydroxy-3-methoxypropyl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate in 3 ml of toluene were added 0.1 ml of o-fluorophenol and 250 mg of cyanomethylenetributylphosphorane, followed by stirring at 80° C. for 20 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 277 mg of t-butyl 5-cyclopropyl-4-[2-(2-fluorophenoxy)-3-methoxypropyl]-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a pale yellow viscous substance.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1C=CC=CC=1>[CH3:18][S:19]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:21])=[O:20]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Ethyl 2-hydroxyimino-2-cyanoacetate (7.1 g) and triethylamine (7.0 ml) are dissolved in benzene (50 ml). To the solution is added dropwise a solution of methanesulfonyl chloride (3.9 ml) in benzene (8 ml) with stirring under ice-cooling and the mixture is stirred at the temperature for 3 hours and then allowed to stand overnight. The reaction mixture is filtered to remove the precipitates and the filtrate is concentrated to give crystals of ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (10.6 g; 96.3%), melting point: 79°-83° C. The product is recrystallized from benzene-petroleum ether to give crystals having a melting point of 79°-81.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH2:26]([O:25][C:23](=[O:24])[NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2)[CH3:27]
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 80 °C
Yield: 27.9 %

Procedure:
To a stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.41 g, 1.3 mmol) in tetrahydrofuran (10 mL), was added ethyl chloroformate (0.45 mL, 4.7 mmol) and heated at 80° C. for three hours. The mixture was quenched with a few drops of methanol. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-carbamic acid ethyl ester as a white solid (130 mg, 27% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.26 min (99.2%); mp, 284-286° C. (decomposed); 1HNMR (DMSO-d6)1.26 (t, J=7 Hz, 3H, CH2CH3), 2.15-2.19 (m, 1H, CHH), 2.58-2.90 (m, 6H, CHCH2, CH3), 4.16 (q, J=7 Hz, 2H, CH2CH3), 5.31 (dd, J=6, 11 Hz, 1H, CH), 7.23-8.24 (m, 3H, Ar), 11.08 (s, 1H, NH), 11.30 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.28, 20.72, 23.28, 30.53, 56.70, 60.99, 107.14, 113.36, 119.59, 135.73, 140.00, 147.95, 152.66, 154.73, 169.31, 172.54. LCMS MH=359; Anal Calcd For C17H18N4O5+0.8H2O: C, 54.78; H, 5.30; N, 15.03. Found: C, 54.67; H, 4.99; N, 14.80.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH:12]([C:15]([O:17]CC)=O)[NH:11][C:10]3[N:20]([CH3:29])[N:21]=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:9]2=3)=[C:4]([CH3:30])[CH:3]=1.[OH-].[Na+].[N:33]1(C(N2C=CN=C2)=O)C=CN=C1>O1CCOCC1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH:12]([C:15]([NH2:33])=[O:17])[NH:11][C:10]3[N:20]([CH3:29])[N:21]=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:9]2=3)=[C:4]([CH3:30])[CH:3]=1
Reactant: CCOC(=O)C1CSC(c2ccc(Br)cc2C)c2c(-c3ccccn3)nn(C)c2N1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(Br)ccc1C1SCC(C(N)=O)Nc2c1c(-c1ccccn1)nn2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A mixture of rac-(4R,7S)-ethyl 4-(4-bromo-2-methylphenyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepine-7-carboxylate (0.170 g, 0.174 mmol, Preparation #39) and 2 M NaOH (1 mL, 2.00 mmol) in 1,4-dioxane (2 mL) was stirred at rt for about 2 h. The reaction was partitioned between 1 M HCl (40 mL) and EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried with Na2SO4, filtered and was concentrated in vacuo. The residue was suspended in THF (4 ml) and di(1H-imidazol-1-yl)methanone (0.085 g, 0.52 mmol) was added followed by DMAP (0.026 g, 0.21 mmol). The reaction was stirred at rt for about 1 h. The reaction was quenched with NH4OH (5.0 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried with Na2SO4, filtered and was concentrated in vacuo. The residue was recrystallized from DCM/Et2O to give rac-(4R,7S)-4-(4-bromo-2-methylphenyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepine-7-carboxamide (0.080 g, 0.087 mmol, 50%), as a white solid: LC-MS (Table 1, Method g) Rt=2.12 min, m/z 458/460 (M+H)+; 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 8.43-8.40 (m, 1H), 7.81-7.77 (m, 1H), 7.73-7.65 (m, 1H), 7.34 (d, J=1.8 Hz, 1H), 7.23-7.19 (m, 1H), 7.17-7.12 (m, 1H), 7.11-7.08 (m, 2H), 6.99 (s, 1H), 6.61 (s, 1H), 5.82 (d, J=5.0 Hz, 1H), 4.11-4.07 (m, 1H), 3.77 (s, 3H), 3.20 (dd, J=15.2, 5.5 Hz, 1H), 2.83 (dd, J=15.3, 2.8 Hz, 1H), 2.48 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([NH2:17])=[O:16].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]([N:13]1[CH2:20][CH2:19][CH2:18][CH:14]1[C:15](=[O:16])[NH2:17])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N1CCCC1C(N)=O
Temperature: 25 °C
Yield: 96 %

Procedure:
N-tert-butyloxycarbonyl glycine 1a (5 g, 28.56 mmol) and L-prolinamide (3.25 g, 28.50 mmol) were dissolved in 75 mL of N,N-dimethylformamide, the resulting solution was cooled down to 0° C. (centigrade), and 1-hydroxybenzotriazole (11.8 g, 87.3 mmol), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide (11.3 g, 59 mmol) and triethylamine (12.1 mL, 87.3 mmol) were then added with stirring. Upon completion of the addition, the reaction mixture was allowed to increase to room temperature, and stirred overnight. After thin lay chromatography showed the starting material disappeared, N,N-dimethylformamide was evaporated below 50° C., and the reaction solution was extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization with ethyl acetate to obtain the title compound [2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1b (7.42 g, yield 95.8%) as a white powder.