Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].O=[C:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]#[N:17].[Cl-].[Ca+2].[Cl-]>>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][C:11]1[CH2:15][CH2:14][CH2:13][C:12]=1[C:16]#[N:17]
Reactant: Nc1cc(F)ccc1F
Reactant: N#CC1CCCC1=O
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2cc(F)ccc2F)CCC1

Procedure:
2,5-Difluoro-aniline (2.6 g, 20.0 mmol) (Aldrich Chemicals) cyano-ketone (Example 11) (2.2 g, 20.2 mmol), calcium chloride (2.5 g, 22.5 mmol) and T.H.F. (30 ml) were heated under reflux for 22 hours. After cooling, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (160° C., 0.9 mmHg) gave the produce as white crystals.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].O.[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1>C(O)(C)C.CCOCC>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH:11]([CH3:16])[CH3:12])=[O:8]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: CCOCC
Solvent: O
Product: CC(C)OC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Yield: 955.6 %

Procedure:
A solution of L-pyroglutamic acid (Aldrich, 25.0 g, 195 mmol) and para-toluenesulfonic acid mono hydrate (3.71 g, 19.5 mmol) was refluxed in isopropanol (40 mL) under nitrogen for 6 hours using a Dean-Stark trap variation (condensate returned through a Soxhlet extractor filled with 4 Å molecular sieves). After cooling to room temperature, the reaction was diluted with ether, washed with saturated aqueous sodium bicarbonate and then saturated aqueous NaCl, dried (MgSO4) and evaporated to give a colorless syrup. It crystallized upon setting. Triturating the crystalline residue in hexane provided 31.9 g (96%) of isopropyl pyrrolidin-5-one-2(S)-carboxylate as white prisms: 1H NMR (300 MHz, Chloroform-D) δ 6.35 (br s, 1H), 5.04 (sept. 1 H, J=6.2 Hz), 4.18 (dd, 1 H, J=8.4, 5.3 Hz), 2.51-2.28 (m, 3 H), 2.27-2.12 (m, 1 H), 1.24 (d, 6 H, J=6.2 Hz). LCMS m/z 172 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[C:13]3([CH2:17][CH2:16][C:15](=[S:18])[NH:14]3)[CH:11]3[CH2:12][CH:8]2[CH:9]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][I:20]>CC(C)=O>[IH:20].[CH3:19][S:18][C:15]1[CH2:16][CH2:17][C:13]2([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]3[CH2:12][CH:11]2[CH:10]=[CH:9]3)[N:14]=1
Reactant: CI
Reactant: S=C1CCC2(N1)C1C=CC(C1)C2c1ccccc1
Solvent: CC(C)=O
Product: CSC1=NC2(CC1)C1C=CC(C1)C2c1ccccc1
Product: I

Procedure:
6 mmoles of 3-phenyl-spiro[bicyclo[2.2.1]-hept-5-ene-2,2'-pyrrolidine]-5'-thione are dissolved in 30 ml of acetone, 1 ml of methyl iodide is added and the mixture is refluxed for 10 minutes. After cooling, the precipitate is filtered off. The crystalline compound, which is pure according to a thin layer chromatogram, is further processed immediately.
Reaction SMILES: C(O[C:4](=[O:12])[CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])C.[CH3:13][O:14][C:15](=[O:17])[CH3:16].[Na]>>[CH2:10]([O:9][CH:5]([O:6][CH2:7][CH3:8])[C:4](=[O:12])[CH2:16][C:15]([O:14][CH3:13])=[O:17])[CH3:11]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: COC(C)=O
Agent: [Na]
Product: CCOC(OCC)C(=O)CC(=O)OC
Temperature: 0 °C

Procedure:
Ethyldiethoxyacetate (32 g.) and methylacetate (25 g.) are placed in a flask equipped with stirrer and reflux condenser and heated to reflux. Metallic sodium wire (6.5 g.) is introduced into the flask in small portions and heating continued until the sodium is completely dissolved. Methylacetate (25 g.) and metallic sodium wire (6.5 g.) are then added and heating continued until the solution is clear. The mixture is cooled, a large volume of ice water cautiously added and the mixture extracted with ether. The aqueous solution is acidified with hydrochloric acid at 10° C. to 15° C. and the desired product extracted with ether. The ethereal extract is dried (Na2SO4), the ether removed and the residue distilled in vacuo to give methyl γ,γ-diethoxyacetoacetate.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].S(Cl)([Cl:18])(=O)=O.C(O)=O>O>[Br:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=[O:14])[CH2:13][Cl:18])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=NOCCBr)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: O=CO
Solvent: O
Product: CCOC(=O)C(=NOCCBr)C(=O)CCl
Temperature: 40 °C
Reaction time: 5.5 h
Yield: 82.2 %

Procedure:
A mixture of ethyl 2-(2-bromoethoxyimino)-3-oxobutyrate (syn isomer, 168 g.), sulfuryl chloride (87.3 g.) and formic acid (168 ml.), was stirred at 40° C. for 10 minutes and at room temperature for 5.5 hours. After adding water (1 l.) to the resultant solution, the mixture was extracted with methylene chloride. The extract was washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate, and then concentrated in vacuo to give ethyl 2-(2-bromoethoxyimino)-4-chloro-3-oxobutyrate (syn isomer, 156 g.), oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[S:18][C:17]([CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[C:16]([CH3:25])[CH:15]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1.C([N:28](CC1SC(C2ON=C(C3C=CC(COS(C)(=O)=O)=CC=3)N=2)=CC=1C)CC)C>N.CO>[NH2:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[S:18][C:17]([CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[C:16]([CH3:25])[CH:15]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(COS(C)(=O)=O)cc3)no2)cc1C
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCl)cc3)no2)cc1C
Agent: N
Solvent: CO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CN)cc3)no2)cc1C

Procedure:
To a solution of {4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methanol (971 mg, 2.72 mmol) in DCM (40 mL), DIPEA (526 mg, 4.07 mmol) and methanesulfonyl chloride (373 mg, 3.26 mmol) is added. The reaction mixture is stirred at rt for 15 h before it is diluted with DCM and washed with sat. aq. NaHCO3 solution. The washing is extracted back three times with DCM. The combined organic extracts are dried over MgSO4, filtered, concentrated and dried to give crude methanesulfonic acid 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzyl ester (1.48 g) as an orange solid containing {5-[3-(4-chloromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-diethyl-amine; LC-MS: tR=0.58 min; [M+1]+=436.11. b) A solution of the above crude methanesulfonic acid 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzyl ester (248 mg, 0.569 mmol) in 7 N NH3 in methanol (10 mL) is stirred in a sealed vial at 80° C. for 16 h. The solvent is removed in vacuo and the residue is dissolved in EA and washed with brine and water. The organic extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with DCM containing 5% of 7N NH3 in methanol to give the title compound (137 mg) as a pale yellow oil; LC-MS: tR=0.38 min; [M+1]+=357.30; 1H NMR (CDCl3): δ 1.11 (t, J=7.0 Hz, 6H), 2.26 (s, 3H), 2.64 (q, J=7.0 Hz, 4H), 3.73 (s, 2H), 3.98 (s, 2H), 7.47 (d, J=7.8 Hz, 2H), 7.67 (s, 1H), 8.13 (d, J=7.5 Hz, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][CH:8]([CH2:10][CH2:11][CH2:12][C@H:13]([C@@H:15]1[C@:33]2([CH3:34])[C@H:18]([C@H:19]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:22]([CH2:23][C@H:24]([CH2:26][CH2:27]2)[OH:25])=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)[CH3:14])[CH3:9].N1C=CC=CC=1>C(Cl)Cl>[Cl:6][CH2:5][O:4][C:2]([C@:24]1([OH:25])[CH2:26][CH2:27][C@@:28]2([CH3:29])[C:22](=[CH:21][CH2:20][C@@H:19]3[C@@H:30]2[CH2:31][CH2:32][C@@:33]2([CH3:34])[C@H:18]3[CH2:17][CH2:16][C@@H:15]2[C@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:8]([CH3:9])[CH3:7])[CH2:23]1)=[O:3]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@](O)(C(=O)OCCl)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 24 h

Procedure:
Chloromethyl chloroformate (1.96 g, 15.2 mmol) and cholesterol (5.0 g, 12.9 mmol) was dissolved in CH2Cl2 (10 ml). The solution was cooled. Pyridine (1.21 g, 15.3 mmol) was dripped into the stirred solution over 5 minutes. Heat was produced and the reaction gave a clear solution from a somewhat unclear starting solution. After 24 hours at room temperature, the mixture was diluted with CH2Cl2 (50 ml), washed with 0.5M HCl (50 ml) and water (3×25 ml). After treatment with MgSO4, the solution was evaporated to dryness.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:32]=[CH:33][CH:34]=1)[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1)=[O:24].C(N(CC)CC)C.C.[O:43]1CCOC[CH2:44]1>C(#N)C>[CH3:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:23]([C:22]1[CH:21]=[C:20]([NH:19][C:44]([CH2:3][C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:43])[CH:34]=[CH:33][CH:32]=1)=[O:24]
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: C1COCCO1
Reactant: Cc1cccc(C(=O)c2cccc(N)c2)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)c2cccc(NC(=O)Cc3ccn4c3CSC4c3cccnc3)c2)c1
Temperature: 64 °C
Reaction time: 8 h

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 64° and 70° C., to a solution of 3-amino-3'-methylbenzophenone (4.25 g) and triethylamine (4.05 g) in dioxane (150 cc) which is heated to a temperature in the vicinity of 64° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 8 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 1N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (9 g) is thereby obtained, which is dissolved in boiling acetonitrile (75 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 10° C. for 3 hours. The crystals formed are separated by filtration, washed 3 times with acetonitrile cooled to a temperature in the vicinity of 4° C. (30 cc in total) and 3 times with diethyl ether (90 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(3-methylbenzoyl)phenyl]-3-(3-pyridyl)-1H, 3H-pyrrolo[1,2-c]thiazole-7-carboxyamide (2.4 g) in the form of beige-coloured crystals, m.p. 164° C., is thereby obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7]C.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[O:36][CH3:37])#[N:26]>>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:14])=[CH:11][N:10]=3)[C:6]=2[OH:7])=[CH:29][C:28]=1[O:36][CH3:37])#[N:26]
Reactant: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: COc1cc(B(O)O)ccc1C#N
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)ccc1C#N

Procedure:
The title compound was prepared in a manner similar to Example 213 using 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (50 mg, 0.127 mmol), (4-cyano-3-methoxyphenyl)boronic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.14 (d, J=10.6 Hz, 2H) 1.55 (d, J=11.9 Hz, 3H) 3.11 (br. s., 2H) 3.72-3.90 (m, 7H) 6.47 (s, 1H) 7.41 (d, J=15.4 Hz, 3H) 7.77 (br. s., 1H) 8.03-8.23 (m, 3H) 8.41-8.60 (m, 2H) 8.77 (br. s., 1H). MS m/z [M+H]+ 434.4.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([NH2:10])[CH3:9]>C(O)C>[CH2:8]([NH:10][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH3:9]
Reactant: C=CC(=O)OCC
Reactant: CCN
Solvent: CCO
Product: CCNCCC(=O)OCC
Reaction time: 3 h
Yield: 69.6 %

Procedure:
50 g (0.50 mole) of ethyl acrylate was dissolved in 500 ml of ethanol. To the resulting solution being stirred in an ice bath was added dropwise a mixed solution consisting of 36 g of a 70% aqueous ethylamine solution (containing 0.55 mole of ethylamine) and 100 ml of ethanol, in 3.5 hours. The reaction was continued for further 3 hours and then the solvent was distilled off. The resulting residue was subjected to vacuum distillation to obtain 50.5 g of a desired product with an yield of 70%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]2[O:13][C@H:14]3[C:23]4([O:27][CH2:26][CH2:25][O:24]4)[CH2:22][CH2:21][C@@H:20]4[C@@:15]53[CH2:16][CH2:17][N:18]([CH3:29])[C@@H:19]4[CH2:28][C:10]([C:11]=25)=[CH:9][CH:8]=1)(=O)=O.[CH3:32][N:33](C)C=O>C(OCC)(=O)C.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.[C-]#N.[Zn+2].[C-]#N>[CH3:29][N:18]1[CH2:17][CH2:16][C@@:15]23[C:11]4[C:10]5[CH2:28][C@@H:19]1[C@@H:20]2[CH2:21][CH2:22][C:23]1([C@@H:14]3[O:13][C:12]=4[C:7]([C:32]#[N:33])=[CH:8][CH:9]=5)[O:24][CH2:25][CH2:26][O:27]1
Reactant: CN(C)C=O
Reactant: CN1CC[C@]23c4c5ccc(OS(=O)(=O)C(F)(F)F)c4O[C@H]2C2(CC[C@H]3[C@H]1C5)OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CN1CC[C@]23c4c5ccc(C#N)c4O[C@H]2C2(CC[C@H]3[C@H]1C5)OCCO2
Temperature: 40 °C
Yield: 63 %

Procedure:
To a solution of (4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolan]-9-yl trifluoromethanesulfonate (20.77 g, 45.0 mmol) in degassed dimethylformamide (400 mL) was added tetrakis(triphenylphosphine)palladium(0) (5.21 g, 4.50 mmol). After heating to 40° C., zinc cyanide (3.18 g, 27.0 mmol) was added and the reaction mixture heated at 110° C. for 6 hours. The reaction mixture was cooled to room to temperature and diluted with ethyl acetate and filtered through a pad of celite. The filtrate was diluted further with ethyl acetate and washed with water (3×500 mL). The aqueous phase was basified with sodium hydrogen carbonate solution and re-extracted with ethyl acetate and the combined organics dried (MgSO4), filtered and concentrated under reduced pressure. Purification by silica chromatography (100% dichloromethane to 5% NH3/methanol in dichloromethane) gave (4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile (10.0 g, 91% pure LCMS, 63% yield over three steps); [M+H]+ 339.1.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH:19]=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][NH:29][CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC(=O)C)C.[ClH:57]>C(OCC)(=O)C.ClCCCl.C(O)(=O)C>[ClH:57].[ClH:57].[ClH:57].[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:29]([CH2:28][CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:30][C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Reactant: c1cncc(CCNCc2ccncc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)Cc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (0.92 g) and acetic acid (0.1 ml) were added to a 1,2-dichloroethane solution (15 ml) of (2-pyridine 3-ylethyl)pyridin-4-ylmethylamine (0.81 g), and the mixture was stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (0.90 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→90:10). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (1.0 ml) was added to an ethyl acetate solution (20 ml) of the residue, and the liquid was stirred at room temperature. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (0.83 g) as a white solid 1H-NMR (DMSO-d6) δppm: 0.68 (3H, s), 1.06 (3H, t, J=7.1 Hz), 1.33 (3H, s), 3.00 (2H, br), 3.32 (3H, s), 3.10-3.45 (4H, m), 3.74-3.79 (1H, m), 3.94-4.00 (3H, m), 7.43 (2H, br), 7.98-8.02 (2H, m), 8.45 (1H, d, J=8.0 Hz), 8.82-8.88 (6H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[H-].[Na+].Cl[C:16]1[N:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:17]=1>CN(C)C=O>[OH:12][C:7]1[NH:8][C:9]2[C:5]([C:6]=1[C:16]1[CH:17]=[C:18]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:19]=[CH:20][N:21]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: Clc1cc(OCCN2CCOCC2)ncn1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(O)c(-c3cc(OCCN4CCOCC4)ncn3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.2 %

Procedure:
To a solution of 5-cyanooxindole (411 mg, 2.60 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (181 mg, 4.52 mmol, 60% dispersion in oil). After 10 min, a solution of 4-(2-[(6-chloropyrimidin-4-yl)oxy]ethyl )morpholine (367 mg, 1.51 mmol) in N,N-dimethylformamide (1.5 mL) was added dropwise. The mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo, and the residue was suspended in a 2 M aqueous HCl solution and washed twice with ethyl acetate. The aqueous layer was alkalized to pH 8 by adding a 45% aqueous NaOH solution. The obtained suspension was extracted twice with ethyl acetate. The combined phases were washed with brine, dried (Na2SO4) and the solvent was removed in vacuo. The crude product was purified on a silica gel column using chloroform/ethanol, (9:1), to chloroform/methanol, (8:2), as the eluent affording 172 mg (31% yield) of the title compound as a yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.89 (br s, 1 H), 8.62 (s, 1 H), 8.02 (s, 1 H), 7.30 (d, J=7 Hz, 1 H), 6.97 (d, J=8 Hz, 1 H), 6.83 (br s, 1 H), 4.52 (t, J=5 Hz, 2 H), 3.60 (t, J=4 Hz, 4 H), 2.77 (m, 2 H), 2.54 (m, 4 H); MS (TSP) m/z 366 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]2[N:29]=[CH:28][CH:27]=[N:26]2)[C:3]=1[C:4]([N:6]1[C@H:13]2[C@H:8]([CH2:9][CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12]2)[CH2:7]1)=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:13]12[N:6]([C:4]([C:3]3[C:21]([N:25]4[N:26]=[CH:27][CH:28]=[N:29]4)=[CH:22][CH:23]=[CH:24][C:2]=3[F:1])=[O:5])[CH2:7][C@H:8]1[CH2:9][CH2:10][NH:11][CH2:12]2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)c3c(F)cccc3-n3nccn3)[C@@H]2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1c(F)cccc1-n1nccn1)N1C[C@H]2CCNC[C@H]21

Procedure:
To (1S,6R)-tert-butyl 8-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (400 mg, 1.0 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL). After the reaction was judged complete, the volatiles were removed under reduced pressure. The resulting residue was neutralized using 5% Na2CO3(aq) followed by extraction with CH2Cl2 (3×). The combined organics were dried (Na2SO4) and concentrated to give the title compound as an oil that was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH:8]2[CH:4]([CH2:5][CH:6]=[C:7]2[C:9]([OH:11])=[O:10])[CH2:3]1.[N+](=[CH2:14])=[N-]>O1CCCC1>[O:1]=[C:2]1[CH:8]2[CH:4]([CH2:5][CH:6]=[C:7]2[C:9]([O:11][CH3:14])=[O:10])[CH2:3]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C1=CCC2CC(=O)C12
Solvent: C1CCOC1
Product: COC(=O)C1=CCC2CC(=O)C12
Yield: 64 %

Procedure:
A solution of 800 mg of 7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid in 10 mL of tetrahydrofuran was treated at room temperature with ethereal diazomethane. The crude reaction product was purified by chromatographic filtration through 10 g of silica gel (100-200 mesh), eluting with ether petroleum ether, first 2:3 and then 1:1, to afford 560 mg (64%) of methyl 7-oxobicyclo[3.2.0]hept-2-en-2-carboxylate as colorless crystals, mp 58° to 61°. IR (Nujol mull): 1630, 1715, 1790 cm-1 ; NMR (60 MHz, CDCl3): δ 2.5-3.3 (5H, m), 3.75 (3H, s), 4.3-4.6 (1H, m), and 6.90 (1H, broad s). HRMS: Calcd for C9H10O3, 166.0629; found, 166.0633.
Reaction SMILES: [NH2:1][CH:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH:26]2[CH2:28][CH2:27]2)[S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:37](C)=O.[Na+].CC(O)=O>CO.CCOC(C)=O>[CH:26]1([N:12]([CH:9]2[CH2:10][CH2:11][N:6]([C:4](=[O:5])[CH2:3][CH:2]([NH:1][CH3:37])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:7][CH2:8]2)[S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])[CH2:27][CH2:28]1
Reactant: CC(C)CC(N)CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of a compound 46 prepared in Example 30 (0.325 mmol, 150 mg) in methanol (5 mL) was added paraformaldehyde (0.813 mmol, 25 mg), Na(OAc)3BH and a catalytic amount of HOAc at room temperature. The resulting mixture was kept stirred at room temperature overnight. Then EtOAc (20 mL) was added to the mixture and the mixture was washed with saturated NaHCO3 and water. The organic layer was dried over Na2SO4 and concentrated to dryness. The crude product was purified through a column of silica gel with a gradient of 0% to 50% MeOH in DCM to afford the title compound 47. 1H NMR (CDCl3): δ 8.21 (d, J=8.1 Hz, 1H), 8.18 (br s, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.87 (dd, J=7.84, 7.86 Hz, 1H), 4.63 (m, 1H), 4.15 (m, 1H), 3.95 (m, 1H), 3.52 (m, 1H), 3.23 (m, 1H), 2.90-2.55 (m, 3H), 2.70 (d, J=5.4 Hz, 3H), 2.07-1.54 (m, 8H), 1.00 (m, 6H), 0.92 (m, 2H), 0.80 (m, 2H). LC: 100%. MS: 490.2 (M+1).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO.[NH:6]1[CH:10]=[N:9][C:8]([S:11](F)(=[O:13])=[O:12])=[N:7]1>C(O)(=O)C>[CH2:1]([NH:3][S:11]([C:8]1[N:9]=[CH:10][NH:6][N:7]=1)(=[O:13])=[O:12])[CH3:2]
Reactant: O=S(=O)(F)c1nc[nH]n1
Reactant: CCN
Solvent: CC(=O)O
Solvent: CO
Product: CCNS(=O)(=O)c1nc[nH]n1
Temperature: 0 °C

Procedure:
To a solution of ethylamine in methanol (2 M, 2.4 mmol, 4.8 mmol) was added 1H-1,2,4-triazole-3-sulfonyl fluoride (200 mg, 1.18 mmol, J. Heterocycl. Chem. 1988, 25, 1857). After ten minutes the reaction was concentrated in vacuo to give a yellow oil. Ice-cold water (2-3 mL) was added and the resulting solution was sonicated for approximately one minute. Several drops of acetic acid were added which immediately caused precipitation of the title compound which was obtained as a white solid after filtration (57 mg).