Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:26]1[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=1>>[N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][N:19]=[C:18]([NH:22][C:26]4[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=4)[CH:17]=3)[CH2:12][CH2:11]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N#Cc1cnc(Cl)s1
Reactant: Nc1cc(N2CCN(CCCN3CCOCC3)CC2)ncn1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCN(CCCN4CCOCC4)CC3)ncn2)s1

Procedure:
6-[4-(3-Morpholin-4-ylpropyl)piperazin-1-yl]pyrimidin-4-amine 10-2 (0.317 g, 1.04 mmol), sodium hydride (0.083 g, 2.08 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.15 g, 1.04 mmol) were treated as in Scheme 4 above. The product was purified on a C18 preparative column and isolated via lyophilization. Hi-Res MS: calc: 415.2023 found: 415.2030. 1NMR (CD3OD): 8.48 ppm (s, 1H); 8.02 ppm (s, 1H); 6.27 ppm (s, 1H); 3.94 ppm (m, 6H); 3.43–3.27 ppm (m, 14H); 2.29 ppm (m, 2H).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH2:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@H:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][NH:7]1.C(N(CC)CC)C.C([O:31][C:32](=O)[C:33](OCC)=[O:34])C>C(Cl)(Cl)Cl>[CH3:3][N:4]1[C:32](=[O:31])[C:33](=[O:34])[N:7]2[CH2:8][C@@H:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[C:15]([C@@H:6]2[CH2:5]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CCOC(=O)C(=O)OCC
Reactant: CNC[C@@H]1NC[C@H](c2ccccc2)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1C[C@H]2c3ccccc3[C@H](c3ccccc3)CN2C(=O)C1=O
Yield: 77.4 %

Procedure:
To a stirred solution of cis-1,2,3,4-tetrahydro-1-methylaminomethyl-4-phenylisoquinoline dihydrochloride (30.6 g, 0.094 m) in chloroform (500 ml) maintained under nitrogen at ambient temperature was added triethylamine (42.6 g, 0.42 m) and then in one portion diethyloxalate (30.1 g, 0.206 m) and the mixture heated to reflux for 4 hours. The mixture was cooled and washed with 10% HCl (3×150 ml) and water (150 ml), then dried over MgSO4. The solvent was evaporated to give 22.3 g of cis-1,3,4,6,7,11b-hexahydro-2-methyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline-3,4-dione as a pale yellow solid. An analytical sample, recrystallized from isopropanol, had m.p. 193°-194°.
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13](Cl)[N:14]=[CH:15][C:16]([C:17](=[O:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:11]2[C:10]([CH3:25])=[CH:9]1)=O)(C)(C)C.[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH2:29].CO>C(OCC)C>[C:19]([NH:18][C:17]([C:16]1[C:11]2[C:10]([CH3:25])=[CH:9][NH:8][C:12]=2[C:13]([NH:29][C:28]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:27]=2[F:26])=[N:14][CH:15]=1)=[O:23])([CH3:20])([CH3:21])[CH3:22]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)NC(C)(C)C)c12
Reactant: Nc1ccc(F)cc1F
Solvent: CO
Solvent: CCOCC
Product: Cc1c[nH]c2c(Nc3ccc(F)cc3F)ncc(C(=O)NC(C)(C)C)c12

Procedure:
Prepared in a similar manner to Example 4(d) from 4-tert-butylcarbamoyl-7-chloro-3-methyl-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (68 mg) and using 2,4-difluoroaniline (38 ul) instead of 3-bromoaniline. Isolated by trituration with methanol rather than trituration with diethyl ether to give the title compound (28 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].S(Cl)(Cl)=O.[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:11][C:10]([C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:8])[CH:5]=[CH:6][N:1]=1)=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccnc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: O=C(OCc1ccccc1)c1ccnc(C(=O)OCc2ccccc2)c1

Procedure:
30g of pyridine-2,4-dicarboxylic acid are converted into the acid chloride using 30 ml of thionyl chloride analogously to Example 1 and the acid chloride is reacted with 43.8 g of benzyl alcohol. The product is recrystallized from diisopropyl ether.
Reaction SMILES: Cl.O[C:3]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:7]2=[O:21].[OH-].[Na+]>C(Cl)Cl>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([CH:3]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:7]3=[O:21])=[CH:34][CH:33]=1
Reactant: O=C1c2ccc(C(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc2C(=O)N1Cc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1c2ccc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc2C(=O)N1Cc1cccnc1
Yield: 55.2 %

Procedure:
To 12 ml of conc. hydrochloric acid were added 546 mg of stannous chloride and 352 mg of 5-[hydroxybis(4-chlorophenyl)methyl]-2-(3-pyridylmethyl)-1H-isoindole-1,3-dione, and the resultant mixture was stirred at 70° C. for 1.5 hours. After ice cooling, the reaction mixture was made alkaline with 1N aqueous sodium hydroxide and shaken with methylene chloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate and hexane (1:1) to give 188 mg of the titled compound.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[N+]=[N-].N#N>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])CC1CCCCC1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CN)CC1CCCCC1
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A solution of (S)-tert-butyl 1-azido-3-cyclohexylpropan-2-ylcarbamate (7.2 g, 25.5 mmol) in methanol (250 mL) was added to wetted Pd/C (1.0 g) in a N2-filled Parr bottle. After 3 vac/purge cycles with H2, the vessel was charged to 50 psi and shaken on a Parr apparatus overnight. Theoretical equivalents (36 psi) of H2 were consumed. The reaction mixture was filtered through a pad of Celite and the solvent was removed to give (S)-tert-butyl 1-amino-3-cyclohexylpropan-2-ylcarbamate (5.9 g, 90%) as a white solid. 1H NMR (D6-DMSO) δ 0.70-1.30 (m 10H), 1.38 (s, 9H), 1.58 (d, 2H), 1.80 (d, 1H), 2.66 (m, 1H), 2.78 (d, 1H), 3.74 (m, 1H), 6.77 (d, 1H), 8.0 (bs, 2H). MS ESI+ve m/z 157 (M(−BOC)+1).
Reaction SMILES: CSC1C=CC(C=C([N+]([O-])=O)C)=CC=1.CSC1C=CC([CH2:23][C:24](=[O:26])C)=CC=1.[CH3:27][S:28]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[CH3:27][S:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][C:24](=[O:26])[CH3:23])=[CH:33][CH:32]=1)(=[O:30])=[O:29]
Reactant: CSc1ccc(CC(C)=O)cc1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Agent: CSc1ccc(C=C(C)[N+](=O)[O-])cc1
Product: CC(=O)Cc1ccc(S(C)(=O)=O)cc1

Procedure:
The title compound is prepared by the procedures described in experiments 27a and 27b, replacing 4-methylsulfanyl-benzaldehyde with 4-methanesulfonyl-benzaldehyde (31a).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][CH:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:13][CH:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=2)[CH2:18][CH2:17]1)[CH3:15]
Reactant: CC(C)N1CCNCC1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 5 h
Yield: 89.5 %

Procedure:
To 4-chloro-2-(methyloxy)-1-nitrobenzene (3.0 g, 16.0 mmol) in dioxane (75 mL) was added 1-(1-methylethyl)piperazine (4.1 g, 32.0 mmol), XANTPHOS (1.4 g, 2.4 mmol), and Cs2CO3 (10.4 g, 32.0 mmol). The mixture was bubbled with N2 for 15 min prior to the addition of Pd2(dba)3 (1.5 g, 1.6 mmol). The reaction was stirred at 100° C. for 5 h. Following cooling to rt, the reaction mixture was diluted with EtOAc (150 mL) and H2O (100 mL). The organic layer was dried over NaSO4 taken to a residue under reduced pressure, and purified by silica gel chromatography to afford the title compound of step A (4.0 g, 90% yield). MS (ESI) (M+H)+=280.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6]Cl.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1ccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 321.2 %

Procedure:
A mixture of 2-(trimethylsilyl)ethoxymethyl chloride (11.6 g, 0.07 moles), imidazole (9.5 g, 0.014 moles) and dry toluene (100 ml) was stirred at room temperature for 18 hours, and the resulting imidazole hydrochloride was removed by filtration. The filtrate was concentrated to provide 13.4 g (97%) of crude product. Kugelrohr distillation at 94°-100° C. (0.2 mm) gave 8.92 g (65%) of the desired product as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[O:13][CH:12]([CH3:14])[NH:11][CH2:10]1.[F:21][C:22]([F:34])([F:33])[C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[O:13][CH:12]([CH3:14])[N:11]([S:29]([C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:33])[F:34])=[CH:28][CH:27]=2)(=[O:31])=[O:30])[CH2:10]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC1NCC(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1
Product: CC1OC(Cn2cncn2)(c2ccc(Cl)cc2Cl)CN1S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
Following the general sulfonylation procedure explained in example 1 but using 5-(2,4-dichlorophenyl)-2-methyl-5-[(1H-1,2,4-triazol-1yl]methyl)oxazolidine, obtained according to patent ES 334509/91 and 4-trifluoromethylbenzenesulfonyl chloride, the title product is obtained in similar yield as a single isomer.
Reaction SMILES: O[NH:2]/[C:3](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:4]1\[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[S:8]\1.[H][H].O>C(O)(=O)C.[Pt](=O)=O>[NH2:2]/[C:3](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:4]1\[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[S:8]\1
Reactant: O=C1/C(=C(\NO)c2ccccc2)Sc2ccccc21
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: O
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1

Procedure:
0.5 gm (0.00186 mol) of (E)-2-[(hydroxyamino) phenylmethylene]-benzo[b]thiophen-3(2H)-one, dissolved in 10 cc of glacial acetic acid, was catalytically hydrogenated for 21/2 hours at a hydrogen pressure of 5 bar in the presence of 0.2 gm of platinum(IV) oxide. At the end of the hydrogen uptake, the catalyst-free solution was stirred into 100 cc of water, exhaustively extracted with ether, the combined ether extracts are successively washed with water, saturated aqueous sodium bicarbonate solution and then again with water, followed by drying over sodium sulfate. The crystalline residue left behind after expelling the solvent was recrystallized twice in the presence of activated carbon from a mixture of petroleum ether and ethyl acetate (2:1). 0.37 gm (79% of theory) of egg-yellow crystals, m.p. 121°-122° C., were obtained which, on the basis of the thin-layer chromatogram, mixed melting point and IR spectrum, were found to be identical to the product obtained according to Example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].[Br:9]Br.[OH-].[Na+]>S(=O)(=O)(O)O>[Br:9][C:5]1[CH:4]=[C:3]([CH3:7])[C:2]([CH3:8])=[N:1][CH:6]=1
Reactant: BrBr
Reactant: Cc1cccnc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Br)cnc1C
Temperature: 155 °C

Procedure:
To a solution of 2,3-lutidine (0.51 mL) in fuming sulfuric acid (10 mL) at 155° C. was added bromine (0.3 mL) dropwise over 2 h. The reaction mixture was then heated at 155° C. for 16 h. After cooling to room temperature, the mixture was poured onto ice and the ph adjusted to 10 with aqueous sodium hydroxide solution. The product was extracted into ethylacetate (3×40 mL) and the organic layers were dried (MgSO4), reduced in vacuo and purified on silica to give 5-bromo-2,3-dimethyl-pyridine as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20](F)[CH:19]=2)=[C:15]([CH3:17])[N:16]=1)=[O:10])[CH3:2].[N:30]1(C2C=C(C3SC(N)=NC=3C)C=CC=2S(C)(=O)=O)[CH:34]=[CH:33][N:32]=[CH:31]1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)[CH:19]=2)=[C:15]([CH3:17])[N:16]=1)=[O:10])[CH3:2]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Reactant: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Product: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(-n3ccnc3)c2)s1

Procedure:
The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17](Br)=[CH:18][N:19]=3)[N:16]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:25][O:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+].CC#N>CCOC(C)=O.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].O>[NH2:1][C@@H:2]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([C:32]4[C:27]([O:26][CH3:25])=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:18][N:19]=3)[N:16]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)C[C@H](N)C(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Reactant: COc1ncccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ncccc1-c1cnc2ccc(N3CCN(C(=O)[C@@H](N)CC(C)C)CC3)nn12
Yield: 60.9 %

Procedure:
To 124 mg (0.20 mmol) of (S)-2-amino-1-(4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-4-methylpentan-1-one (di-TFA acid salt) in a microwaveable vial was added 51 mg (0.33 mmol) of the (2-methoxypyridin-3-yl)boronic acid, 110 mg (0.80 mmol) of K2CO3, 31 mg of PdCl2(dppf)2 3 mL of MeCN and 1.5 mL of water. This was microwaved for 0.5 hr at 140° C. It was then diluted with EtOAc, washed with brine, and the organic layer was dried over MgSO4 and concentrated. It was purified on by neutral PREP HPLC to obtain 51.6 mg (61%) of the desired product. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.98-1.10 (m, 6H) 1.60-1.84 (m, 3H) 3.48-3.60 (m, 2H) 3.62-3.81 (m, 5H) 3.94-4.02 (m, 1H) 4.05 (s, 3H) 4.48 (dd, J=9.47, 4.17 Hz, 1H) 7.13 (dd, J=7.45, 4.93 Hz, 1H) 7.27 (d, J=9.85 Hz, 1H) 7.88 (d, J=9.85 Hz, 1H) 8.01 (s, 1H) 8.17 (dd, J=5.05, 1.77 Hz, 1H) 8.51 (s, 2H) 8.66 (dd, J=7.58, 1.77 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: COCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of diethylene glycol monomethylether (12 g, 100 mmol) in pyridine (70 ml) was added p-toluenesulfonyl chloride (22.8 g, 120 mmol) at 0° C., which was then stirred at room temperature for 2 hours. Water was added thereto, and the mixture was extracted with diethyl ether. The extracted organic layer was washed with 0.5N-HCl, water and saturated sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The organic solvent was removed under reduced pressure to give the title compound (27 g, stoichiometric yield) as a yellow oil. The compound thus obtained was used in the next reaction without further purification.
Reaction SMILES: O.NN.[Cl:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][N:12]2C(=O)C3=CC=CC=C3C2=O)=[CH:7][CH:6]=1.O>CCO>[Cl:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ccc(Cl)nc1
Yield: 70.1 %

Procedure:
Hydrazine hydrate (1.7 ml) was added to a refluxing solution of 6.5 g (2.4×10-2 mole) of N-(6-chloro-3-pyridylmethyl)phthalimide in 100 ml of EtOH, and the mixture was further refluxed for 1 hour. After addition of 20 ml of water, the ethanol was distilled off under reduced pressure. Concentrated hydrochloric acid (25 ml) was added to the residue and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was neutralized with NaOH and the aqueous layer was saturated with NaCl and extracted with Et2O. The extract was dried over Na2SO4 and the solvent was distilled off to give 2.4 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH:10]([CH3:17])[CH2:9][NH:8][C:7]=2[N:18]=1.I[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH:10]([CH3:17])[CH2:9][N:8]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[C:7]=2[N:18]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: COc1ccc2c(n1)NCC(C)c1nnc(C)n1-2
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc2c(n1)N(c1ccc(C#N)cc1)CC(C)c1nnc(C)n1-2
Temperature: 110 °C
Reaction time: 12 h
Yield: 3.8 %

Procedure:
To a solution of 8-methoxy-1,4-dimethyl-5,6-dihydro-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepine (50 mg, 0.203 mmol) in toluene (2 mL) was added 4-iodobenzonitrile (94 mg, 0.406 mmol), Bis(dibenzylideneacetone) Palladium (28 mg, 0.03 mmol), 2-dicyclohexylphosphin-2′,6′-dimethoxybiphenyl (25 mg, 0.06 mmol) and cesium carbonate (132 mg, 0.406 mmol). The mixture was purged with N2 and stirred at 110° C. for 12 hours. The reaction mixture was washed with brine (5 mL), and then the mixture was filtered. The filtrate was extracted with acetic ester (10 mL×3), the combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by preparative HPLC (Mobile phase A: water with 0.05% ammonia solution; Mobile phase B: MeCN; column temperature: 30° C., Gradient: 30-60% B 10 min) to give 4-(8-methoxy-1,4-dimethyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (2.7 mg, 31%) as a colorless solid.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[C:10]([C@@H:15]([C@H:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[OH:18])O)([O:12][CH2:13][CH3:14])=[O:11]>>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([CH:7]2[O:18][C@@H:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C@H:15]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:8]2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: Cc1ccc(C=O)cc1
Product: CCOC(=O)[C@@H]1OC(c2ccc(C)cc2)O[C@H]1C(=O)OCC

Procedure:
In a fashion similar to that described in Example 3, p-tolualdehyde was condensed with diethyl L-tartrate to provide (4R,5R)-2-(4-methylphenyl)-4,5-dicarboethoxy-1,3-dioxolane, an oil, GLC analysis: 93%, [α]D25 -9.6° (c,0.1,methanol), 1H-NMR (CDCl3)δ7.47 (2H,d,J=8.0 Hz), 7.18 (2H,d,J=8.0 Hz) 6.12 (1H,s), 4.93 (1H,d,J=4.0 Hz), 4.81 (1H,d,J=7.2 Hz), 4.34-4.22 (4H,2 q, overlapping, J=7.2 Hz), 2.34 (3H, s), 1.35-1.26 (6H 2 t, overlapping, J=7.2 Hz). IR (film) 2980, 1740, 1615 cm-1. MS m/e (% abundance) 308(2), 293(1), 279(1), 235(12), 136(68), 119(100), 105(50), 91(20), 77(8), 43(6).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:6]([C:7]([O-:9])=[O:8])[N:5]2[C:10](=[O:23])[C@@H:11]([NH:12][C:13](=[O:22])[CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:4]2[S:3]1.[K+].O(CC(O)=O)C1C=CC=CC=1.[C:37]1([C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[N+]=[N-])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O.ClCCl>[CH3:1][C:2]1([CH3:24])[CH:6]([C:7]([O:9][CH:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:8])[N:5]2[C:10](=[O:23])[C@@H:11]([NH:12][C:13](=[O:22])[CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:4]2[S:3]1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)[O-]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: O=C(O)COc1ccccc1
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
To a solution of potassium (5R,6R)-2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylate (10 g, 25.7 mM) and phenoxyacetic acid (2 g, 13.1 mM) in water (100 ml) was added a solution of diphenyldiazomethane (5.2 g, 27 mM) in dichloromethane (100 ml). The pH was adjusted to 4.0 and the mixture stirred for 10 minutes. After separation, the solvent was washed with water (100 ml), 5% w/v sodium bicarbonate solution (100 ml) and water (100 ml). The solvent was removed in vacuo to give the title compound (11.4 g).
Reaction SMILES: [Br:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].C([N:9](CC)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.NC1C=CC=CC=1.Cl>C(Cl)Cl>[Br:1][C:2](=[CH2:6])[C:3]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: CCN(CC)c1ccccc1
Reactant: C=C(Br)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: Nc1ccccc1
Product: C=C(Br)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
A vigorously stirred solution of 4.5 grams (0.027 mole) of 2-bromopropenoyl chloride (Step B product) in 150 ml of dried methylene chloride was cooled to 5°±5°. To this was added dropwise 4.0 grams (0.027 mole) of N,N-diethylaniline at such a rate that the reaction mixture temperature did not exceed 10°. Upon completion of addition, 2.5 grams (0.027 mole) of aniline was added dropwise while continuing to maintain the reaction mixture temperature below 10°. The reaction mixture was allowed to warm to ambient temperature where it was stirred for two hours. After dilution with 100 ml of aqueous 1N hydrochloric acid, the reaction mixture was poured into a separatory funnel. The organic layer was separated and extracted with 50 ml of aqueous 1N hydrochloric acid, then with 100 ml of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual solid. The solid was dissolved in methylene chloride and decolorized with silica gel. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual solid. The solid was recrystallized from hexane to give 4.0 grams of 2-bromo-N-phenyl-2-propenamide; mp 90.5°-92.5°.