Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC>O>[CH3:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([O:12][CH2:11][C:10]2[CH:20]=[CH:21][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=2)[CH:18]=1
Reactant: C1CCOC1
Reactant: Cc1ccnc(OCc2ccc(Br)cc2)c1
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccnc(OCc2ccc(C=O)cc2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
To a tetrahydrofuran (150 mL) solution of 2-(4-bromo-benzyloxy)4-methyl-pyridine (5.70 g, 20.5 mmol) described in Manufacturing Example 43-1-1 was added dropwise n-butyl lithium (2.67 M n-hexane solution, 9.21 mL, 24.6 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 20 minutes at −78° C. N,N-dimethylfornamide (3.16 mL, 41.0 mmol) was then added dropwise thereto and stirred for 10 minutes at −78° C. The reaction solution was allowed to room temperature, water was added, and the solution was extracted with ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (2.58 g, 55.4%).
Reaction SMILES: ClCCl.[C:4]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(OC(Cl)=O)C(C)C.[C:40](#[N:44])[CH2:41][C:42]#[N:43]>C(N(CC)CC)C>[C:4]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](=[C:41]([C:40]#[N:44])[C:42]#[N:43])[OH:30])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#CCC#N
Reactant: O=C(O)CCCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC(C#N)=C(O)CCCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a dichloromethane solution of 6-(tritylamino)-caproic acid (20.0 g, 53 mmole) and triethylamine (20 mL) in an ice bath was added dropwise over 30 min isobutylchloroformate (8.3 mL, 64 mmole). After the mixture was stirred for 2 hr in an ice bath, freshly distilled malononitrile (4.2 g, 64 mmole) was added all at once. The solution was stirred for 2 hr in an ice bath and for 2 hr at RT. The dichloromethane solution was washed with ice cold 2N HCl (300 mL) and the biphasic mixture was filtered to remove product that precipitated (13.2 g). The phases were separated and the organic layer dried and evaporated to a thick syrup. The syrup was covered with dichloromethane and on standing deposited fine crystals of product. The crystals were filtered and dried to give 6.3 g for a total yield of 19.5 g (87%) of the product, which is useful as an intermediate.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(O[C:14](=O)[CH:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.ClCCl.C(O)C.C(O)(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:14][NH:35][CH2:34][C:33]1[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=1)[CH3:20]
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH3-]C#N
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(CNCc1ccc(F)cc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.8 %

Procedure:
Diisobutylaluminum hydride (39 mL of a 1.0 M solution in toluene, 39 mmol) was added over 5 min to a solution of 2-benzyl-malonic acid diethyl ester (4.82 g, 19.3 mmol) in dichloromethane (45 mL) at −78° C. The reaction mixture was stirred at that temperature for 4 h, and then was quenched with saturated aqueous ammonium chloride (33 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 1.5 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford the crude product (0.96 g, 4.66 mmol, 24%). This material was dissolved in ethanol (20 mL) at 25° C. and 4-fluorobenzylamine (0.532 mL, 4.66 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (0.585 g, 9.31 mmol) were added sequentially. The mixture was stirred at 25° C. for 17 h, and then was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-70% ethyl acetate in hexanes) to afford rac-2-benzyl-3-(4-fluoro-benzylamino)-propionic acid ethyl ester (0.643 g, 2.04 mmol, 44%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.18 (3H, t, J=7.0 Hz), 2.72-2.76 (1H, m), 2.81-3.02 (4H, m), 3.72 (1H, d, J=13.3 Hz), 3.79 (1H, d, J=13.2 Hz), 4.11 (2H, q, J=6.9 Hz), 6.96-7.00 (2H, m), 7.13-7.15 (2H, m), 7.17-7.21 (1H, m), 7.24-7.28 (4H, m).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[CH:8][CH:9]=1)=[O:4].[OH-].[Na+]>CCO>[Cl:32][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][CH2:23][N:13]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:12][CH2:11][CH2:10][C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(CCCN(CCCc2cccc(Cl)c2)S(=O)(=O)c2cccnc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(CCCN(CCCc2cccc(Cl)c2)S(=O)(=O)c2cccnc2)s1

Procedure:
A solution of 5-(3-((3-(3-chloro-phenyl)-propyl)-(pyridine-3-sulfonyl)-amino)-propyl)-thiophene-2-carboxylic acid methyl ester prepared of Example 4, Step B (0.119 g, 0.241 mmol), in 5 mL EtOH and 0.72 mL 1N NaOH was stirred at room temperature overnight. The reaction mixture was adjusted to pH 6.2 and the layers were separated. The organic solution was washed with water, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (16 mg). 1H NMR (400 MHz, CDCl3) δ 8.00 (d, 1H, J=8), 7.70 (d, 1H, J=4), 7.30-7.60 (m, 6H), 6.75 (d, 1, J=4), 3.20 (m, 4H), 2.95 (t, 2H, J=7), 2.60 (t, 2H, J=7), 1.70-2.00 (m, 4H); MS 478 (M+1), 476 (M−1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:40])[CH:22]([O:33]C4CCCCO4)[C:23]4[N:24]=[C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[S:26][CH:27]=4)[C:18](=[O:41])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.C(O)C.Cl.C(=O)(O)[O-].[Na+]>O>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:40])[CH:22]([OH:33])[C:23]4[N:24]=[C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[S:26][CH:27]=4)[C:18](=[O:41])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(OC3CCCCO3)c3csc(NS(C)(=O)=O)n3)[C@H]2SC1
Agent: Cl
Agent: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(OC3CCCCO3)c3csc(=NS(C)(=O)=O)[nH]3)[C@H]2SC1
Agent: O=C([O-])O
Solvent: CCO
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3csc(NS(C)(=O)=O)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (0.85 g.), ethanol (15 ml.), water (5 ml.) and 2 N hydrochloric acid (5 ml.) was stirred for 2.5 hours at room temperature. After the reaction, the reaction mixture was diluted with water (20 ml.), adjusted to pH 8 with 5% sodium bicarbonate aqueous solution and then washed with diethyl ether. Thus obtained aqueous layer was adjusted to pH 4 to 5 with 10% hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 1 to 2 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off from the extract, and the residue was washed in diethyl ether, collected by filtration and then dried to give pale brown powder of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (0.2 g.), mp. 120° to 146° C. (dec.).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[Cl:23][C:18]1[CH:17]=[C:16]([CH:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][CH:6]([CH2:4][OH:3])[CH2:15]2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: CCOC(=O)C1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
A solution of 10 (2.55 g, 7.3 mmol) in THF (40 ml) was added dropwise to a stirring mixture of LiAlH4 (0.304 g, 8.0 mmol) in THF (20 ml) at 0° C. The resulting suspension was stirred at room temperature for 3 hours, then, the mixture was cooled to 0° C., and water (0.15 ml) was added dropwise to destroy the excess hydride. The mixture was filtered, and the solvent was evaporated in vacuo to give colorless oil. The residue was purified by chromatography, CombiFlash silica gel column, MeOH/CH2Cl2, MeOH from 0% to 3%, to give 11 as a clear oil (mixture of cis and trans diastereomers, 1.80 g, 80%). 1H NMR (CDCl3) δ 1.31-1.54 (m, 1H), 1.92-1.98 (m, 2H), 2.10-2.26 (m, 1H), 2.54-2.71 (m, 1H), 2.92-3.03 (m, 1H), 3.53-3.75 (m, 2H), 4.07 (dd, J=12 Hz, 5.2 Hz) and 4.25 (t, J=3.6 Hz, total 1 H), 6.72-7.38 (m, 7H). 13C NMR (CDCl3) δ 32.0, 32.5, 33.4, 34.6, 37.5, 37.6, 43.3, 46.3, 67.5, 67.9, 126.3, 126.4, 126.6, 127.0, 128.4, 128.5, 129.5, 129.7, 130.2, 130.5, 130.7, 130.9, 132.4, 132.7, 136.7, 136.9, 138.8, 147.5, 147.9.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]2[C:5](=[C:6]([C:15]([F:18])([F:17])[F:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[N+:21]([CH:24]([CH3:26])[CH3:25])([O-:23])=[O:22]>C(Cl)Cl>[N+:21]([C:24]([CH:13]([C:11]1[C:10]2[C:5](=[C:6]([C:15]([F:18])([F:16])[F:17])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:19])([F:1])[F:20])[CH:12]=1)[OH:14])([CH3:26])[CH3:25])([O-:23])=[O:22]
Reactant: CC(C)[N+](=O)[O-]
Reactant: O=Cc1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Solvent: ClCCl
Product: CC(C)(C(O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 43.1 %

Procedure:
A mixture of 2,8-bis(trifluoromethyl)-4-quinolinecarboxaldehyde (200 mg, 0.85 mmol), 2-nitropropane (0.1 mL, 1.1 mmol) and Amberlyst 21 resin (200 mg) was stirred at room temperature for 17 h, treated with CH2Cl2 (3 mL), filtered to remove the resin, the filtrate concentrated in vacuo to give a viscous oil which was crystallised from heptane to give a white solid which was recrystallised (ether/heptane) to give the product (140 mg, 51%) as a white crystalline solid: IR νmax (Nujol)/cm−1 3484, 2923, 1544, 1311, 1134 and 780; NMR δH (400 MHz, CDCl3) 1.37 (3H, s), 1.54 (3H, s), 3.03 (1H, d, J 4.5 Hz),6.36 (1H, d, J 4.4 Hz), 7.80 (1H, t, J 8.1 Hz), 8.07 (1H, s), 8.21 (1H, d, J 7.1 Hz) and 8.44 (1H, d, J 8.5 Hz).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:17]1[N:21]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[C:20]2[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:19]=2[N:18]=1)[CH3:16])(C)(C)C>C(Cl)Cl>[F:32][C:29]1[CH:30]=[CH:31][C:19]2[N:18]=[C:17]([C@@H:15]([NH2:14])[CH3:16])[N:21]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)[C:20]=2[CH:28]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
TFA (10 mL) was added to a solution of {(S)-1-[6-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (0.268 g, 0.75 mmol) in DCM (5 mL) and stirred for 15 minutes. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM (×3) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) to give the title compound as an oil (0.113 g, 59%). LCMS (Method C): RT 1.72 min [M+H]+ 260.1
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].[CH:15]([OH:18])([CH3:17])[CH3:16].C(N(CC)CC)C.S(Cl)(Cl)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOCC>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:18][CH:15]([CH3:17])[CH3:16])(=[O:11])=[O:10]
Reactant: CC(C)O
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)OS(=O)(=O)c1ccccc1C(F)(F)F
Reaction time: 3 h
Yield: 86.8 %

Procedure:
A solution of 6.2 g of 2-trifluoromethylbenzenesulfonyl chloride and 0.3 g of 4-dimethylaminopyridine in 30 mL of methylene chloride was cooled to 5° C. A solution of 2.2 g isopropanol and 3.7 g of triethylamine in 20 mL of methylene chloride was prepared and added dropwise to the solution of the sulfonyl chloride. The reaction mixture was returned to room temperature and allowed to stir for 3 hours. The mixture was treated with 200 mL of ether and washed with 60 mL of water. After removal of solvent in vacuo, 5.9 g of isopropyl 2-trifluoromethylbenzenesulfonate was isolated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31]1(/[CH:37]=[CH:38]/[C:39]([NH2:41])=[O:40])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[CH3:30][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2](/[C:37](/[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:38]\[C:39]([NH2:41])=[O:40])[CH:7]=[CH:6][CH:5]=2)[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Reactant: NC(=O)/C=C/c1ccccc1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(/C(=C\C(N)=O)c5ccccc5)c4)n3n2)cc(OC)c1OC
Temperature: 110 °C
Yield: 19.7 %

Procedure:
To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (40 mg, 0.085 mmol), (2E)-3-phenylprop-2-enamide (15.0 mg, 0.10 mmol), tetrakis(triphenylphosphine) palladium (0) (5.0 mg, 0.004 mmol) and potassium carbonate (17.6 mg, 0.127 mmol) was added 1,4-dioxane (1.0 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 110° C. for 20 minutes. Analysis by LCMS indicated that no reaction occurred. To the mixture was added diisopropylethylamine (0.044 mL, 0.255 mmol), Combiphos catalyst POPd (Dihydrogen dichlorobis(di-tert-butylphosphinito-κP)palladate(2-)) (5.0 mg, 0.01 mmol) and tetrabutylammonium bromide (5.0 mg, 0.015 mmol) and heated with microwave radiation at 130° C. for 70 minutes. After cooling to room temperature, removed solvent under reduced pressure, dissolved residue in methanol (25 mL), and added silica gel (200 mg). Following evaporation of the volatiles under reduced pressure, the pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethylacetate:methanol (100:0 to 80:20) using a RediSep silica gel cartridge (4.2 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give a gold oil. Added diethyl ether (15 mL) to precipitate, and vacuum filtered to give (2Z)-3-(3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)-3-phenylprop-2-enamide (0.009 g) as a yellow solid. 1H NMR (CDCl3): δ8.80 (s, 1H), 8.48-8.46 (m, 1H), 7.40-7.28 (m, 7H), 7.17-7.15 (m, 1H), 7.02 (s, 1H), 6.89-6.86 (m, 2H), 6.44 (m, 1H), 5.34 (s, 2H), 3.83-3.79 (m, 9H), 2.60-2.57 (m, 3H). MS m/z 537 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:22])[C:20]=2[CH3:21])=[C:17](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-:36].[K+]>C1COCC1>[C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:22])[C:20]=2[CH3:21])=[C:17]([F:36])[CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc3oc(SCc4ccc(C(C)(C)C)cc4)c(C)c(=O)c23)cc1
Reactant: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(SCc2ccc(C(C)(C)C)cc2)oc2cccc(F)c2c1=O
Temperature: 25 °C

Procedure:
2-(4-tertbutylbenzylmercapto)-3-methyl-5-tosyloxy chromen-4-one (200 mg, 0.39 mmol) is dissolved in THF in a 15 mL round bottom flask and potassium fluoride (0.39 mmol) and Kryptofix (0.39 mmol) are added to it. The solution is heated to reflux for 3 hours after which it is cooled to room temperature. The reaction mixture is then concentrated and the crude residue obtained is purified by silica gel flash chromatography to obtain the above product.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[C@@H:10]([CH3:28])[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24](=[O:25])[C:23]2[N:22]([CH3:26])[CH:21]=[N:20][C:19]=2[N:18]([CH3:27])[C:16]1=[O:17])(=O)=O.O>CS(C)=O>[N:1]([C@H:10]([CH3:28])[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24](=[O:25])[C:23]2[N:22]([CH3:26])[CH:21]=[N:20][C:19]=2[N:18]([CH3:27])[C:16]1=[O:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)N=[N+]=[N-]
Temperature: 50 °C
Reaction time: 12 h
Yield: 78.8 %

Procedure:
Sodium azide (7.11 g, 0.1 mol) was added to a solution of (S)-1-(5-methanesulfonyloxyhexyl)-3,7-dimethylxanthine (19.6 g, 54 mmol) in dimethylsulfoxide (100 ml) and stirred at 50° C. for 12 hours. The mixture was treated with water (200 ml) and extracted with ethyl acetate (3x 100 ml). The combined extracts were washed with water (125 ml), with saturated aqueous sodium chloride solution (150 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to give (R)-1-(5-azidohexyl)-3,7-dimethylxanthine (13 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH2:10][CH:9]1[C:27](=[O:38])[NH:28][CH2:29][C:30]1[O:31][CH:32]=[C:33]([OH:37])[C:34](=[O:36])[CH:35]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)CC)C>C(#N)C>[C:39]([O:37][C:33]1[C:34](=[O:36])[CH:35]=[C:30]([CH2:29][NH:28][C:27]([CH:9]2[CH2:10][N:11]([S:14]([C:17]3[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=4)(=[O:16])=[O:15])[CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:38])[O:31][CH:32]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1C(=O)NCc1cc(=O)c(O)co1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Oc1coc(CNC(=O)C2CN(S(=O)(=O)c3cc4cc(Cl)ccc4[nH]3)CCN2C(=O)OC(C)(C)C)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In acetonitrile (10 ml) was dissolved 1-(tert-butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]-2-[N-[(5-hydroxy-4-oxo-4H-pyran-2-yl)methyl]carbamoyl]piperazine (411 mg), followed by the addition of acetic anhydride (0.075 ml) and triethylamine (0.11 ml). The resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. Methylene chloride was added to the residue. The resulting mixture was washed successively with 0.2N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated aqueous NaCl solution. The organic layer was then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (methylene chloride:methanol=50:5), whereby the title compound (256 mg) was obtained as a colorless foam.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:22])[C:13]1[CH:21]=[CH:20][CH:19]=[C:15]([C:16](Cl)=O)[CH:14]=1>CC(N(C)C)=O>[C:13]1([C:12]2[O:22][C:6]([C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)[CH:21]=[CH:20][CH:19]=[C:15]([C:16]2[O:7][C:6]([C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)[CH:14]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Solvent: CC(=O)N(C)C
Product: Oc1ccc(-c2nnc(-c3cccc(-c4nnc(-c5ccc(O)cc5)o4)c3)o2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
Into a 250 ml three neck round bottom flask equipped with a magnetic stirbar, thermometer, addition funnel, and glass stopper is placed 4-hydroxybenzoic hydrazide (6.0 g, 0.039 mol) and dry DMAc (90 ml). After the solid dissolves the solution is cooled to approximately 0° C. via an ice water bath. A solution of isophthaloyl chloride (4.0 g, 0.0195 mol) in dry DMAc (30 ml) is placed in the addition funnel. The isophthaloyl chloride solution is added dropwise over approximately one hour while maintaining the reaction temperature between 0° and 5° C. After the entire solution has been added, the ice bath is removed and the solution is allowed to warm to room temperature, stirring is continued for 16 hours. The DMAc solution is poured into ice/water to give a white precipitate which is collected by filtration and subsequently dried at 70° C. under vacuum. Yield 7.1 g (76%) of the intermediate dihydrazide, m.p. 298° C. (DTA). The intermediate dihydrazide (6.0 g) is placed in a vacuum oven and heated to 280° C. for approximately 4 hours to achieve cyclodehydration to the oxadiazole. The solid is pulverized and washed in hot ethanol to yield a yellow solid (4.3 g, 85%) m.p. greater than 400° C. The solid is used without further purification.