Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].Cl.[CH3:27][NH:28][O:29][CH3:30]>C(Cl)Cl>[CH3:30][O:29][N:28]([CH3:27])[C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:14]=1[CH3:13]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CNOC
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Carbonyl diimidazole (9.8 g, 60.7 mmol) was added to a solution of 2-methyl-3-nitrobenzoic acid (10 g, 55 mmol) in CH2Cl2 (200 mL) at 0° C. and stirred for 30 min. The reaction mixture was warmed to room temperature, stirred for 2 h, and cooled to 0 C. N,O-dimethylhydroxylamine hydrochloride was added to the reaction mixture at 0 C, stirred for 30 min., and heated to 45 C for 1 h. The reaction mixture was cooled to room temperature, stirred for 12 h, and quenched with aqueous K2CO3 (10%, 200 mL). The reaction mixture was extracted with CH2Cl2 (3×200 mL) and the combined extracts were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash column chromatography (silica, 6:4 hexanes:EtOAc) provided the title compound a white solid (2.6 g, 21%). MS: 225 (MH+); HPLC Rf: 3.96 min. (HPLC method 4); HPLC purity: 98%.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH:13]=[O:14])=[CH:8][C:7]=1[CH3:15]>CO.[OH-].[Na+]>[CH:13]([C:9]1[CH:10]=[C:11]([CH3:12])[C:6]([CH:5]=[CH:4][C:3]([OH:16])=[O:2])=[C:7]([CH3:15])[CH:8]=1)=[O:14]
Reactant: COC(=O)C=Cc1c(C)cc(C=O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C=O)cc(C)c1C=CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 3-(4-formyl-2,6-dimethyl-phenyl)-acrylic acid methyl ester (2.9 g, 13.3 mmol) in methanol (70 mL), 2 N aq. NaOH (35 mL) is added. The suspension is stirred for 30 min at rt. Methanol is evaporated and the aq. solution is extracted twice with DCM. The aq. layer is acidified with 2 N aq. HCl and extracted twice with EA. The combined EA extracts are dried over MgSO4, filtered and evaporated. The crude product is recrystallized from EA to give 3-(4-formyl-2,6-dimethyl-phenyl)-acrylic acid (2.2 g) as pale yellow crystals; LC-MS: tR=0.83 min; 1H NMR (D6-DMSO): δ 12.65 (s br, 1H), 9.92 (s, 1H), 7.66 (d, J=16.4 Hz, 1H), 7.61 (s, 2H), 6.12 (d, J=16.4 Hz, 1H), 2.35 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C@H:15]1[C:19](=O)[O:18][CH2:17][N:16]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[SiH](CC)(CC)CC.ClC(OC(C)(C)C)=O.Cl>C(Cl)Cl.C1COCC1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][CH2:14][C@H:15]([N:16]([CH3:17])[C:21](=[O:22])[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:19][OH:18]
Reactant: O=C1OCN(C(=O)OCc2ccccc2)[C@H]1CCCN1C(=O)c2ccccc2C1=O
Agent: CC(C)(C)OC(=O)Cl
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C(=O)OCc1ccccc1)[C@H](CO)CCCN1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a solution of (S)-benzyl 4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-5-oxooxazolidine-3-carboxylate (11.6 g, 28.40 mmol) in DCM (30.0 mL) was added Et3SiH (13.6 mL, 85.3 mmol). The reaction mixture was stirred overnight. The mixture was concentrated under reduced pressure and dissolved in THF (100 mL). To this THF solution was added tert-butyl chloroformate (4.4 mL, 34.08 mmol) at 0° C. followed by TEA (12.0 mL, 85.2 mmol) and stirred at RT for 30 min. The precipitate was filtered off and the filtrate was added into a NaBH4 suspension in water (1.0 mL) at 0° C., and the mixture was stirred at RT for 30 min. LC/MS indicated the completion of the reaction. The mixture was acidified to pH 3 using HCl (1 N). The aqueous layer was extracted with EtOAc (300 mL×2). The combined organic layer was washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-benzyl 5-(1,3-dioxoisoindolin-2-yl)-1-hydroxypentan-2-yl(methyl)carbamate (5.01 g, 45%). LRMS (M+H+) m/z 397.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(N1CC[O:41][CH2:40][CH2:39]1)C.C(Cl)(=O)C>ClCCl>[C:1]([O:5][C:6](=[O:35])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:40](=[O:41])[CH3:39])=[CH:22][C:21]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:19])=[O:18])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1
Reactant: CCN1CCOCC1
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCc1ccccc1
Temperature: 0 °C
Yield: 100.5 %

Procedure:
A mixture of 11.2 g (21.7 mmol) (S)-3-(4-amino-2-benzyloxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester and 50 mL dichloromethane and cooled to 0° C. in an ice/water bath. 3.2 mL (25 mmol) N-ethylmorpholine was added, followed by dropwise addition of 1.71 mL (24 mmol) acetyl chloride. After 10 min reaction time, TLC analysis showed complete reaction. The mixture was transferred to a separatory funnel and washed with 50 mL water, 50 mL brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 12 g (21.8 mmol, 100%) of (S)-3-(4-acetylamino-2-benzyloxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester as a brown oil. MS (APCI) m/z 549.1 (M−1), 459.1 (M-CH2Ph).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:25])[C:20]([O:22]CC)=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.[F:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:25])[C:20]([NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:27]([F:26])[CH:28]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12
Reactant: Nc1cccc(F)c1
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Product: O=C(Nc1cccc(F)c1)C(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Temperature: 100 °C
Yield: 16.5 %

Procedure:
Prepared from ethyl 2-(3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylamino)-2-oxoacetate (Example 2; 36 mg, 0.10 mmol) and 3-fluoroaniline (139 mg, 1.25 mmol) according to the procedure for Example 3, except the reaction was heated to 100° C. for 18 hours. The product was purified by preparative TLC (1:1 EtOAc/hexanes). The product was obtained as a white powder (7 mg, 6%). 1H NMR (400 MHz, CDCl3+MeOD-d3) δ 8.48 (d, J=6 Hz, 1H), 7.92 (m, 1H), 7.83 (d, J=6 Hz, 1H), 7.67 (m, 1H), 7.57 (d, J=6 Hz, 1H), 7.51 (m, 1H), 7.35 (m, 3H), 6.94 (m, 1H), 6.57 (d, J=6 Hz, 1H). LRMS (ESI pos) m/e 426 (M+1). HPLC: 97% purity (220 nm).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]1([CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH:25]([CH:26]1[N:10]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:2][O:1]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)CNC(CO)c1ccccc1
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1C(c2ccccc2)COC1C(c1ccccc1)c1ccccc1

Procedure:
Scheme 4 and 5 show routes for preparation of compound of formula 2b. The protected amino acid is either commercially available material or prepared as described in known literature. For example, the CBZ protected (2S,3S)-hydroxyleucine (CBZ: benzyloxycarbonyl) is prepared according to the analogous procedure to that described in the literature (Panek, J., J. Org. Chem., 1998, 63, 2382). As shown in scheme 4, phenylglycinol is alkylated with tert-butyl bromoacetate in the presence of base such as triethylamine in a solvent such as anhydrous tetrahydrofuran, to provide tert-butyl (2-hydroxy-1-phenyl-ethylamino)-acetate. Reaction of tert-butyl (2-hydroxy-1-phenyl-ethylamino)-acetate and diphenylacetaldehyde in the presence of a drying agent such as magnesium sulfate in a solvent such as anhydrous methylene chloride provides tert-butyl (2-benzhydryl-4-phenyl-oxazolidin-3-yl)-acetate. The oxazolidine is treated with a nucleophile such as lithium diisopropylamide in an anhydrous solvent such as anhydrous tetrahydrofuran at low temperature such as −78° C., followed by addition of an electrophile such as isopropylaldehyde, to provide tert-butyl 2-(2-benzhydryl-4-phenyl-oxazolidin-3-yl)-3-hydroxy-4-methyl-pentanoate. The oxazolidine ring is cleaved by treatment with acid such as formic acid in a solvent such as a mixture of water and tetrahydrofuran to provide tert-butyl 3-hydroxy-2-(-2-hydroxy-1-phenyl-ethylamino)-4-methyl-pentanoate. The amine is freed by hydrogenolysis using catalyst such as 5-10% palladium on carbon in a solvent such as methanol or ethanol, to provide tert-butyl 2-amino-3-hydroxy-4-methyl-pentanoate. The resulting free amine is protected by treatment with an agent such as (benzyloxycarbonyloxy)succinimide or benzyloxycarbonyl chloride in a solvent such as anhydrous methylene chloride, then the ester is cleaved by treatment with an acid such as trifluoroacetic acid to provide 2-{[(benzyloxy)carbonyl]-amino}-3-hydroxy-4-methylpentanoic acid. Optically pure compound can be prepared by using an optically pure starting material. For example, optically pure (S)-phenylglycinol provides (2S,3S)-2-{[(benzyloxy)carbonyl]-amino}-3-hydroxy-4-methylpentanoic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([O-])=O.O.NN>COCCO>[NH2:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:30]=[CH:31][CH:32]=[C:4]([NH2:1])[CH:5]=3)=[CH:13][CH:12]=2)=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cccc(Oc2ccc(-c3ccc(Oc4cccc([N+](=O)[O-])c4)cc3)cc2)c1
Agent: NN
Solvent: O
Solvent: COCCO
Product: Nc1cccc(Oc2ccc(-c3ccc(Oc4cccc(N)c4)cc3)cc2)c1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
In the next step, a 1 l glass reaction vessel was charged with 100 grams (0.23 mol) of crude 4,4'-bis(3-nitrophenoxy)biphenyl, 10 grams of active carbon, 1 gram of ferric chloride hexahydrate and 500 ml of 2-methoxyethanol. The mixture was stirred for 30 minutes under reflux and then added dropwise with 46 grams (0.92 mol) of hydrazine hydrate during 3 hours at 70°-80° C. The reaction was terminated by stirring for 5 hours at 70°-80° C. after ending the dropwise addition. The reaction mixture was cooled, filtered to remove the catalyst and poured into 500 ml of water. The separated crystals were filtered, added with 48 grams of 35% hydrochloric acid and 540 ml of 50% isopropyl alcohol and warmed. The solution thus obtained was allowed to cool. The separated 4,4'-bis(3-aminophenoxy)biphenyl hydrochloride was filtered, added with 540 ml of 50% isopropyl alcohol and warmed. The solution thus obtained was added with 5 grams of active carbon, filtered and neutralized with aqueous ammonia. The separated crystals were filtered, washed with water and dried to give 72.0 grams (85% yield) of 4,4'-bis(3-aminophenoxy)biphenyl as colorless crystals having a melting point of 144°-146° C. The purity was 99.6% according to high-speed liquid chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[N:27]1[CH:28]=[CH:29][N:30]2[CH2:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[NH:33][CH2:32][C:31]=12>C(Cl)Cl>[N:27]1[CH:28]=[CH:29][N:30]2[CH2:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[N:33]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[CH2:32][C:31]=12
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)Cn1ccnc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.5 ml of triethylamine. After stirring for 3 minutes, 5 mmol of 10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is added. The cooling bath is removed and after about 30 minutes a complete solution is obtained. The reaction mixture is allowed to stir at room temperature for 1 hour and the volatiles are concentrated in vacuo. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, and brine. The solution is dried with Na2 SO4 and the volatiles concentrated in vacuo to give the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)[CH:3]=1.C(N(CC)CC)C.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:13]=2)[CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(N)c(-c2nc(C(F)(F)F)cs2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2CC2)c(-c2nc(C(F)(F)F)cs2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a stirred solution of the product obtained in Step E (0.46 g, 1.8 mmol) and triethylamine (250 μL, 1.8 mmol) in anhydrous tetrahydrofuran (THF, 15 mL) cooled to 0° C. was added dropwise a solution of cyclopropanecarbonyl chloride (160 μL, 1.8 mmol) in THF (5 mL). The mixture was stirred at 0° C. for 30 min and then at room temperature overnight. The reaction mixture was filtered and the solids were washed with ethyl acetate. The filtrate was evaporated to dryness and the residue purified by recrystallization from hexane to yield 0.41 g (71% yield) of the title compound as a white solid melting at 155°-156° C. 1H NMR (400 MHz, CDCl3) δ 11.75 (s,1H), 8.61-8.63 (m,1H), 7.76 (s, 1H), 7.55 (s,1H), 7.26-7.27 (m,1H), 2.37 (s,3H), 1.56-1.62 (m,2H), 1.07-1.13 (m,2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[C:3]1=[N:10][O:11][C:12](=[O:15])[NH:13][CH3:14].C(OO)(=[O:19])C>C(OC(=O)C)C>[CH3:1][C:2]1([CH3:16])[S:6](=[O:19])[C:5]2=[N:7][CH:8]=[CH:9][N:4]2[C:3]1=[N:10][O:11][C:12](=[O:15])[NH:13][CH3:14]
Reactant: CNC(=O)ON=C1n2ccnc2SC1(C)C
Reactant: CC(=O)OO
Solvent: CCOC(C)=O
Product: CNC(=O)ON=C1n2ccnc2S(=O)C1(C)C
Reaction time: 24 h
Yield: 70 %

Procedure:
A 2.0 g (8.32 mmol) quantity of 2,2-dimethyl-3-[O-(methyl carbamoyl)oximino]-2,3-dihydroimidazo[2,1-b]thiazole was dissolved in 300 ml of ethylacetate. The solution was cooled to -15° before 1.33 g (17.5 mmol) of peracetic acid was added. The reaction mixture was allowed to warm to 25° and stirred for 1 d, followed by concentration to ca. 100 ml and placing in the freezer overnight. The precipitate was collected to give 1.5 g (70%) of product. m.p. 147.5°-149°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:10](=[O:12])[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:8]2
Reactant: O=C(O)C(Cc1cccc(Cl)c1)c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: O=C1c2ccc(Cl)cc2CC1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The crude product from Step A was combined with 50 ml of thionyl chloride and then heated at reflux for 2 hours. Thionyl chloride was removed by concentration at reduced pressure and then the mixture was concentrated several times from carbon tetrachloride. The residue was combined with 200 ml of dichloroethane, cooled under nitrogen to 0° C., and 24.5 g of aluminum trichloride was then added. After stirring overnight the reaction was poured onto a mixture of ice in 1N hydrochloric acid, extracted three times with ether and chromatographed on silica gel (10% ethyl acetate/hexane) to afford 18.6 g of a yellow oily solid.
Reaction SMILES: [Na+].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([O-])=[O:13])=[C:5]([N+:15]([O-])=O)[CH:4]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:10][CH2:11][C:12](=[O:13])[NH:15]2)=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc2c(cc1Cl)NC(=O)CN2
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A solution of N-(4'-chloro-5'-methyl-2'-nitrophenyl)glycine sodium salt (0.300 g, 1.23 mmol, as prepared above) and tin (II) chloride dihydrate (0.830 g, 3.68 mmol, Aldrich, used as received) in ethanol (4.0 mL) was refluxed for 30 min. It was then cooled to room temperature and the precipitated solid was filtered, washed with ethanol (1.0 mL) and dried under vacuum to yield 0.160 g (66%) of the title compound as a yellow powder; 1H NMR (DMSO-d6): δ 2.099 (s, 3H), 3.655 (s, 2H), 6.037 (s, 1H), 6.538 (s, 1H), 6.685 (s, 1H), 10.241 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Cl)[C:3]=1[CH:4]=[O:5].[CH3:11][S-:12].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:12][CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cccc(Cl)c1C=O
Temperature: 25 °C

Procedure:
To a solution of 2,6-dichlorobenzaldehyde (20 g, 114.28 mmol) in N,N-dimethylformamide (200 ml), sodium thiomethoxide (8.81 g, 125.7 mmol) was added at 0° C. The reaction mixture was allowed to warm to room temperature overnight, then poured into water. A yellow precipitate was collected by vacuum filtration and dried to afford 2-chloro-6-(methylthio)benzaldehyde (11. g), as a light yellow solid. (This method is general for other 2-haloaldehydes). 1H NMR (300 MHz, CDCl3): 10.6 (s, 1H), 7.4 (t, 1H), 7.2 (dd, 2H), 2.4 ppm (s, 3H). MW=187 confirmed by LC-MS, tr=13.18 min (Method Y) MH+=188.
Reaction SMILES: [SH:1][CH:2]([CH2:5][SH:6])[CH2:3][OH:4].[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])=O.B(F)(F)F.CCOCC>C(Cl)Cl>[SH:6][CH2:5][CH:2]1[CH2:3][O:4][C:10]([CH3:12])([CH2:9][CH2:8][C:7]([O:14][CH2:15][CH3:16])=[O:13])[S:1]1
Reactant: OCC(S)CS
Reactant: CCOC(=O)CCC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CCC1(C)OCC(CS)S1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.2 %

Procedure:
A stirred solution of 2,3-dimercapto-1-propanol (20.0 g, 0.161 mol) and ethyl levulinate (22 g, 0.161 mol) in methylene chloride (600 ml) under a nitrogen atmosphere was treated with boron trifluoride etherate (5 ml). After stirring for 3 days at room temperature, the reaction was quenched by addition of 250 ml of 5% potassium bicarbonate solution. The organic phase was separated and dried over anhydrous sodium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator. The residue was chromatographed on silica gel using 6% ethyl acetate/hexane as eluent to give 17 g (43%) of the title compound as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:8][O:7]1)=[O:5])C.[OH-].[Na+]>O1CCCC1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]2([C:4]([OH:5])=[O:3])[CH2:8][O:7]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1(CCCCCOc2ccc(Cl)cc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C1(CCCCCOc2ccc(Cl)cc2)CO1

Procedure:
2.0 g of 2-[5-(4-chlorophenoxy)pentyl]oxirane-2-carboxylic acid ethyl ester, 6.4 ml of 1 N sodium hydroxide solution and 6.4 ml of tetrahydrofuran are stirred at room temperature until a clear solution has formed (after about one hour). The solution is concentrated to one half of its volume in vacuo and 6.5 ml of 1 N hydrochloric acid are added while cooling with ice. The resulting mixture is extracted 3 times with 20 ml of diethyl ether each time. After drying the combined organic phases over sodium sulfate and evaporating off the solvent 1.65 g of the title compound as a viscous oil are obtained.
Reaction SMILES: [Cl-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)#[N:10].[OH-].[Na+]>C(O)C.O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:10]=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]2[N:2]=1
Reactant: N[n+]1ccccc1
Reactant: N#Cc1ccccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(-c2nc3ccccn3n2)nc1
Reaction time: 72 h
Yield: 36.5 %

Procedure:
To a stirred and cooled solution of N-amino-pyridinium chloride (26.1 g) and 2-cyanopyridine (31.2 g) in ethanol (100 ml) was added a solution of sodium hydroxide (8.0 g) in water (50 ml) over a period of one hour. The mixture was then left at room temperature for 72 hours, after which time the ethanol was removed in vacuo and the residue extracted with chloroform. The chloroform extract was dried and evaporated. The residue, on recrystallisation from acetone, yielded 14.3 g of 2-(2-pyridyl)-s-triazolo[1,5-a]pyridine.
Reaction SMILES: Cl.CC1(C)[O:7][C@@H:6]2[C:8]([CH2:21][O:22]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:9][C@@H:10]([C:11]3[N:15]4[CH:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]4=[N:13][CH:12]=3)[C@@H:5]2[O:4]1>CO>[NH2:20][C:19]1[C:14]2[N:15]([C:11]([C@H:10]3[C@H:5]([OH:4])[C@H:6]([OH:7])[C:8]([CH2:21][OH:22])=[CH:9]3)=[CH:12][N:13]=2)[CH:16]=[CH:17][N:18]=1
Reactant: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C[C@H]2c1cnc2c(N)nccn12
Agent: Cl
Solvent: CO
Product: Nc1nccn2c([C@@H]3C=C(CO)[C@@H](O)[C@H]3O)cnc12
Temperature: 65 °C

Procedure:
Concentrated HCl solution (0.6 mL) was added to 3-((3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)imidazo[1,2-a]pyrazin-8-amine (1-9) (130 mg, 0.239 mmol, 1 equiv) in methanol (3 mL) and heated to 65° C. After 2 hours the mixture was cooled to 23° C. C and purified via reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA present) to afford (1S,2R,5S)-5-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol (1-10) as an amber solid. 1H NMR (500 MHz, CD3OD) δ 8.04 (d, 1H, J=5.5 Hz), 7.62 (s, 1H), 7.24 (d, 1H, J=5.5 Hz), 5.93 (s, 1H), 4.51 (d, 1H, J=5.5 Hz), 4.31 (m, 2H), 4.23 (br m, 1H), 4.10 (t, 1H, J=5.5 Hz). LRMS m/z (M+H) 263.1 found, 263.1 required.
Reaction SMILES: C(C1C=C(N[C:10]2[N:15]=[C:14]([O:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[C:13](F)=[C:12](C)[C:11]=2F)C=CC=1)#N.IC.[H-].[Na+].[C:32](#[N:34])[CH3:33]>>[N:15]1[C:14]([O:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])=[CH:13][CH:12]=[CH:11][C:10]=1[O:16][C:17]1[CH:18]=[CH:19][C:33]([C:32]#[N:34])=[CH:23][CH:24]=1
Reactant: Cc1c(F)c(Nc2cccc(C#N)c2)nc(Oc2cccc(C#N)c2)c1F
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: N#Cc1ccc(Oc2cccc(Oc3cccc(C#N)c3)n2)cc1
Reaction time: 18 h

Procedure:
To 3-[(6-(3-cyanophenyl)amino-3,5-difluoro-4-methylpyridin-2-yl)oxy]-benzonitrile (0.10 g, 0.28 mmol) in acetonitrile (10 mL) was added iodomethane (0.20 g, 1.4 mmol) and sodium hydride (0.055 g, 1.4 mmol). After stirring for 18 hours the reaction was partitioned with water and ethyl acetate. The organic layer was separated, dried (Na2SO4), and the solvent was removed in vacuo. Chromatography of the residue on silica gel with ethyl acetate/hexane (1/3) as eluent gave 3-[(6-(3-cyanophenyl)-methylamino-3,5-difluoro-4-methylpyridin-2-y))oxy]-benzonitrile; NMR (CDCl3) 7.4 (m, 5), 7.25 (m, 1), 7.1 (m, 2), 3.25 (s, 3), 2.3 (s, 3) ppm.