Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCCI)C1C=CC=CC=1.[CH2:12]([O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH:35]([CH2:36][O:37]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:34][N:33]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:32][CH:31]2[O:64][CH2:65][C:66]2[CH:75]=[CH:74][C:73]3[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=3)[CH:67]=2)=[CH:26][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:12]([O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH:31]([O:64][CH2:65][C:66]3[CH:75]=[CH:74][C:73]4[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=4)[CH:67]=3)[CH2:32][N:33]([C:57]([O:59][C:60]([CH3:61])([CH3:62])[CH3:63])=[O:58])[CH2:34][CH:35]2[CH2:36][OH:37])=[CH:28][CH:29]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccc(COCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: ICCOCc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(COCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22 (d), from tert-butyl (3RS,4RS,5SR)-1-benzyl-4-(4-bromo-phenyl)-5-hydroxymethyl-piperidin-3-ol [Example 68 (e)] by a palladium catalyzed carbonylation with carbon monoxide in methanol there was obtained methyl (3RS,4RS,5SR)-4-(1-benzyl-3-hydroxy-5-hydroxymethyl-piperidin-4-yl)-benzoate, hydrogenolysis of which in the presence of 5% palladium-charcoal at atmospheric pressure in methanol analogously to Example 2 (e) gave methyl 4-(3-hydroxy-5-hydroxymethyl-piperidin-4-yl)-benzoate. Subsequent introduction of the BOC group analogously to Example 1 (f) yielded tert-butyl (3RS,4RS,5SR)-3-hydroxy-5-hydroxymethyl-4-(4-methoxycarbonyl-phenyl)-piperidine-1-carboxylate, from which by reaction with triphenylchloromethane analogously to Example 68 (i) there was obtained tert-butyl (3RS,4RS,5SR)-3-hydroxy-4-(4-methoxycarbonyl-phenyl)-5-trityloxymethyl-piperidine-1-carboxylate. Subsequent alkylation by means of 2-bromomethyl-naphthalene analogously to Example 1 (g) yielded tert-butyl (3RS,4RS,5SR)-4-(4-methoxycarbonyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, reduction of which with lithium borohydride analogously to Example 22 (e) yielded tert-butyl (3RS,4RS,5SR)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate as a colourless foam; MS: 737 (M+NH4)+. Further alkylation with 2-(benzyloxy)-ethyl iodide [Helv.Chim. Acta Vol.71, (1988), 2039] analogously to Example 1 (g) gave tert-butyl (3RS,4RS,5SR)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, from which after cleavage of the trityl group by means of a mixture of trifluoroacetic acid and trifluoroacetic anhydride in methylene chloride analogously to Example 86 (u) there was obtained tert-butyl (3SR,4RS,5RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 629 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH3:17])[C:13]([NH:18][C:19]([N:21]([CH2:23][CH2:24]O)[CH3:22])=[O:20])=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH3:17])[C:13]([N:18]3[CH2:24][CH2:23][N:21]([CH3:22])[C:19]3=[O:20])=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNc1nc(Nc2ccc(Cl)c(Cl)c2)ncc1NC(=O)N(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(Cl)c(Cl)c2)ncc1N1CCN(C)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg of 2-(3,4-dichlorophenylamino)-4-methylamino-5-[[N-methyl-(2-hydroxyethyl)-amino]carbonylamino]-pyrimidine and 205 mg of triphenylphosphine in 6 ml of tetrahydrofuran are combined with 0.13 ml of diethyl azodicarboxylate and stirred overnight at ambient temperature. The reaction mixture is purified by chromatography through a silica gel column with ethyl acetate/methanol/conc. aqueous ammonia (19:1:0.5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][C:9]#[N:10])=[CH:5][CH:4]=1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][C:9](=[N:14][OH:15])[NH2:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(OCC#N)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OCC(N)=NO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the (4-methoxyphenoxy)acetonitrile product (5.0 g, 31 mmol) from step 1, hydroxylamine hydrochloride (4.3 g, 62 mmol) and sodium acetate (5.1 g, 62 mmol) in MeOH (100 mL) was stirred at r.t. for 2 h. The resulting mixture was filtered on Celite®, concentrated, stirred in CHCl3 for 18 h and filtered. The resulting solution was concentrated to yield (4-methoxyphenoxy)acetamide oxime as a gum.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][C:6](=[O:8])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[CH2:14](O)[CH2:15][OH:16].C(OC(OCC)OCC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCOC(C)=O>[CH2:1]([CH:3]1[CH2:7][C:6]2([O:16][CH2:15][CH2:14][O:8]2)[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)C1CC(=O)CC1CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Solvent: ClCCl
Product: CCOC(=O)C1CC2(CC1CC)OCCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.5 %

Procedure:
A round bottom flask was charged with ethyl 2-ethyl-4-oxocyclopentanecarboxylate (1.5 g, 8.1 mmol, Example #22, Step B) in DCM (22 mL). To the flask were added ethylene glycol (0.91 mL, 16 mmol), triethylorthoformate (2.0 mL, 12 mmol), and p-toluenesulfonic acid monohydrate (0.31 g, 1.6 mmol). The reaction mixture was stirred at rt for about 24 h. The solution was concd under reduced pressure to give brown oil that was dissolved in EtOAc and purified by silica gel chromatography eluting with a gradient of 0-50% EtOAc in heptane. The product containing fractions were combined and concd to dryness under reduced pressure to give ethyl 8-ethyl-1,4-dioxaspiro[4,4]nonane-7-carboxylate as a light yellow oil (1.6 g, 83%): LC/MS (Table 1, Method c) MS m/z 229 (M+H)+; 1H NMR (CDCl) δ 4.14 (q, 2H), 3.90 (m, 4H), 2.99 (q, 1H), 2.32-2.27 (m, 1H), 2.26-2.11 (m, 1H), 2.05-1.99 (m, 1H), 1.96-1.91 (m, 1H), 1.83-1.78 (m, 1H), 1.46-1.39 (m, 1H), 1.31-1.24 (m, 1H), 1.26 (t, 3H), 0.90 (t, 3H).
Reaction SMILES: [ClH:1].[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C([NH:17][C@H:18]([C:23](O)=[O:24])[C@H:19]([CH2:21][CH3:22])[CH3:20])(OC(C)(C)C)=O>>[ClH:1].[NH2:17][C@@H:18]([CH:19]([CH3:20])[CH2:21][CH3:22])[C:23]([N:6]1[CH2:7][CH2:8][C:3]([F:9])([F:2])[CH2:4][CH2:5]1)=[O:24]
Reactant: FC1(F)CCNCC1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CCC(C)[C@H](N)C(=O)N1CCC(F)(F)CC1

Procedure:
(S)-2-amino-1-(4,4-difluoro-piperidin-1-yl)-3-methyl-pentan-1-one hydrochloride was prepared from 4,4-difluoro-piperidine hydrochloride and Boc-(L)-isoleucine as described in Example 1 (mp 190-192° C.).
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:8][C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.C([O:25][C:26](=O)[C:27]([F:30])=[CH:28][O-])C.[Na+]>C(O)C>[F:30][C:27]1[C:26]([OH:25])=[N:16][C:15]([C:7]2[CH:8]=[C:9]([C:10]3[CH:14]=[CH:13][O:12][N:11]=3)[N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=3[F:1])[N:6]=2)=[N:17][CH:28]=1
Reactant: CCOC(=O)C(F)=C[O-]
Reactant: N=C(N)c1cc(-c2ccon2)n(Cc2cccc(F)c2F)n1
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)ncc1F

Procedure:
This was generated via the cyclization of known intermediate 1-(2,3-difluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide (213 mg, 0.702 mmol) with sodium 3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olate (440 mg, 2.81 mmol) in ethanol (5.0 mL)—stirring at 90° C. for 14 hour. The solvent was removed in vacuo, and purification by silica gel chromatography (0-10% methanol in DCM) provided a mixture of the desired compound and a side-product. The mixture was then subjected to reverse-phase preparative HPLC which afforded Compound 93 (15 mg, 7.2% yield) as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:10]([F:13])([F:12])[F:11])[C:3]([F:9])([F:8])[S:4]([O-:7])(=[O:6])=[O:5].[C:14]1([S+:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:33][CH2:34][C:35](Cl)=[O:36].N1C=CC=CC=1>C(#N)C>[Cl:33][CH2:34][C:35]([O:1][CH:2]([C:10]([F:13])([F:11])[F:12])[C:3]([F:8])([F:9])[S:4]([O-:7])(=[O:6])=[O:5])=[O:36].[C:27]1([S+:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Cl)CCl
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(CCl)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
To a mixture of 148 g (0.30 mole) of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate synthesized in Synthesis Example 1-11, 37.3 g (0.33 mole) of chloroacetyl chloride, and 600 g of acetonitrile, 28.5 g (0.36 mole) of pyridine was added dropwise, followed by stirring at room temperature for 3 hours. The reaction solution was then concentrated and combined with 300 g of 5% dilute hydrochloric acid and 600 g of dichloromethane whereupon the organic layer was separated. The organic layer was washed with 300 g of water, from which dichloromethane was distilled off under vacuum. To the residue was added 600 g of methyl isobutyl ketone. This was washed with 300 g of water, with 300 g of dilute aqueous ammonia, and three times with 300 g of water whereupon methyl isobutyl ketone was distilled off under vacuum. The residue was purified by adding ether for recrystallization, filtered and dried. The target compound was obtained as white crystals (158 g, yield 92%).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH3:11])=[CH:10][C:5]2=[N:4][CH:3]=1.Cl.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]3[N:7]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH3:11])=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: CCCCNc1nn2c(Br)cnc2cc1C
Reactant: NCc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CCCCNc1nn2c(-c3ccc(CN)cc3)cnc2cc1C
Temperature: 150 °C

Procedure:
A mixture of (3-bromo-7-methyl-imidazo[1,2-b]pyridazin-6-yl)-butyl-amine (115 mg, 0.41 mmol), (4-aminomethylphenyl)boronic acid hydrochloride (99.9 mg, 0.53 mmol), K2CO3 (170 mg, 1.23 mmol) and dichlorobis(triphenylphosphine)palladium(II) (14.4 mg, 0.021 mmol) in MeCN/water (3.2 ml/0.8 ml) was heated in a microwave at 150° C. for 15 min. The reaction mixture was diluted with MeCN and filtered. The filtrate was subjected to preparative HPLC to give the titled compound as AcOH salt (66.5 mg). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.01 (t, J=7.39 Hz, 3H) 1.42-1.52 (m, 2H) 1.73 (t, J=7.28 Hz, 2H) 2.23 (s, 3H) 3.41 (t, J=7.28 Hz, 2H) 4.16 (s, 2H) 7.44 (s, 1H) 7.52 (d, J=8.38 Hz, 2H) 7.75 (s, 1H) 8.25 (d, J=8.38 Hz, 2H) 8.54 (s, 1H). LRMS (ESI) m/z 310.2 [(M+H)]+, calc'd for C18H23N5: 309.42.
Reaction SMILES: [OH:1][C:2]1[C:14]2[O:13][C:9]3([CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7](=[O:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH:17]([F:19])[F:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:18][CH:17]([F:19])[O:1][C:2]1[C:14]2[O:13][C:9]3([CH2:10][CH2:11][CH2:12]3)[CH2:8][C:7](=[O:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)Cl
Reactant: O=C1CC2(CCC2)Oc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CC2(CCC2)Oc2c(OC(F)F)cccc21

Procedure:
This compound was prepared by difluoromethoxylation of 3,4-Dihydro-8-hydroxy-4-oxo-spiro[2H-1-benzopyran-2,1′-cyclobutane] using chlorodifluoromethane gas in the presence: of potassium carbonate in DMF at 30-80° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C:12]2[C:13]([C:27](O)=[O:28])=[N:14][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:16]=2[CH3:17])[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)[C:12]3[C:13](=[N:14][N:15]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[C:16]=3[CH3:17])[C:27]2=[O:28])[CH:3]=1
Reactant: COc1ccc(Cn2nc(C(=O)O)c(C(Nc3cc(Cl)c(=O)n(C)c3)c3ccc(Cl)cc3)c2C)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Cn2nc3c(c2C)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)(4-chlorophenyl)methyl)-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylic acid (Step 5.4). tR: 4.74 min (HPLC 1); tR; 1.04 min (LC-MS 2); ESI-MS: 509/511 [M+H]+ (LC-MS 2); Rf=0.64 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13](OCC)=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.COCCO[AlH2-]OCCOC.[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][OH:14])[NH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Br)cc2)c[nH]1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1nc(-c2ccc(Br)cc2)c[nH]1
Temperature: 0 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a solution of ethyl 4-(4-bromophenyl)-1H-imidazole-2-carboxylate (1.30 g, 4.40 mmol) in THF (30 mL) was slowly added Red-Al (65 wt % in toluene, 2.0 mL, 6.16 mmol) at −25° C. The reaction mixture was stirred for 4 h at the same temperature then slowly warmed to 0° C. over 1 h and quenched with 20% sodium tartrate solution (30 mL). The reaction was extracted with ethyl acetate (70 mL) and the organic layer was left for 3 h at room temperature. A solid separated and was collected by filtration, washed with ethyl acetate and dried to afford (4-(4-bromophenyl)-1H-imidazol-2-yl)methanol (778 mg, 71.0%). MS (EI) for C10H9BrN2O: 254.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:12][CH:13]=O>C(O)CCC>[N:1]1[CH:12]=[CH:13][N:6]2[C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[S:3][C:2]=12
Reactant: Nc1nc2ccccc2s1
Reactant: O=CCCl
Solvent: CCCCO
Product: c1ccc2c(c1)sc1nccn12

Procedure:
In 250 ml of n-butanol were heated 10.0 g of 2-aminobenzothiazole and 30 ml of 40% chloroacetaldehyde at 90° C. for 27 hours. After the solvent was removed (evaporated to dryness), the residue was crystallized in isopropanol-acetone to give 6.2 g of imidazo[2,1-b]benzothiazole. Subsequently, 4.0 g of the crystals were added to a mixture of 50 ml of dry dimethylformamide and 3.5 ml of phosphorus oxychloride followed by heating at 60° C. for 3 hours and at 75° C. for 6 hours. After completion of the reaction, the reaction mixture was poured onto ice water. After neutralizing with potassium carbonate, the mixture was extracted with ethyl acetate. The ethyl acetate was removed to give 2.2 g of 3-formylimidazo[2,1-b]benzothiazole. The thus obtained formyl compound, 1.3 g, was added to 20 ml of ethanol and furthermore 0.1 g of sodium borohydride was added to the mixture while stirring under ice cooling. After stirring at the same temperature for 10 minutes, the solvent was removed. The residue was treated with water and filtered to give 1.2 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[CH3:21]I>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]=[C:9]1[N:13]([CH3:21])[CH:12]=[CH:11][S:10]1
Reactant: CCOC(=O)C(C)c1ccc(Nc2nccs2)c(F)c1
Reactant: CI
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(N=c2sccn2C)c(F)c1
Yield: 58.5 %

Procedure:
A mixture of ethyl 2-[3-fluoro-4-(N-thiazol-2-ylamino)phenyl]propionate (11.l g), methyl iodide (44.5 ml) and ethanol (44.5 ml) is heated at 50°-55° C for 48 hours. The resultant mixture is treated in the same manner as in Example (1) and (2) to give ethyl 2-[3-fluoro-4-(3-methyl-4-thiazolin -2-ylideneamino)phenyl]propionate (6.8 g). (Yield 58.5 %).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:16].C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH3:37])=[CH:31][C:30]=1[O:38][CH3:39])=[O:27]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:25][C:26](=[O:27])[NH:28][C:29]2[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH3:37])=[CH:31][C:30]=2[O:38][CH3:39])[C:6]1=[O:16]
Reactant: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Reactant: COC(=O)Cn1c(=O)[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)c2ccccc2n(CC(=O)Nc2cc(Cl)c(OC)cc2OC)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid methyl ester (1 g, 4.27 mmol), K2CO3 (910 mg, 6.404 mmol) and 2-bromo-N-(5-chloro-2,4-dimethoxy-phenyl)-acetamide (Intermediate C) (1.42 g, 4.697 mmol) in dry DMF (6 ml) is left to stir at RT overnight. The reaction mixture is diluted with water resulting in a cream precipitate which is filtered, washed with water and dried under vacuum to give the title compound as a pale yellow solid [M+H]+ 462.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:27]([F:30])([F:29])[F:28])=[C:18]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCN(C2N=NC(C(F)(F)F)=C([C:50]3[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=3)C=2)CC1)=O)(C)(C)C.FC1C=CC(B(O)O)=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:27]([F:30])([F:29])[F:28])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:50]4[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=4)=[CH:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(Br)cc3)c(C(F)(F)F)nn2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(F)cc3)c(C(F)(F)F)nn2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: OB(O)c1ccc(F)cc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(-c4ccc(F)cc4)cc3)c(C(F)(F)F)nn2)CC1
Yield: 56 %

Procedure:
A mixture of 4-[5-(4-bromophenyl)-6-trifluoromethyl-pyridazin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.2 g, 0.41 mmol) (prepared by procedures similar to those described for D8), 4-fluorobenzeneboronic acid (0.069 g, 0.49 mmol), trans-Pd(OAc)2(Cy2NH)2 (0.015 g, 0.026 mmol), prepared by following the procedure described in Tao, B.; Boykin, D. W. Tetrahedron Lett. 2003, 44, 7993-7996, and potassium phosphate (0.261 g, 1.23 mmol) in dioxane (3 ml) was stirred at 80° C. overnight. The reaction mixture was then diluted with dichloromethane and extracted with a saturated solution of sodium carbonate. The organic layers were separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was then purified by column chromatography (silica gel; dichloromethane/heptane 3:7 to 10:0). The desired fractions were collected and evaporated in vacuo to yield D12 (0.115 g, 56%). C26H26F4N4O2 requires 502; Found 503 (MH+).
Reaction SMILES: [OH-].[Li+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([O:16]C)=[O:15])=[N:8][CH:9]=1.Cl>CO.O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([OH:16])=[O:15])=[N:8][CH:9]=1
Reactant: COC(=O)[C@H](CCCc1cnc(N)cn1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCc1cnc(N)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
Lithium hydroxide (1.2 g, 28.6 mmol) is added, at 0° C., to a solution of methyl (S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoate (7.75 g, 23.9 mmol) in methanol (60 ml) and water (20 ml). The mixture is allowed to warm to room temperature and stirring is continued for 18 hours. The methanol is evaporated off under reduced pressure and the residue obtained is cooled to 0° C., acidified to pH 3-4 with 1N hydrochloric acid (30 ml), extracted with ethyl acetate (2×200 ml), washed with brine (50 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. 7.17 g of (S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoic acid are obtained in the form of a white powder, which is used without further purification in the following step.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([N:6]1[C@H:10]([C:11]([OH:13])=[O:12])[C@@H:9]([CH3:14])[O:8][CH2:7]1)=[O:5].[OH-:15].[Na+].II>O.C(O)C>[O:15]=[C:4]([N:6]1[C@H:10]([C:11]([OH:13])=[O:12])[C@H:9]([CH3:14])[O:8][CH2:7]1)[CH2:3][CH2:2][S:1][S:1][CH2:2][CH2:3][C:4]([N:6]1[CH:10]([C:11]([OH:13])=[O:12])[CH:9]([CH3:14])[O:8][CH2:7]1)=[O:5]
Reactant: [OH-]
Reactant: C[C@H]1OCN(C(=O)CCS)[C@@H]1C(=O)O
Agent: II
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1OCN(C(=O)CCSSCCC(=O)N2CO[C@@H](C)[C@H]2C(=O)O)C1C(=O)O

Procedure:
(4S-trans)-3-(3-Mercapto-1-oxopropyl)-5-methyl-4-oxazolidinecarboxylic acid from Example 1 is dissolved in water and the pH is adjusted to about 6.5 with 1 N sodium hydroxide. To this stirred solution is added dropwise 0.5 M iodine solution in 95% ethanol (6.34 g., iodine/50 ml. solution) while maintaining the pH at 5.5 to 6.5 with 1 N sodium hydroxide. Excess iodine is removed from the reaction mixture with dilute sodium thiosulfate and the solution is then concentrated, cooled and acidified with 1:1 hydrochloric acid. Solvent is added and the mixture is saturated with sodium chloride, stirred, and the layers separated. The organic layer is dried and the solvent evaporated to yield (S,S)-3,3'-[dithiobis(1-oxo-3,1-propanediyl)]bis[5-methyl-4-oxazolidinecarboxylic acid].
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][CH:12]3[N:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]4=[N:14][C:13]3=[S:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][S:21][C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]2[C:12]=1[CH2:11][C:9]1[C:10]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[S:7][CH:8]=1
Reactant: Cc1cccc2scc(CC3C(=S)N=C4C=CC=CN43)c12
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCSc1nc2ccccn2c1Cc1csc2cccc(C)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 472 mg (1.5 mmol) of 3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-imidazo[1,2-a]pyridine-2-thione and 407 mg (2.3 mmol) of methyl 4-bromobutyrate and 415 mg (3.0 mmol) of potassium carbonate in 5 mL of DMF is stirred at room temperature for 18 h. The mixture is diluted with water and the product is extracted with ethyl acetate. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel eluted with 1˜5% methanol in dichloromethane to give the desired compound.