Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([NH:11][C:12](=[O:23])[C@@H:13]([NH:15]C(OC(C)(C)C)=O)[CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3](=[O:24])[CH:4]([NH:11][C:12](=[O:23])[C@@H:13]([NH2:15])[CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)C(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C(NC(=O)[C@H](C)N)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.8 %

Procedure:
To a solution of ((S)-2-tert-Butoxycarbonylamino-propionylamino)-pyridin-2-yl-acetic acid methyl ester (337 mg, 1.00 mmol) in dioxane (2 mL) was added 4 N HCl in dioxane (1.00 mL, 4.00 mmol). The reaction was stirred at room temperature for 1 h. Removal of solvents in vacuo provided the title compound ((S)-2-Amino-propionylamino)-pyridin-2-yl-acetic acid methyl ester (270 mg) as a HCl salt, m/z 210.96 [M+1]+
Reaction SMILES: [H][H].[CH3:3][C:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[C:5]=1[CH2:12][CH2:13][CH2:14][CH3:15]>CO.[Pd]>[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:10])([CH3:11])[CH:5]1[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: [H][H]
Reactant: CCCCC1=C(C)CCCC1(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCC1C(C)CCCC1(C)C

Procedure:
18 g Of the mixture of alkenes obtained by dehydration of dihydro-β-ionol as described in example 1 was dissolved in 150 ml of methanol and hydrogenated at atmospheric pressure using 0.5 g of a catalyst consisting of 5% Palladium on charcoal. Hydrogenation was stopped when the uptake of hydrogen markedly slowed down. A 1:1 mixture of 1,3,3-trimethyl-2-(but-1-yl)-cyclohex-1-ene and 1,3,3-trimethyl-2-(but-1-yl)-cyclohexane was obtained. This mixture was oxidized with tert.butyl chromate as described in example 1, yielding a mixture of the title compound and 1,3,3-trimethyl-2-(but-1-yl)-cyclohexane. The mixture was fractionated yielding 6.75 g of the title compound boiling at 90°-92° C. (4 Torr).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH2:27])[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH:21]=1
Reactant: NCc1cccnc1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCc3cccnc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and pyridin-3-ylmethyl amine to afford the title compound. MS: m/e=349 (M+H).
Reaction SMILES: [C:1]([C:3]([CH3:51])([CH3:50])[C:4]1[CH:5]=[C:6]([NH:19][C:20]([NH:22][C@@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@H:26]([O:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([C:40]([N:43]5[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]5[CH3:49])=[N:41][N:42]=4)[CH:39]=3)[CH2:25][CH2:24]2)=[O:21])[N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][OH:18])[CH:10]=2)[N:8]=1)#[N:2].C[C@H]1CCC[C@@H](C)N1C1N2C=C(O[C@H]3C4C(=CC=CC=4)[C@@H](NC(=O)NC4N(C5C=NN(CC[O:95][S:96]([CH3:99])(=O)=[O:97])C=5)N=C(C(C)C)C=4)CC3)C=CC2=NN=1>>[C:1]([C:3]([CH3:50])([CH3:51])[C:4]1[CH:5]=[C:6]([NH:19][C:20]([NH:22][C@@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@H:26]([O:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([C:40]([N:43]5[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]5[CH3:49])=[N:41][N:42]=4)[CH:39]=3)[CH2:25][CH2:24]2)=[O:21])[N:7]([C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[O:15][CH2:16][CH2:17][O:18][S:96]([CH3:99])(=[O:97])=[O:95])[N:8]=1)#[N:2]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C#N)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Reactant: CC(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C#N)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12

Procedure:
The title compound was prepared using Intermediate 20f in an analogous fashion to the procedures described for Intermediate A step e. LCMS (Method 3): Rt 3.64 min, m/z 768.5 [MH+].
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15]>>[O:15]=[C:7]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:10]=2)[NH:6]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=S(=O)(O)Cl
Product: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of chlorosulfonic acid (25 mL, 37.5 mmol) at 0° C. was slowly added oxindole over 40 min. The resulting solution was stirred at RT for 1.5 h and then heated to 50° C. for 10 min until gas evolution ceased. After cooling to RT, the reaction mixture was carefully poured onto ice. A white precipitate was formed which was filtered, washed with ice-water and dried under HV. Yield: 14.35 g (82%). LC/MS (10-99%): M/Z: M+(obs)=232; tR=2.24 min.
Reaction SMILES: [NH2:1][C@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11](OCC)=[O:12])[C:6]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:5]=2[S:4][C@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH3:27]>CO>[NH2:1][C@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([NH2:27])=[O:12])[C:6]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:5]=2[S:4][C@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N
Reactant: CCOC(=O)CN1C(=O)[C@H](N)[C@H](c2ccccc2)Sc2cc(Cl)ccc21
Solvent: CO
Product: NC(=O)CN1C(=O)[C@H](N)[C@H](c2ccccc2)Sc2cc(Cl)ccc21
Reaction time: 8 h

Procedure:
In 220 ml of methanol is dissolved 6.9 g of ethyl cis-3-amino-8-chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, into which ammonia gas is blown to the level of saturation under ice-cooling. The reaction temperature is slowly elevated to room temperature, and the mixture is allowed to stand still overnight. Then, the reaction mixture is concentrated under reduced pressure. The separated crystals are collected by filtration to give 6.2 g of cis-3-amino-8-chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:14])(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)O>C(O)C>[CH3:2][C:1]([O:4][C:12]1[CH:11]=[CH:10][CH:9]=[CH:7][C:6]=1[C:5]([OH:14])=[O:13])=[O:3]
Reactant: CC(=O)O
Reactant: O=C(O)c1ccccc1O
Solvent: CCO
Product: CC(=O)Oc1ccccc1C(=O)O

Procedure:
Desalted egg phosphatides (Hepar) were dissolved in ethanol at a concentration of 250 mg/ml in a 1000 ml flask. To 400 mg of salicylic acid acetate, 1.6 ml of the above solution containing 400 mg of phosphatides was added and the solution adjusted with absolute ethanol to 4 ml. The final concentration of both ingredients in this pharmacological agent-lipid solution was 100 mg/ml. This procedure was performed at about 22.5° C.+/- about 2.5° C. and atmospheric pressure.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[Si:18]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of butane-1,4-diol (180.0 g, 2.0 mol), triethylamine (242.4 g, 2.4 mol) in DCM (1500 mL) was dropwised tert-butylchlorodimethylsilane (306 g, 2.03 mol) in 500 mL DCM, the mixture was stirred for about 1 hr at 0° C., then was warmed at RT for overnight. the reaction was washed with water (500 mL×3) and brine (500×3 mL), dried over Na2SO4 and concentrated to give the desired compound of 4-(tert-butyl dimethylsilyl oxy) butan-1-ol
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:48])[C@@H:24]([NH:25][C:26](=[O:47])[C:27]([C:30]4[N:31]=[C:32]([NH:36][C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])[S:33][C:34]=4[F:35])=[N:28][OH:29])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:51])=[N-]>ClCCl.CCOCC>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:48])[C@@H:24]([NH:25][C:26](=[O:47])[C:27]([C:30]4[N:31]=[C:32]([NH:36][C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])[S:33][C:34]=4[F:35])=[N:28][O:29][CH3:51])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(Nc1nc(C(=NO)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=CCS[C@H]23)c(F)s1)OCc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12)c1nc(NC(=O)OCc2ccccc2)sc1F
Reaction time: 0.5 h

Procedure:
To a solution of 7β-[2-(2-carbobenzoxyamino-5-fluoro-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester (180 mg) in dichloromethane (3 ml) is added a solution of diazomethane in ether until yellow color of the solution does no more fade out. After 30 minutes, the reaction mixture is concentrated to give 7β-[2-(2-carbobenzoxyamino-5-fluoro-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester (153 mg). Similarly prepared are compounds of Table 1.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([CH2:17][CH3:18])[CH2:10][S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].O>CS(C)=O>[O:8]=[C:9]([CH2:17][CH3:18])[CH2:10][S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CCC(O)CSCC(=O)OC
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)CSCC(=O)OC
Reaction time: 1 h

Procedure:
Triethylamine (28.3 ml) is added to a solution of methyl 2-(2-hydroxybutylthio)acetate (6.00 g, Reference compound No. 35-1) in dimethyl sulfoxide (180 ml). A sulfur trioxide-pyridine complex (20.0 g) is added to the mixture, and the whole is stirred for one hour. Water is added to the reaction mixture, and the whole is stirred for 20 minutes and extracted with ethyl acetate. The extract is washed with water, 1 N hydrochloric acid and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (5.93 g).
Reaction SMILES: CI.[CH2:3]([O:10][C:11]1[C:16](=[O:17])[C:15]([CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:14][NH:13][C:12]=1[CH3:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:24](=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[CH2:3]([O:10][C:11]1[C:16](=[O:17])[C:15]([CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]([CH3:24])[C:12]=1[CH3:23])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1[nH]cc(CC(F)(F)F)c(=O)c1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Solvent: ClCCl
Product: Cc1c(OCc2ccccc2)c(=O)c(CC(F)(F)F)cn1C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95 %

Procedure:
Methyl iodide (11 mL, 176 mmol) was added to a suspension of 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (1.18 g, 4.0 mmol) and potassium carbonate (1.06 g, 7.7 mmol) in acetonitrile (25 mL). The resulting mixture was heated to reflux, and the reaction was completed within 40 min. The mixture was cooled to RT, and the solid particulates was filtered off. The filtrate was concentrated in vacuo to give a solid. The solid was taken up in dichloromethane, and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 3-benzyloxy-1,2-dimethyl-5-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as a colorless oil (1.3 g, 95% yield, HPLC Method 1 (Example 24), RT=15.9 min, HPLC purity (peak percent area): 98% at λ=280 nm).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([NH:12][CH2:13][C:14]2[S:18][C:17]([CH3:19])=[N:16][C:15]=2[CH3:20])[C:3]=1[CH3:21].[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH2:32][CH2:33][CH2:34][OH:35].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:35][CH2:34][CH2:33][CH2:32][C:23]2[CH:24]=[CH:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:22]=2)[N:5]=[C:4]([NH:12][CH2:13][C:14]2[S:18][C:17]([CH3:19])=[N:16][C:15]=2[CH3:20])[C:3]=1[CH3:21]
Reactant: Cc1nc(C)c(CNc2nc(S(C)(=O)=O)nc(Cl)c2C)s1
Reactant: OCCCc1ccc2ccccc2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C)c(CNc2nc(OCCCc3ccc4ccccc4n3)nc(Cl)c2C)s1
Reaction time: 2 h

Procedure:
To a solution of 6-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl]-5-methyl-2-methylsulfonyl-pyrimidin-4-amine F5 (51 mg, 0.15 mmol) and 3-(quinolin-2-yl)propan-1-ol G6 (25 mg, 0.13 mmol) in 3 mL of THF was added LiHMDS (200 μL of a 1M solution in THF, 0.20 mmol). After stirring for 2 hours, the reaction was quenched by the addition of a saturated ammonium chloride solution. The mixture was partitioned between a saturated solution of NaHCO3 and EtOAc, the layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated by rotary evaporation. The residue was purified by silica gel flash column chromatography (EtOAc/hexanes gradient) to provide 17 mg (28%) of G7 as an off-white solid. 1H NMR δ (400 MHz, CDCl3): 8.1-8.0 (2H, m), 7.75 (1H, m), 7.65 (1H, m), 7.5 (1H, m), 7.35 (1H, m), 4.9 (1H, m), 4.7 (2H, d), 4.4 (2H, t), 3.15 (2H, t), 2.6 (3H, s), 2.35 (5H, m), 2.0 (3H, s). HRMS (ES) calculated M+H for C23H24ClN5OS: 454.1463. Found. 454.1455.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[C:3]([C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([C:13]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]4[C:14]=3[CH2:15][CH2:16][C@H:17]4[O:23][C:24]3[CH:36]=[CH:35][C:27]4[C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][O:30][C:26]=4[CH:25]=3)=[C:8]([CH3:37])[CH:7]=2)[CH2:2]1>C(OCC)(=O)C.[Pd]>[CH3:12][C:10]1[CH:11]=[C:6]([CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[CH:7]=[C:8]([CH3:37])[C:9]=1[C:13]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]2[C:14]=1[CH2:15][CH2:16][C@H:17]2[O:23][C:24]1[CH:36]=[CH:35][C:27]2[C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][O:30][C:26]=2[CH:25]=1
Reactant: Cc1cc(C2=CCOC2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(C2CCOC2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O

Procedure:
The title compound is prepared from 2-((S)-6-((R)-4-(4-(2,5-dihydrofuran-3-yl)-2,6-dimethylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid by hydrogenation in the presence of palladium (10% on carbon) in ethyl acetate at room temperature. LC (method 9): tR=1.17 min; Mass spectrum (ESI+): m/z=503 [M+H]+.
Reaction SMILES: [CH2:1]1[C@H:8]2[NH:9][C@H:3]([CH2:4][C:5]([CH2:7]2)=[O:6])[CH2:2]1.Cl[C:11]1[N:16]=[CH:15][C:14]([B:17]([OH:19])[OH:18])=[CH:13][N:12]=1>>[O:6]=[C:5]1[CH2:4][CH:3]2[N:9]([C:11]3[N:16]=[CH:15][C:14]([B:17]([OH:19])[OH:18])=[CH:13][N:12]=3)[CH:8]([CH2:1][CH2:2]2)[CH2:7]1
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: O=C1C[C@H]2CC[C@@H](C1)N2
Product: O=C1CC2CCC(C1)N2c1ncc(B(O)O)cn1
Yield: 48.1 %

Procedure:
Prepared from nortropan-3-one (2.00 g, 16.0 mmol) and (2-chloropyrimidin-5-yl)-boronic acid (2.53 g, 16.0 mmol) in accordance with General Method C to give the title compound (1.90 g, 48%) as a pale orange oil. δH (DMSO-d6) 8.93 (s, 2H), 8.70 (s, 2H), 4.95-4.90 (m, 2H), 3.68-3.60 (m, 2H), 2.65-2.59 (m, 2H), 2.35-2.26 (m, 2H), 2.12-2.07 (m, 2H), 1.75-1.68 (m, 2H). LCMS (pH 3): MH+ (248.8), RT 0.87 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][NH:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:21][CH3:22])[N:14]=2)[N:4]=1.BrN1C(=O)CCC1=O>C(#N)C>[CH3:22][O:21][C:15]1[N:16]=[C:17]([O:19][CH3:20])[N:18]=[C:13]([N:12]=[N:11][C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)[N:14]=1
Reactant: COc1nc(NNc2nc(OC)nc(OC)n2)nc(OC)n1
Agent: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1nc(N=Nc2nc(OC)nc(OC)n2)nc(OC)n1
Yield: 77.7 %

Procedure:
The product of Example 1a (7.4 g. 23.8 mmol) was added slowly to a stirred mixture of 20.4 g. (115 mmol) of N-bromosuccinimide and 80 mL of acetonitrile at ambient temperature. A dark orange solution formed after 2 h of stirring. A brown/orange powder was isolated by filtration. After a water-wash, the solid was dried in a desiccator to give 5.7 g (77%) of crude product. Recrystallization from acetic acid gave brick-red needles: mp 228-232° C. (dec); 1H-NMR (d6-DMSO): δ4.060 (—OCH3); (CDCl3) δ(—OCH3); 13C-NMR (CDCl3) δ(—OCH3), 173.8 (C-OMe), 176.4 (C—N═N). Anal. Cacld for C10H12N8: C, 38.96; H, 3.92; N, 36.35. Found: C, 38.78; H, 3.94; N, 36.02.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[N:9]/[S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[N:6][CH:7]=1.[CH3:16][Mg]Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH3:16])=[N:6][CH:7]=1
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(F)cn1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: C[C@@H](NS(=O)C(C)(C)C)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[(1E)-(5-fluoropyridin-2-yl)methylene]-2-methylpropane-2-sulfinamide (52.12 g, 228 mmol) in dichloromethane (1000 mL) at −78° C. was added methylmagnesium bromide (3.0 M in THF; 198 mL, 594 mmol). The mixture was allowed to warm to ambient temperature. After 30 min, the mixture was cooled down to −78° C. and was quenched with saturated aqueous ammonium chloride (100 mL). The mixture was allowed to warm to ambient temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% ethyl acetate) gave the title compound. MS 245 (M+1).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:23][C@H:24]([C:26]([OH:28])=O)[CH3:25])([O:18]C(C)(C)C)=O.[CH2:29]([NH:36][CH2:37]C(OCC)=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:29]([N:36]1[CH2:37][C:16](=[O:18])[NH:23][C@@H:24]([CH3:25])[C:26]1=[O:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.9 %

Procedure:
The title compound was prepared according to the procedure described by John S. Kiely and Stephen R. Priebe in Organic Preparations and Procedures Int., 22 (6), 761-768 (1990). Thus 100 mL of a stock solution of dicyclohexylcarbodiimide in methylene chloride (0.5M) was added to methylene chloride (250 mL). This solution was cooled to 0° C. under nitrogen and Boc-L-alanine (9.46 g, 50.00 mmol) was added. The resulting slurry was stirred for 5 min, and then ethyl N-benzylglycinate (9.37 mL, 50.00 mmol) was added. The reaction was stirred for 2 h at 0° C., then at 20° C. overnight. The precipitate was removed by filtration, and hydrogen chloride gas bubbled through the methylene chloride solution for 2-4 h, until the reaction was shown to be complete by tlc. The solvent was removed in vacuo, and the residue partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate solution (42 mL). The organic phase was washed with saturated sodium chloride, dryed over magnesium sulfate, filtered and evaporated. The crude product was recrystallized from toluene to give the title compound as white crystals (5.88 g). NMR (300 MHz, CDCl3) δ 7.30-7.38 (3H, m), 7.22-7.30 (2H, m), 6.94 (1H, br s), 4.59 (2H, s), 4.14 (1H, q, J=7 Hz), 3.84 (2H, s), 1.52 (3H, d, J=7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]([OH:21])=O)[CH2:14]2)=[CH:9][CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:38][NH:39][O:40][CH3:41].N1C=CC=CC=1.Cl>CN(C)C=O.O>[CH3:41][O:40][N:39]([CH3:38])[C:19]([C@@H:15]1[CH2:16][C:17](=[O:18])[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]3[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=3)=[CH:12][CH:11]=2)[CH2:14]1)=[O:21]
Reactant: CNOC
Reactant: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CON(C)C(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (0.200 g, 0.001 mol) was dissolved in dry N,N-dimethylformamide (1 ml) under argon and the solution cooled to 0° C. 1,1′-Carbonyl-diimidazole (0.108 g, 0.001 mol) was added to the mixture and the reaction stirred for one hour while the temperature rose from 0° C. to room temperature. After the addition of N,O-dimethylhydroxylamine hydrochloride (0.063 g, 0.001 mol) and pyridine (0.053 ml, 0.001 mmol), the reaction was stirred for two hours at room temperature. Water (10 ml) and hydrochloric acid (0.1 N) was added and the mixture extracted with ethyl acetate. The organic phase was washed with a solution of sodium carbonate (1 M) and extracted again with ethyl acetate to yield 0.225 g (99% of theory). The crude product obtained in this way was used in the next step without further purification. MS: m/e=373.4(M+H)+.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:26][C:27]([CH3:30])=[N:28][N:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:31])[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:26][C:27]([CH3:30])=[N:28][N:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:31])[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nnc(C)o4)ccc3C)csc12
Reactant: N
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(C)o4)ccc3C)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-[2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy-methyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.12 g, 0.28 mmol) (from Example 12 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140° C. for 2 hours. The reaction mixture was concentrated. The residue was purified by flash chromatography eluting with 30% ethyl acetate in dichloromethane to give recovered staring material (25 mg) and 4-amino-3-[2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.053 g, 44%). HRMS (ES+) m/z Calcd for C21H20N4O4S+H [(M+H)+]: 425.1278. Found: 425.1274.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:13]([O:14][C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:12][C:11]([N:21]2[C:25](=[O:26])[NH:24][N:23]=[N:22]2)=[C:10]([F:27])[CH:9]=1.Br[CH2:29][CH2:30][CH2:31][F:32]>CN(C)C=O>[Cl:7][C:8]1[C:13]([O:14][C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)=[CH:12][C:11]([N:21]2[C:25](=[O:26])[N:24]([CH2:29][CH2:30][CH2:31][F:32])[N:23]=[N:22]2)=[C:10]([F:27])[CH:9]=1
Reactant: FCCCBr
Reactant: O=c1[nH]nnn1-c1cc(Oc2ncccn2)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCCF)nnn1-c1cc(Oc2ncccn2)c(Cl)cc1F
Temperature: 80 °C
Reaction time: 26 h

Procedure:
A suspension of potassium carbonate (0.36 g), 1-[4-chloro-2-fluoro-5(2-pyrimidyloxy)phenyl]-1,4-dihydro-5-oxo-5H-tetrazole (0.54 g) and 1-bromo-3-fluoropropane (0.37 g) in N,N-dimethylformamide (10 ml) was stirred in an oil bath at 80° C. for 26 hours. The reaction mixture was processed and the resulting oil chromatographed on silica gel eluting with hexane:ethyl acetate, 2:1, to give the product, mp 111-3° C. 1H NMR (CDCl3, TMS): 2.30(2H, m), 4.20(2H, t, J=6.9 Hz), 4.59(2H, dt, J=46.9, 6.6 Hz), 7.13(1H, dd, J=4.8 Hz), 7.48(1H, d, J=9.3 Hz), 7.58(1H, d, J=6.8 Hz), 8.58(2H, d, J=4.8 Hz),