Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)O.C(N(C(C)C)CC)(C)C.Cl.[CH3:53][O:54][NH:55][CH3:56]>O.CN1C(=O)CCC1>[CH3:53][O:54][N:55]([CH3:56])[C:25]([C:24]1[CH:23]=[N:22][N:10]2[C:11]([CH3:21])([CH3:20])[CH2:12][CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=12)=[O:26]
Reactant: CNOC
Reactant: CC1(C)CC(c2ccccc2)N(Cc2ccccc2)c2c(C(=O)O)cnn21
Agent: CN(C)C(O)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CON(C)C(=O)c1cnn2c1N(Cc1ccccc1)C(c1ccccc1)CC2(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a 5 mL NMP solution containing 0.72 g (1.99 mmol) of 2 was added 0.91 g (2.39 mmol) of O-7-azabenzotriazolo-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) and 0.416 mL (2.39 mmol) of diisopropylethylamine. After stirring for 30 min, 0.233 g (2.39 mmol) of O,N-dimethyl-hydroxylamine hydrochloride was added and the reaction heated to 50° C. After 1 h, the reaction mixture was poured into water and extracted with AcOEt. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a crude oil. Purification of this oil by flash chromatography eluting with a 60 to 50% hexanes/AcOEt gradient gave 0.65 g (81%) of the title compound as a light golden colored solid. 1H NMR (CDCl3) δ 1.37 (s, 3H), 1.56 (s, 3H), 2.06-2.16 (m, 2H), 3.25 (s, 3H), 3.49 (s, 3H), 3.90 (d, J=16.0 Hz, 1H), 4.45 (dd, J=5.1, 11.3 Hz, 1H), 5.06 (d, J=16.2 Hz, 1H), 6.98 (dd, J=1.8, 6.1 Hz, 2H), 7.20-7.24 (m, 3H), 7.30-7.34 (m, 1H), 7.37-7.41 (m, 4H), 7.74 (s, 1H). MS Calcd.: 404. Found: 405 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]>CO.[Pd]>[NH2:13][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([CH2:2][OH:1])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(CO)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)cc(CO)c1
Reaction time: 8 h

Procedure:
Methyl 3-(hydroxymethyl)-5-nitrobenzoate (11.2 g, 53 mmol) in methanol (50 mL) was flushed with nitrogen, and treated with palladium (10% on charcoal, 1.1 g). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography on silica gel (50% ethyl acetate/hexanes) afforded 2.8 g (29%). 1H-NMR (CD3OD, 300 MHz) δ 7.34 (s, 1H), 7.27 (s, 1H), 6.94 (s, 1H), 4.55 (s, 2H), 3.88 (s, 3H). Mass spec.: 182.09 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH:23]=C)[CH:20]=[C:19]([Cl:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH:8]=1)=[O:5].C[OH:27]>C(Cl)Cl>[Cl:25][C:19]1[CH:20]=[C:21]([CH:23]=[O:27])[CH:22]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]2[CH2:17][CH2:18]2)=[O:15])[CH:8]=1)=[O:5]
Reactant: C=Cc1cc(Cl)c(C(=O)Nc2ccnc(NC(=O)C3CC3)c2)c(Cl)c1
Reactant: CO
Solvent: ClCCl
Product: O=Cc1cc(Cl)c(C(=O)Nc2ccnc(NC(=O)C3CC3)c2)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
2,6-dichloro-N-(2-(cyclopropanecarboxamido)pyridin-4-yl)-4-vinylbenzamide (750 mg, 1.99 mmol) was dissolved in a solution of MeOH (14 mL) and DCM (28 mL). The resulting mixture was cooled to −78° C., O3 was bubbled into the solution for 7 min, N2 was bubbled for 10 min, and then Me2S (14 mL) was added. The reaction mixture was slowly warmed to room temperature and stirred for 20 min. The mixture was concentrated under reduced pressure to provide 2,6-dichloro-N-(2-(cyclopropanecarboxamido)pyridin-4-yl)-4-formylbenzamide (0.70 g, yield: 86%). LCMS (ESI) m/z: 378.1 [M+H+].
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].O.[OH-].[CH3:26][N+:27]([CH2:30][CH2:31][OH:32])([CH3:29])[CH3:28].C(O)(C)C>CO.CC(C)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([O-:23])=[O:22])=[CH:4]1)[CH3:2].[CH3:26][N+:27]([CH2:30][CH2:31][OH:32])([CH3:29])[CH3:28]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCn1cc(C(=O)[O-])c(=O)c2cc(F)c(N3CCNCC3)cc21
Temperature: 25 °C

Procedure:
In a round-bottomed 1000 ml. flask 20 g. of 1-ethyl-4-oxo-6-fluoro-7-(piperazinyl)-1,4-dihydro-quinoline-3-carboxylic acid are suspended in a mixture of 150 ml. methanol and 50 ml. distilled water. From a dropping funnel 18 ml. of N,N,N-trimethyl-2-hydroxyethyl-ammonium hydroxide (choline base) dissolved in 50% methanol are added dropvise to the suspension under constant stirring at room temperature. A clear, light yellow solution is obtained. The aqueous-methanolic solution is evaporated above 40% water bath in vacuo. The yellow, adhesive solution thus obtained is suspended in 200 ml of acetone and heated to boiling, then isopropanol (36 ml.) is added dropwise under boiling until total dissolution. The solution is cooled slowly. The precipitated material is filtered under vacuo on a glass filter G-4 and washed. Wet-weight after filtration: 27.4 g.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]#[N:18])=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1.[CH2:19]([C:21]1[CH:26]=[C:25]([O:27][CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([F:36])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1)[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.[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>[CH2:19]([C:21]1[CH:26]=[C:25]([O:27][CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[C:24]([F:36])=[CH:23][C:22]=1[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]#[N:18])=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1)[CH3:20]
Reactant: N#Cc1nn(C2CCCCO2)c2cc(Br)ccc12
Reactant: CCc1cc(OCOCC[Si](C)(C)C)c(F)cc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(OCOCC[Si](C)(C)C)c(F)cc1-c1ccc2c(C#N)nn(C3CCCCO3)c2c1
Temperature: 110 °C
Yield: 81.1 %

Procedure:
To a solution of 6-bromo-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carbonitrile (Preparation 2, 28.5 g, 93 mmol) and 2-[2-ethyl-5-fluoro-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Preparation 5, 73.8 g, 112 mmol) in dioxane (500 mL) was added a solution of potassium phosphate (59.2 g, 279 mmol) in water (120 mL). The mixture was degassed with nitrogen and then tetrakis (triphenylphosphine) palladium(0) (10.8 g, 9.3 mmol) was added. The reaction mixture was heated at 110° C. for 18 hours. The reaction mixture was concentrated in vacuo and the residue was redissolved in EtOAc (1 L) and filtered through Arbocel®, washing with EtOAc (2×500 mL). The combined organic phases were concentrated in vacuo to give a brown oil. The residue was purified by column chromatography on silica gel eluting with 10% EtOAc in heptane to give the title compound as a viscous oil (37.4 g) in an 81% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[N:7]2[C:25](=[O:36])[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1)=O.[C:37]([NH:40][NH2:41])(=[O:39])[CH3:38].Cl>O1CCCC1.O>[C:37]([NH:40][N:41]=[CH:1][C:3]1[CH:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[N:7]2[C:25](=[O:36])[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)NN
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NN=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 82.4 %

Procedure:
In a procedure similar to that described in Example I-3, diphenylmethyl 3-formyl-7-(2-thienylacetamido)-2-cephem-4-carboxylate (104 mg) and acetylhydrazine (30 mg) are left to react in a mixture of tetrahydrofuran (8 ml) and water (1.5 ml) in the presence of hydrochloric acid (2 equivalents) at room temperature overnight to give diphenylmethyl 3-(2-acetylhydrazono)methyl-7-(2-thienylacetamido)-2-cephem-4-carboxylate (95 mg). m.p. 168-178° C (decomposition). Yield: 83%. IR: λmaxNujol 3280, 1760, 1743, 1695, 1667, 1697, 1677, 1538cm-1. UV: λmaxEtOH 301nm(ε=31700). NMR: δCDCl 3 (60MHz) 1.82s3H, 3.82s2H, 5.07d(4Hz)1H, 5.40s1H, 5.50br1H, 6.63br1H, 6.83s1H. 6.88-7.58m15-16H. [α]D23 +416° (c= 0.501, CHCl3).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].[CH3:16][O:17][CH2:18]Cl.[Cl-].[NH4+]>CN(C=O)C.C1COCC1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][O:17][CH3:18]
Reactant: COCCl
Reactant: COc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCOc1ccccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.6 %

Procedure:
Potassium tert-butoxide (67.9 g, 605 mmol) was dissolved in a mixed solvent of DMF (500 mL) and THF (500 mL), then with cooling with ice, 2-methoxyphenol (68.28 g, 550 mmol) was dropwise added. This was stirred at room temperature for 2 hours, and then chloromethyl methyl ether (46 mL, 605 mmol) was added. After stirred for 5 hours at room temperature, aqueous saturated ammonium chloride solution was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline, then dried with sodium sulfate, and concentrated. Purified by silica gel column chromatography, the intended compound (97.66 g, 100%) was obtained as a pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])=[O:9])(=[O:3])[CH3:2].[Cl-].[C:27](OC1C(=CC=CC=1)C(O)=O)(=[O:29])[CH3:28].C(O)COCCOCCOCCO>C(N(CC)CC)C>[C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:28][CH2:27][OH:29])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)OCCOCCOCCO)c(O)c1C(C)=O
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: OCCOCCOCCOCCO
Product: CC(=O)c1ccc(C(=O)OCCOCCOCCOCCO)c(O)c1C(C)=O

Procedure:
The compound (II) was prepared according to the procedure described for the synthesis of triethylenglycol bis-acetylsalicylate (XIX), starting from 2 g of the chloride of acetylsalicylic acid, 0.93 g of tetraethylenglycol and 1.5 ml of trietylamine. The product was purified on silica gel chromatography utilizing an eluent mix constituted by methylene chloride/ethyl acetate 1:1 (v/v). The intermediate fractions were collected, the solvent was evaporated under reduced pressure and 0.6 g of tetraethylenglycol bis-acetylsalicylate (II) were obtained.
Reaction SMILES: I[C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C(O)(C(F)(F)F)=O.C1C(=O)N(I)C(=O)C1>C(#N)C>[O:9]1[C:5]2[CH:4]=[C:3]([S:11][C:12]3[NH:13][C:14]4[C:19]([N:20]=3)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=4)[CH:2]=[CH:10][C:6]=2[CH2:7][CH2:8]1
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3I)CCO4)nc12
Agent: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2[nH]c(Sc3ccc4c(c3)OCC4)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8-(5-iodo-2,3-dihydrobenzofuran-6-ylthio)-9H-purin-6-amine (S6-4) To a solution of S6-3 (40 mg, 0.14 mmol) in 6 mL of acetonitrile was added TFA (40 μL) and NIS (63 mg, 0.28 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (CH2Cl2:MeOH, 100:0 to 90:10) to afford S6-4 (48 mg, 53%) as a yellow gum. 1H NMR (500 MHz, CDCl3) δ 8.26 (s, 1H), 7.79 (s, 1H), 7.12 (s, 1H), 4.65 (t, J=8.8 Hz, 2H), 3.28 (t, J=8.7 Hz, 2H); MS (ESI) m/z 412.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[N+:1]([C:4]1[CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Yield: 73 %

Procedure:
A suspension of 2-nitro-4-bromoaniline (5 g, 23 mmol) in toluene was admixed with 2.8 g (23 mmol) of phenylboronic acid, 9.5 g (0.069 mol) of potassium carbonate and 1.3 g of tetrakis(triphenylphosphine)palladium. The mixture was heated to reflux for 4 hours and the reaction was stopped by adding 100 ml of water. The mixture was extracted with ethyl acetate and dried over sodium sulphate, and the solvent was removed under reduced pressure. Purification by column chromatography gave 3.6 g (73% yield).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].[C:10](Cl)(=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:8]([C:3]1[C:4]([CH3:7])=[N:5][S:6][C:2]=1[NH:1][C:10](=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])#[N:9]
Reactant: Cc1nsc(N)c1C#N
Reactant: CC(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1nsc(NC(=O)CC(C)C)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 5-amino-3-methylisothiazole-4-carbonitrile (method 4) (6.38 g, 45.9 mmol) in pyridine (20 mL) at 0° C., isovaleryl chloride (6.65 g, 55 mmol) was added dropwise. After the completion of the addition the reaction mixture was allowed to warm to r.t. and stirred overnight. The TLC and the MS showed the complete disappearance of the starting material and the reaction mixture was diluted with CHCl3 (200 mL), washed with water (200 mL), 2N HCl (225 mL), satd. NaHCO3 (200 mL), brine (200 mL) and dried over Na2SO4. Concentration of the CHCl3 layer provided the crude product which was triturated from DCM/hexanes ( 1/10) and filtered off to isolate N-(4-cyano-3-methyl-isothiazol-5-yl)-3-methyl-butyramide (8.1 g, 79%) as an off-white crystalline solid. 1H NMR (300 MHz) δ 1.04 (d, 6H), 2.18-2.32 (m, 1H), 2.46 (d, 2H), 2.53 (s, 3H), 9.87 (bs, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1>[Ni].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[CH:13]([OH:14])[CH:12]3[CH2:11][CH2:10][N:9]2[CH2:16][CH2:15]3)[CH:2]=1
Reactant: O=C1C(=Cc2cccnc2)N2CCC1CC2
Agent: [Ni]
Solvent: CO
Product: OC1C2CCN(CC2)C1Cc1cccnc1
Reaction time: 12 h

Procedure:
Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were dissolved in methanol (25 ml) and stirred for 15 mins. Pyridine-3-carboxaldehyde (3.2 g, 29.5 mmol) was then added in one portion and the mixture was stirred for an additional 20 hrs. The reaction mixture was then diluted with 40 ml water and cooled to 0° C. yielding 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was collected, washed with distilled water and dried under vacuum (5.16 g, 81.4%). 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (1.0 g, 4.7 mmol) was combined with 50 ml methanol in a hydrogenation vessel, then wet Raney nickel (5 grams) was added in one portion. Hydrogenation (50 psig) was carried out for 12 hrs., after which time the slurry was carefully filtered through a pad of Celite filter aid. Evaporation of solvent gave 2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-ol as a light yellow oil, which dissolved in ethanol/HCl give a white crystalline solid upon cooling (0.78 g 77%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][C@H:17]([OH:19])[C@H:16]([OH:20])[CH2:15]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1(C)[C@]2(CS(O)(=O)=O)C(C[C@H:23]1CC2)=O.COC(OC)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:15][C@H:16]3[O:20][C:22]([CH3:23])([CH3:21])[O:19][C@H:17]3[CH2:18]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Reactant: O[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)OC
Solvent: CN(C)C=O
Product: CC1(C)O[C@H]2CN(c3cccc(Cc4ccccc4)n3)C[C@H]2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 2.5 g of 2-benzyl-6-(cis-3,4-dihydroxypyrrolidine-1-yl)pyridine, 2.3 g of dl-10-camphorsulfonic acid, 20 ml of 2,2-dimethoxypropane and 5.0 ml of N,N-dimethylformamide was stirred at room temperature overnight. Aqueous saturated sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, and the solvent was removed. Then, the residue was subjected to filtration through silica gel and eluted with ethyl acetate, to give 2.87 g of the target compound.
Reaction SMILES: [CH3:1][N:2]([N:4]=[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])=[C:7]([F:32])[CH2:6]1)[CH3:3].N1CC[CH2:34]1.CC(O)=O>>[N:2]1([N:4]=[C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[CH:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[O:16])=[C:7]([F:32])[CH2:6]2)[CH2:1][CH2:34][CH2:3]1
Reactant: C1CNC1
Reactant: CN(C)N=C1C=CC(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2)=C(F)C1
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cl)cc1)NC(C(=O)NC1=C(F)CC(=NN2CCC2)C=C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
To the thioimidate solution in MeOH (4 mL, 0.284 mmol) from EXAMPLE 33, a pre-mixed azetidine (0.096 mL, 1.43 mmol) and HOAc (0.122 mL, 2.14 mmol) were added. The mixture was then stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give a white powder (24 mg). MS 480.1 and 482.1 (M+H, Cl pattern).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([OH:27])[C:24]([C:28]([OH:30])=[O:29])=[CH:23][N:22]=2)=[CH:17][CH:16]=1>C(N(CC)CC)C.CN(C)C=O.ClCCl>[O:1]=[C:2]1[NH:6][C@H:5]([C:7]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:26]=[C:25]([OH:27])[C:24]([C:28]([OH:30])=[O:29])=[CH:23][N:22]=3)=[CH:19][CH:20]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CC[C@@H](C(=O)Nc2ccc(-c3ncc(C(=O)O)c(O)n3)cc2)N1
Yield: 77708.2 %

Procedure:
A suspension of 12.9 g (0.1 mol) 5-oxo-L-proline, 7.7 ml (0.1 mol) dimethylformamide, and 150 ml of dichloromethane is stirred at 0°-5° C. and 7.3 ml (0.1 mol) of thionyl chloride is added. The reaction mixture is stirred at 0°-5° C. for 1/2 hrs and at room temperature for 2 hrs. After stirring for 20 minutes at room temperature a solution of 11.55 g (0.05 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid, 7.7 ml (0.55 mmol) triethylamine, and 150 ml of dimethylformamide is added and stirred at 0°-5° C. for 1 hr and at room temperature overnight. The reaction mixture is filtered and the solid is washed with dichloromethane, methanol, water, methanol, and ether to give 13.3 g of 2-[4-[(5-oxo-L-prolyl)amino]phenyl]-4-hydroxy-5-pyrimidine carboxylic acid; mp>300° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[O:7][C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][C@@H:13]([SH:18])[C@H:12]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:11]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].IC.[C:34](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6](=[O:31])[O:7][C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][C@@H:13]([S:18][CH3:34])[C@H:12]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:11]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:10]=2[CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC1(CC)c2cc(OC(=O)OC(C)(C)C)ccc2C[C@@H](S)[C@@H]1NC(=O)OC(C)(C)C
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCC1(CC)c2cc(OC(=O)OC(C)(C)C)ccc2C[C@@H](SC)[C@@H]1NC(=O)OC(C)(C)C

Procedure:
To a solution of carbonic acid 7-tert-butoxycarbonylamino-8,8-diethyl-trans-6-mercapto-5,6,7,8-tetrahydro-naphthalen-2-yl ester tert-butyl ester (28.2 mg, 0.062 mmol) in acetone (2 mL) was added the iodomethane (20 μL, 0.31 mmol) and the potassium carbonate (26 mg, 0.18 mmol), and stirred at reflux for 4 h. The mixture was quenched with H2O, diluted with Et2O (50 mL), washed with H2O, brine, dried over MgSO4. The residu was purified by a flash chromatography (10% AcOEt/Hex) (21.2 mg , 73%). 1H NMR (CDCl3): 7.08 (1H, d, J=8.5 Hz, H5), 7.00-6.95 (2H, m, H6 and H8), 4.56 (1H, d, J=11 Hz, NH), 4.09 (1H, t, J=11.0 Hz, CHNH), 3.25-3.00 (3H, m), 2.15 (3H , broad, SCH3), 1.76 (4H, m, CH2), 1.57 (9H, s, t-butyl), 1.50 (9H, s, t-butyl), 0.73 (6H, m, CH3).
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[O:25][CH3:26])[S:17][C:13]=3[C:12](=[O:27])[N:11]([CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[C:10]2=[O:41])=[N:4]1)[CH3:2].[ClH:42]>O1CCOCC1>[ClH:42].[CH2:1]([N:3]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[O:25][CH3:26])[S:17][C:13]=3[C:12](=[O:27])[N:11]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:10]2=[O:41])=[N:4]1)[CH3:2]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl 4-{1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(4-fluoro-2-methoxyphenyl)-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (432 mg, compound B56) in 1,4 dioxane (10 ml) is added a solution of hydrogen chloride in 1,4-dioxane (1.845 ml, 4.0 M). The reaction mixture is stirred for 3 d at RT. All volatiles are evaporated, the residue is treated with DCM and after removal of the solvent under reduced pressure the title compound is obtained as a solid.