Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.OS(O)(=O)=O.[OH-].[Na+]>CC(O)=O.O>[F:10][C:11]1[CH:18]=[CH:17][C:14](/[CH:15]=[CH:2]/[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(/C=C/c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.1 %

Procedure:
A mixture of acetophenone (7.02 gm, 58.4 mmol), p-fluorobenzaldehyde (7.24 gm, 58.4 mmol) and concentrated H2SO4 (10 ml) in glacial HOAc (116 ml) was stirred at room temperature for 2 days. The solution was poured into H2O (250 ml) and neutralized with 10% NaOH (200 ml). The aqueous layer was extracted once with Et2O and the Et2O layer was washed successively with H2O, saturated NaHCO3 (2×) and brine, then dried (MgSO4). Filtration and removal of the solvent afforded a yellow solid which was recrystallized from hot hexane to give (E)-3-(4-fluorophenyl)-1-phenyl-2-propen-1-one (7.94 gm, 60%) as light yellow needles.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:11](=[O:13])[C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 73.7 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.252 g, 1.26 mmol) were, used to afford 0.5 g of the required product. 1H NMR (DMSO-d6): δ 1.40 (9H, s), 1.75 (2H, m), 2.82 (2H, m), 3.18 (2H, d), 3.92 (3H, m), 7.25 (5H, m), 7.54 (2H, d), 7.88 (4H, d), 38 (1H, brs).
Reaction SMILES: [C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(/[CH:10]=[CH:11]/[CH2:12][N:13]2[CH2:18][CH2:17][C:16]([C:25]([O:27]CC)=[O:26])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[ClH:38]>CO>[ClH:38].[C:30]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(/[CH:10]=[CH:11]/[CH2:12][N:13]2[CH2:14][CH2:15][C:16]([C:25]([OH:27])=[O:26])([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)[C:8]#[N:9])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C1(c2ccccc2)CCN(C/C=C/C(C#N)(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC(/C=C/CN1CCC(C(=O)O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 1.0 part 2,2-diphenyl-5-(4-ethoxycarbonyl-4-phenylpiperidino)-3-trans-pentenenitrile, 2.5 parts sodium hydroxide and 4.2 parts methanol is heated for 16 hours at reflux. Then, the solution is cooled and stripped in vacuo. The residue is suspended in ice-cold water, treated with excess aqueous hydrochloric acid, and extracted three times with portions of methylene chloride, resulting in a fine solid at the interface. This solid is collected by filtration, washed with water, air-dried and recrystallized from a methanolether mixture to afford 2,2-diphenyl-5-(4-carboxy-4-phenylpiperidino)-3-trans-pentenenitrile hydrochloride. This compound melts at about 266°-268° C. with gas evolution and is represented by the following structural formula. ##STR6##
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]([OH:15])=O)=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH:57]1[C:65]2[C:60](=[C:61]([CH2:66][NH2:67])[CH:62]=[CH:63][CH:64]=2)[CH:59]=[N:58]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:15])[NH:67][CH2:66][C:61]2[CH:62]=[CH:63][CH:64]=[C:65]3[C:60]=2[CH:59]=[N:58][NH:57]3)=[CH:8][C:9]=1[CH:10]([CH3:11])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1C(C)C
Reactant: NCc1cccc2[nH]ncc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.5 %

Procedure:
To a solution of 3-Isopropyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (190 mg, 0.83 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.35 mL, 2.49 mmol), HBTU (0.38 g, 1.0 mmol), HOBT (0.14 mg, 1.0 mmol), and C-(1H-Indazol-4-yl)-methylamine (180 mg, 1.25 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 30-100% EtOAc in hexane to afford the desired product (0.1262 g, 42% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][NH2:19])=O.Cl.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]2[N:4]([C:16]([C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=3[F:13])=[N:18][N:19]=2)[N:3]=1
Reactant: CC(C)(C)c1cc(Cl)nnc1Cl
Reactant: NNC(=O)c1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)c1cc2nnc(-c3ccccc3F)n2nc1Cl
Yield: 43.8 %

Procedure:
A mixture of 3,6-dichloro-4-(1,1-dimethylethyl)pyridazine (20 g, 0.097 mol), 2-fluorobenzhydrazide (22.6 g, 0.145 mol) and triethylamine hydrochloride (20 g, 0.0145 mol) in dioxan (1.2 l) was stirred and heated at reflux under a stream of nitrogen for 4 days. Upon cooling the volatiles were removed in vacuo and the residue was triturated with dichloromethane (200 ml), filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel eluting with 0%→25% ethyl acetate/dichloromethane to give the title compound (12.95 g. 44%) as a white solid. Data for the title compound: 1H NMR (360 MHz, CDCl3) δ1.57 (9H, s), 7.26-7.35 (2H, m), 7.53-7.60 (1H, m), 7.89-7.93 (1H, m), 8.17 (1H, s); MS (ES+) m/e 305 [MH]+, 307 [MH]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[NH:18][CH2:17][CH:14]1[CH2:16][CH2:15]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: NCC1CC1
Product: CCOC(=O)c1cnc(Cl)cc1NCC1CC1

Procedure:
From 4,6-dichloropyridine-3-carboxylic acid ethyl ester synthesized according to the method described in US2006/0217417 and cyclopropylmethylamine in a manner similar to Example 339, the title compound was obtained as a slight yellow crystalline powder (yield 77%).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:29][C:30]1[CH:31]=[CH:32][C:33]2[C:39](=O)[CH2:38][CH2:37][CH2:36][O:35][C:34]=2[CH:41]=1>C1COCC1>[Br:29][C:30]1[CH:31]=[CH:32][C:33]2[C:39](=[CH:2][O:3][CH3:4])[CH2:38][CH2:37][CH2:36][O:35][C:34]=2[CH:41]=1
Reactant: O=C1CCCOc2cc(Br)ccc21
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=C1CCCOc2cc(Br)ccc21
Temperature: -75 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
14.27 g (1.6 eq.) of (methoxymethyl)triphenylphosphonium chloride was suspended in 50 ml of abs. THF and deprotonated at a temperature of −10° C. and −5° C. by adding via syringe 25.2 ml of 1.6 M n-butyllithium (1.55 eq., in hexane). The resultant red ylide solution was cooled to −75° C. and treated with 6.20 g (26.0 mmol) of 8-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one dissolved in 13 ml of abs. THF. The mixture was then kept for 0.2 h at −78° C. and for 1 h at room temperature, poured onto crushed ice and extracted with diethylether. The organic phase was washed with water and dried over magnesium sulfate, filtrated and the solvent evaporated to yield a crude product which was purified by flash chromatography (SiO2, hexane/ethylacetate=95/5). Thereby, 5.85 g of 8-bromo-5-methoxymethylene-2,3,4,5-tetrahydrobenzo[b]oxepine was obtained as E/Z-mixture which was hydrolyzed as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH2:19][CH:20]([OH:23])[CH2:21][OH:22])=[CH:17][C:16]([O:24][CH3:25])=[C:15]2[C:10]=1[CH:11]1[CH2:27][CH2:26][CH:14]2[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH3:38][C:28]1[CH:33]=[CH:32][C:31]([S:34]([O:22][CH2:21][CH:20]([OH:23])[CH2:19][C:18]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]3[C:15](=[C:16]([O:24][CH3:25])[CH:17]=2)[CH:14]2[CH2:13][CH2:12][CH:11]3[CH2:27][CH2:26]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(CC(O)CO)c(OCc2ccccc2)c2c1C1CCC2CC1
Solvent: c1ccncc1
Product: COc1cc(CC(O)COS(=O)(=O)c2ccc(C)cc2)c(OCc2ccccc2)c2c1C1CCC2CC1
Yield: 89.5 %

Procedure:
Treatment of (±)-3-[5-(benzyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-ethanonaphthalen-6-yl]propane-1,2-diol (15.82 g, 0.043 mol) with p-toluenesulfonyl chloride (9.00 g, 0.047 mol) in anhydrous pyridine (400 mL) generally according to the procedure described for Intermediate 18 gave 20.12 g (90%) of (±)-3-[5-(benzyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-ethanonaphthalen-6-yl]-2-hydroxypropyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C30H34O6S.0.5H2O: C, 67.77; H, 6.64. Found: C, 67.86; H, 6.55.
Reaction SMILES: Cl.[NH2:2][CH:3]([C@@H:5]1[CH2:8][C@H:7]([OH:9])[CH2:6]1)[CH3:4].C(N(CC)C(C)C)(C)C.[F:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([C:30]3[N:31]=[C:32]4[C:38]([C:39](O)=[O:40])=[CH:37][N:36]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:33]4=[N:34][CH:35]=3)=[N:25][N:26]2[CH3:29])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:9][C@@H:7]1[CH2:8][C@H:5]([CH:3]([NH:2][C:39]([C:38]2[C:32]3[C:33](=[N:34][CH:35]=[C:30]([C:24]4[C:23]5[C:27](=[CH:28][C:20]([F:19])=[CH:21][CH:22]=5)[N:26]([CH3:29])[N:25]=4)[N:31]=3)[N:36]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:37]=2)=[O:40])[CH3:4])[CH2:6]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CC(N)[C@H]1C[C@@H](O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cis-3-(1-aminoethyl)-cyclobutanol hydrochloride (crude from step 6, 91 mg, 0.60 mmol) in DMF (2 mL) were added N,N-diisopropylethylamine (0.24 mL, 1.36 mmol), 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.27 mmol), and HATU (114 mg, 0.30 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated to a pale yellow solid. Trituration with EtOAc/Et2O gave 108 mg (74%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-hydroxy-cyclobutyl)-ethyl]-amide as a white solid.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].[C:14]1(=[O:19])[O:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][OH:19])=[CH:8][CH:9]=1
Reactant: O=C1CCCO1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CCCO)CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To 60 mL of benzene was added NaOMe (5.4 g, 99.612 mmol) under nitrogen atmosphere and stirred. The above mixture was added then with 30 mL of 4-chloroacetophenone (5.9 mL, 45.278 mmol) after mixing it with 30 mL of benzene and stirred for 30 min at 40° C. Then, γ-butyrolactone (7.0 mL, 90.556 mmol), after mixing it with 30 mL of benzene, was slowly added thereto and stirred for 16 hrs at 40° C. The progress and completion of the reaction were confirmed by means of TLC. Upon completion of the reaction, the reaction mixture was cooled down to room temperature and the solvent was removed from the reaction mixture under reduced pressure. The reaction mixture was diluted with EtOAc, and added with water. The aqueous layer was extracted with EtOAc and the organic layer was dried with anhydrous MgSO4 and filtered. The resulting filtrate was concentrated under reduced pressure and the resulting concentrate was passed through column chromatography (EtOAc:Hexane=1:1, v/v) to obtain 5.9 g (54%) of target compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16]O)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:19][CH2:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.2 %

Procedure:
To a mixture of [3-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]methanol (J. Med. Chem. 1996, 25, 4871., 4.39 g, 17 mmol) and carbon tetrabromide (8.95 g, 27 mmol) in tetrahydrofuran (60 mL) was added triphenylphosphine (6.82 g, 26 mmol) in two portions at 0° C. and the mixture was stirred for 3 h at room temperature. The mixture was neutralized with aqueous sodium hydrogen carbonate and extracted with dichloromethane. The organic layer was concentrated. The residue was taken up in hexane and the resulting mixture was filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/dichloromethane (10/1) to afford 760 mg (14%) of the title compound as a colorless oil:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH:10](Br)[CH3:11].[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCOc1ccc(Br)cc1
Yield: 82.8 %

Procedure:
A mixture of 4-bromophenol (30 g, 173 mmol), dibromoethane (40 mL, 464 mmol), NaOH (11.0 g, 275 mmol) and water (430 mL) was refluxed for 11 h. The phases were separated and the organic phase was further purified by distillation, yielding the sub-title compound (40.1 g 83%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[CH:6][CH:5]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>>[OH:1][CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]([OH:12])[CH2:11][NH:18][CH:15]([CH3:17])[CH3:16])=[CH:6][CH:5]=1
Reactant: OCCc1ccc(OCC2CO2)cc1
Reactant: CC(C)N
Product: CC(C)NCC(O)COc1ccc(CCO)cc1

Procedure:
10 g of 1-[4-(2-hydroxyethyl)phenoxy]-2,3-epoxypropane produced in Example 1 was refluxed in 50 mL of isopropylamine for 16 hrs. The amine was removed under reduced pressure, the residue dissolved in warm toluene and the toluene removed under reduced pressure. On standing the oil solidified. Yield=12.8 g (98%). After recrystallization in petroleum ether this solid had a melting point of 77°-78° C.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[C:12]([O:29][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])=[N:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:20]=1OS(C(F)(F)F)(=O)=O)([O-:10])=[O:9].[NH2:37][CH2:38][C:39]([CH3:42])([CH3:41])[OH:40]>C(Cl)Cl>[F:36][C:33]([F:34])([F:35])[S:30]([O:29][C:12]1[C:11]([N+:8]([O-:10])=[O:9])=[C:20]([NH:37][CH2:38][C:39]([OH:40])([CH3:42])[CH3:41])[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]=1)(=[O:32])=[O:31]
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)nc2c(c1OS(=O)(=O)C(F)(F)F)CCCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1c2c(nc(OS(=O)(=O)C(F)(F)F)c1[N+](=O)[O-])CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Triethylamine (1.36 mL, 9.8 mmole) was added to a solution of 5,6,7,8-tetrahydro-3-nitro-2,4-bis[(trifluoromethyl)sulfonyloxy]quinoline (4.2 g, 9.4 mmole) in methylene chloride (180 mL). 2-Amino-α,α-dimethylethanol (0.88 g, 9.8 mmole) was added to the reaction mixture which was then stirred at ambient temperature overnight. The reaction mixture was evaporated to provide a residue which was purified by silica gel chromatography eluting with hexane: ethyl acetate 40:60 to provide 3.8 g of the desired product.
Reaction SMILES: [C:1]([Si:5]([CH3:60])([CH3:59])[O:6][C@@H:7]1[CH2:11][C@@H:10]([CH2:12][O:13]OC)[O:9][C@@:8]1(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:16]1[C:39]2[N:38]=[CH:37][N:36]=[C:20]([NH:21][C:22]([O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:23])[C:19]=2[N:18]=[CH:17]1)([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.O>C(Cl)Cl.CO.CCOC(C)=O>[C:1]([Si:5]([CH3:60])([CH3:59])[O:6][C@@H:7]1[CH2:11][C@@H:10]([CH2:12][OH:13])[O:9][C@H:8]1[N:16]1[C:39]2[N:38]=[CH:37][N:36]=[C:20]([NH:21][C:22]([O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:23])[C:19]=2[N:18]=[CH:17]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COOC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@](n2cnc3c(NC(=O)OCCc4ccc([N+](=O)[O-])cc4)ncnc32)(C(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)OCCc3ccc([N+](=O)[O-])cc3)ncnc21
Yield: 94.9 %

Procedure:
Detritylation of the fully protected monomer was accomplished by stirring a mixture of 831 mg (1 mmol) of 17 in CH2Cl2 /MeOH 4:1 (20 ml) containing 2% of TsOH×H2O for 15 minutes at r.t. The mixture was then diluted with EtOAc (130 ml), washed with saturated NaHCO3 solution (2×60 ml) and back-extracted. The organic layer was dried (MgSO4) and evaporated. The residue of the 5'-OH monomer intermediate was purified by FC (silica gel, 11.5×3 cm, gradient toluene/EtOAc 1:1+6% MeOH) to yield 530 mg (95%) of 18 as an amorphous solid. UV (MeOH): 298 (sh, 3.58), 274 (sh, 4.38), 268 (4.44). 1H-NMR ((D6)DMSO): 10.59 (s, NH); 8.70, 8.61 (2s, H--C(8), H--C(2)); 8.15 (d, 2H o to NO2), 7.61 (d, 2H m to NO2); 5.96 (s, H--C(1')); 5.15 (t, OH--C(5')); 4.74 (m, H--C(2')); 4.38 (m, H--C(4'), OCH2CH2 (6-N)); 3.73 (m, H--C (5')); 3.58 (m, H--C(5')); 3.10 (t, OCH2CH2); 2.27 (m, H--C (3')); 1.90 (m, H--C(3')); 0.82 (s, 9H, t-butyl); 0.00 (s, 2×CH3 at Si). Anal. calc. for C25H34N6O7Si (558.7): C 53.75, H 6.13, N. 15.04; found: C 53.98, H 6.12, N 14.80.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].ClCCl.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15]
Reactant: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(C(=O)O)ccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(CO)ccc1OC
Reaction time: 2 h
Yield: 87 %

Procedure:
At 0° C., under an inert atmosphere, 1.5 g of 4-(2-chloro-4-methoxyphenyl)-5methyl-2-[N-(5-carboxy-2-methoxyphenyl)-N-propylamino]thiazole are dissolved in 11 ml of tetrahydrofuran. 5 ml of a 1 M solution of lithium aluminium hydride in tetrahydrofuran are added slowly so that the temperature of the mixture does not exceed 10° C. After 2 hours at room temperature, the reaction mixture is cooled with the aid of an ice bath and then hydrolyzed slowly. The crude material is alkalanized before being filtered over sodium sulphate. After evaporation under vacuum, the product is obtained by purification on a silica gel; eluent: dichloro-methane/ethyl acetate 95/5 (v/v); yield=87%. The expected product is in the form of a powder; m.p.=115° C.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][C:16]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:17]([C:19]#[N:20])[N:18]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][C:16]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:17]([C:19]#[N:20])[N:18]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nc(C#N)c(Nc3ccccn3)s2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc(N2CCC[C@@H](N)C2)sc1Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {(R)-1-[4-cyano-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-carbamic acid tert-butyl ester (prepared as described in Example 1, Step 3) (20.2 mg, 50.4 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (1 mL, 13 mmol) and the mixture stirred under argon at ambient temperature for 30 minutes. The reaction mixture was concentrated in vacuo and the crude 2-((R)-3-amino-piperidin-1-yl)-5-(pyridin-2-ylamino)-thiazole-4-carbonitrile taken on to the next step in the synthesis without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][N:4]1[CH2:9][CH2:8][N:7](C(OCCCC)=O)[CH2:6][CH2:5]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:2]([OH:1])([CH3:17])[CH2:3][N:4]1[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]1
Reactant: CCCCOC(=O)N1CCN(CC(C)(C)O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)CN1CCNCC1
Reaction time: 0.17 h
Yield: 60.1 %

Procedure:
A solution of 563 (460 mg, 1.78 mmol) and TFA (5 ml) in DCM (20 ml) was stirred at rt for 5 h. The reaction mixture was concentrated (azeotropes with DCM), diluted with water, stirred for 10 min. The pH was adjusted to around 10 with 1N NaOH, and the alkaline solution was extracted with DCM. The organic extract was dried over anhydrous magnesium sulfate, filtered, concentrated under high vacuum to afford the desired product 564 (170 mg, 1.07 mmol, 60% yield) as a dark orange sticky solid. The crude product was used in the next step without any further purification. MS (m/z): 159.13 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([NH:25][C@H:26]([C:31](O)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:31](=[O:32])[C@H:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:25][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a solution of N-benzyl-4-amino piperidine (0.50 g) in CH2Cl2 (10 mL) was added CBZ-leucine (695 mg), EDC (552.5 mg) and HOBT (356.6 mg). The reaction was stirred at room temperature until complete as indicated by TLC analysis. The reaction was dissolved in CHCl3 and washed with 10% Na2CO3, brine, dried (MgSO4), filtered, concentrated and chromatographed (3:1 EtOAc:hexanes) to give 0.99 g of the title compound: MS(ES+) 438 (MH+).