Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[N:12]O)[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(NC(C)C)(C)C>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:11][NH:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=NO)c1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: c1cc2c(cc1C1CN1)OCO2
Temperature: 60 °C
Yield: 88.7 %

Procedure:
A solution of oxime 12 (2.7 g, 15 mmol, 1.0 equiv) in tetrahydrofuran (60 mL) at 25° C. was transferred via cannula to a stirred suspension of lithium aluminum hydride (3.5 g, 61 mmol, 4.0 equiv) and di-iso-propyl amine (8.5 mL, 61 mmol, 4.0 equiv) in tetrahydrofuran (70 mL) at 25° C. The emptied reaction vessel was rinsed with tetrahydrofuran (22 mL) and the resulting solution was also transferred via cannula. The reaction vessel was equipped with a reflux condenser under nitrogen atmosphere and heated to 60° C. via oil bath for 4 h. The mixture was cooled to 25° C., diluted with ice water (400 mL), and the product was extracted with dichloromethane (5×200 mL). The combined organic layers were dried (sodium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (5% triethylamine in ethyl acetate) to afford 15 (2.17 g, 88% yield) as a pale yellow oil. Rf=0.40 (5% triethylamine in ethyl acetate); 1H NMR (500 MHz, CDCl3) δ 6.75 (br s, 2H, ArH), 6.70 (br s, 1H, ArH), 5.93 (s, 2H, OCH2O), 2.97 (br s, 1H, ArCH), 2.17 (br s, 1H, CH2), 1.67 (br s, 1H, CH2).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[N:3]2[CH:8]=[N:9][CH:10]=[C:2]12.C(N(CC)CC)C.Cl.[NH2:19][OH:20]>C(O)C>[S:1]1[CH:5]=[C:4]([CH:6]=[N:19][OH:20])[N:3]2[CH:8]=[N:9][CH:10]=[C:2]12
Reactant: O=Cc1csc2cncn12
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: ON=Cc1csc2cncn12
Temperature: 60 °C
Reaction time: 1 h
Yield: 546.1 %

Procedure:
0.12 g of the imidazo[5,1-b]thiazole-3-carbaldehyde prepared in Preparation 43 was dissolved in 3 ml of ethanol. To this solution were added 1 ml of triethylamine and 0.06 g of hydroxylamine hydrochloride, and the mixture was stirred at 60° C. for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a 20:1 mixture of chloroform and methanol to give 0.72 g (yield 56%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]([CH3:22])=[CH:18][C:19](Cl)=[O:20]>CC(C)=O.O>[CH3:16][C:17]([CH3:22])=[CH:18][C:19]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:20]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(NC(=O)C=C(C)C)cc1
Temperature: 0 °C
Yield: 74.6 %

Procedure:
A mixture of p-anisidine (10 g, 81 mmol, Aldrich) and potassium carbonate (13.5 g, 97.5 mmol, Aldrich) in acetone (125 mL) was cooled to 0° C. and treated with dimethyl acryloyl chloride (10.2 mL, 89.3 mmol). The mixture was allowed to warm to room temperature overnight. The reaction was diluted with water and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate, filtered, concentrated, and purified by chromatography on SiO2 (0 to 100% ethyl acetate/dichloromethane) to give 3-methyl-N[4-(methyloxy)phenyl]-2-butenamide (12.4 g, 67%) as a light violet solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 (s, 3 H), 2.13 (s, 3 H), 3.71 (s, 3 H), 5.82 (s, 1 H), 6.85 (d, J=9.0 Hz, 2 H), 7.52 (d, J=9.0 Hz, 2 H), 9.67 (s, 1 H); ESIMS (M+H)+=206.
Reaction SMILES: [C:1]1([CH:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:8]([N:10]2[CH:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:34][CH3:35])[C:16]=3[O:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=3)[CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C1COCC1.[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:16]2[C:15]([O:34][CH3:35])=[CH:14][CH:13]=[C:12]3[C:17]=2[CH2:18][CH:19]([C:20]([O:22][CH3:23])=[O:21])[N:10]([C:8](=[O:9])[CH:7]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11]3)=[CH:26][CH:27]=1
Reactant: COC(=O)C1Cc2c(ccc(OC)c2Oc2ccc([N+](=O)[O-])cc2)CN1C(=O)C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1Cc2c(ccc(OC)c2Oc2ccc(N)cc2)CN1C(=O)C(c1ccccc1)c1ccccc1
Yield: 99 %

Procedure:
A solution of 0.80 g (1.45 mmole) of the nitrobenzene derivative of Example 43 in 50% methanol-THF is reduced with 5% palladium-on-carbon catalyst. The filtered solution is concentrated at reduced pressure to give 0.75 g of pure product as a solid foam; mass spectrum (EI) 522 (M+) .
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[OH:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:26](Br)[CH3:27]>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH2:26][CH3:27])(=[O:3])[CH3:2]
Reactant: CCBr
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc([N+](=O)[O-])ccc1NC(C)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To 400 g of 2-acetamido-5-nitrophenol in a 12-L, 4-necked flask equipped with a reflux condenser, nitrogen inlet, thermocouple, addition funnel, and mechanical stirrer was added 790 g of potassium carbonate and 2.0 L of dimethylformamide. The mixture was stirred at 60° C. as 294 g of ethyl bromide was added over 30 minutes. After 1 hour, an additional 27 g of ethyl bromide was added and the mixture was stirred at 60° C. for another hour. The mixture was cooled to room temperature and poured into 4 L of water. After 30 minutes, the product was collected by filtration and washed with water and heptane. The product was dried in a vacuum oven at 60° C. to give 457 g of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11](OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl.ClC[C@H:21]1[CH2:23][O:22]1.[OH-].[Na+]>ClCCl.O1CCOCC1>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@@H:21]3[CH2:23][O:22]3)[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CC2)CC1
Reactant: ClC[C@H]1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C1CC1CN1CCN(C[C@@H]2CO2)CC1
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate 31a (2 g, 8.30 mmol) was dissolved in 40 mL of dichloromethane followed by the addition of 20 mL of a 4 M solution of hydrogen chloride in dioxane. The reaction solution was stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure followed by the addition of 40 mL of dichloromethane and dropwise with 20 mL of triethylamine to adjust pH to 10 to 11. The resulting solution was concentrated under reduced pressure. The residue was added with 50 mL of ethyl acetate and filtered. The filtrate was concentrated under reduced pressure, added with 50 mL of ethyl acetate and 20 mL of water, then added with (R)-2-chloromethyl-oxirane (0.92 g, 9.96 mmol) and sodium hydroxide (0.66 g, 16.60 mmol). The reaction solution was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, added with 50 mL of water and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-(cyclopropylmethyl)-4-[[(2R)-oxiran-2-yl]methyl]piperazine 31b (0.91 g, yield: 57.0%) as a yellow oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:17].Cl.[NH2:19][CH2:20][CH2:21][O:22][NH2:23].N1C=CC=CC=1>>[ClH:17].[ClH:17].[NH2:19][CH2:20][CH2:21][O:22][N:23]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCON
Reactant: O=C(CCCn1ccnc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: NCCON=C(CCCn1ccnc1)c1ccccc1
Reaction time: 8 h
Yield: 217.5 %

Procedure:
A mixture of 4-(1-(1H)-imidazolyl)-1-phenyl-1-butanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.50 g), 3 equivalents of pyridine, and absolute ethanoI (75 ml) was heated under reflux, under nitrogen, with stirring, overnight. The reaction mixture was evaporated, toluene was added and evaporated. The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was combined with 5.0 g of crude, previously prepared material and purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized from absolute ethanol to give 6.3 g (58%) of product, mp 196°-198° C. (dec).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[C:19]=3[NH:24][C:25]([O:27][C@@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:29])=[O:26])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)C.CO.[OH-].[Li+]>O>[CH3:23][C:20]1[C:19]([NH:24][C:25]([O:27][C@@H:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:29])=[O:26])=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:36])=[O:3])=[CH:11][CH:10]=3)=[CH:13][CH:14]=2)[O:22][N:21]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1noc(-c2ccc(-c3ccc(CC(=O)O)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of {4′-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetic acid ethyl ester (24 g, 49 mmol) in 3:1 MeOH:H2O (300 mL) was added lithium hydroxide (8.3 g, 198 mmol), and the reaction was stirred at room temperature overnight. The mixture was acidified and partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated to give the title compound. Mass spec. data (M+H)=457.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=O.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].CCOCC>C(OC(=O)C)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH2:17]([O:16][C:8](=[O:15])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:2]([C:1]([O:6][CH3:7])=[O:5])[CH3:4])[CH3:18]
Reactant: COC(=O)C(C)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C(=O)OCC)=C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A mixture of ZnCl2 (42 g, 308 mmol) in acetic anhydride (100 mL) was stirred at r.t. for 2 h. The resulting solution was decanted, and to this solution was added methyl pyruvate (15.5 mL, 171 mmol) and diethyl malonate (26 mL, 171 mmol). The resulting mixture was heated at 100° C. for 1 h, then left standing at r.t. for 16 h. Ether (250 mL) was added and the mixture was washed with ice water and saturated NaHCO3. The organic layer was dried over MgSO4 and concentrated to give a dark brown oil, which was distilled under reduced pressure to give 32.3 g of the title compound as a yellow oil. 1H NMR (CDCl3, 200 MHz): δ=4.15-4.40 (m, 4H), 3.78 (s, 3H), 2.20 (s, 3H), 1.20-1.40 (m, 6H).
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]=[CH:6][C:7]1[CH:35]=[CH:34][C:10]([CH2:11][NH:12][C:13](=[O:33])C2C=CC(N3CCN(CC4C=NC=CC=4)CC3)=CC=2)=[CH:9][CH:8]=1)=[O:4].COC(=O)C=CC1C=CC(CNC([O:51][CH2:52][C:53]2[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=2)=O)=CC=1>>[N:55]1[CH:56]=[CH:57][CH:58]=[C:53]([CH2:52][O:51][C:13](=[O:33])[NH:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([CH:6]=[CH:5][C:3](=[O:4])[NH:2][OH:1])=[CH:35][CH:34]=2)[CH:54]=1
Reactant: COC(=O)C=Cc1ccc(CNC(=O)OCc2cccnc2)cc1
Reactant: O=C(C=Cc1ccc(CNC(=O)c2ccc(N3CCN(Cc4cccnc4)CC3)cc2)cc1)NO
Product: O=C(C=Cc1ccc(CNC(=O)OCc2cccnc2)cc1)NO
Yield: 39 %

Procedure:
The titled compound was prepared as described in the process (1-3) using the compound from the process (8-2).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][NH2:11]>C(#N)C>[CH3:10][NH:11][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN
Reactant: N#Cc1ccccc1F
Solvent: CC#N
Product: CNc1ccccc1C#N
Temperature: 60 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
2-Fluorobenzonitrile (10.0 g, 82.8 mmol) was dissolved in acetonitrile (100 ml), and 40% aqueous methylamine solution (200 ml) was added thereto, followed by stirring at 60° C. overnight. 40% aqueous methylamine solution (100 ml) was further added thereto, followed by stirring at 60° C. for 9 hours. The reaction mixture was concentrated under reduced pressure, then water was added to the resulting residue, the mixture was extracted with chloroform. After the organic layer was dried (over anhydrous magnesium sulfate), the drying agent was filtered off, and the organic layer was concentrated under reduced pressure. The resulting oily substances were purified by silica gel column chromatography (the substances were eluted with an increasing concentration of chloroform from chloroform/hexane=1/2 to chloroform/hexane=1/1) to give the title compound (5.38 g, 49%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([C:10]1[S:11][C:12]([S:27][CH3:28])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].I[C:31]1[C:36]([CH3:37])=[CH:35][C:34]([N+:38]([O-:40])=[O:39])=[CH:33][N:32]=1.O>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:27][CH3:28])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:31]3[C:36]([CH3:37])=[CH:35][C:34]([N+:38]([O-:40])=[O:39])=[CH:33][N:32]=3)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc([N+](=O)[O-])cnc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ncc([N+](=O)[O-])cc2C)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.058 mmol, 40 mg, Example 140: step a), 2-iodo-3-methyl-5-nitropyridine (0.08 mmol, 21.1), CuI (0.01 mmol, 2.2) and (Ph3P)4Pd (0.006 mmol) in DMF (0.6 mL) was heated at 100° under Ar for 3 hr. The reaction mixture was allowed to cool to RT and poured in to water (20 mL). The product was extracted with CH2Cl2 (3×10 mL). CH2Cl2 extracts were combined, dried (Na2SO4) and concentrated in vaccuo. The resulting residue was purified on silica (30% EtOAc:Hexane) to obtain (Imino-{4-[3-(3-methyl-5-nitro-pyridin-2-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester. Yield: 48%; 1H NMR (CDCl3) δ 9.36 (br, 1H), 8.37 and 8.25 (s, 1H each), 8.1 and 7.8 (d, J=2.4 Hz, 1H each), 7.93 (s, 1H), 7.74 (t, J=6.8 Hz, 1H), 2.7 and 2.5 (s, 3H each), 1.35 (s, 9H)
Reaction SMILES: C[O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[S:11][C:12]([CH3:18])=[C:13]([C:15]([OH:17])=[O:16])[N:14]=1.[BrH:19]>>[BrH:19].[OH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[S:11][C:12]([CH3:18])=[C:13]([C:15]([OH:17])=[O:16])[N:14]=1
Reactant: COc1c(N)cccc1-c1nc(C(=O)O)c(C)s1
Agent: Br
Product: Cc1sc(-c2cccc(N)c2O)nc1C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
2-(2-Methoxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid 47b (280 mg, 0.94 mmol) was dissolved in 5 mL of hydrogen bromide. The reaction mixture was stirred overnight at 80° C. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was washed with ethyl acetate and dried to obtain the title compound 2-(2-hydroxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid hydrobromide 47c (200 mg, yield 64%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]([CH:14]=O)[CH2:8][CH2:7]1.[CH2:26]([NH:29][C:30]1[CH2:34][S:33][C:32](=[O:35])[N:31]=1)[C:27]#[CH:28].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:24][C:2]([F:25])([F:1])[C:3]1[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:14]=[C:34]2/[C:30]([NH:29][CH2:26][C:27]#[CH:28])=[N:31][C:32](=[O:35])[S:33]/2)[CH2:10][CH2:11][C:12]1=[O:13]
Reactant: O=CC1CCC(=O)N(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C#CCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCC(=O)N(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]-7-oxoazepane-4-carbaldehyde (1.00 g) and 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (0.63 g) in 2-propanol (10 mL) was added piperidinium acetate (0.40 g). The reaction mixture was stirred at 80° C. for 2 hr and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.48 g).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH:18](OC)[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[NH4+]>C(Cl)Cl>[CH:1]([N:14]1[CH2:15][CH:16]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=3)[NH:21][CH:20]=2)[CH2:17]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(c1c[nH]c2ccc(C#N)cc12)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC[SiH](CC)CC
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2[nH]cc(CC3CN(C(c4ccccc4)c4ccccc4)C3)c2c1
Yield: 86 %

Procedure:
A solution of 3-[(1-benzhydryl-azetidin-3-yl)-methoxy-methyl]-1H-indole-5-carbonitrile, triethylsilane (5.5 ml, 34 mmol) and trifluoroacetic acid (6.6 mL, 86 mmol) in methylene chloride (40 mL) was refluxed overnight. The reaction was poured into ice and neutralized with concentrated ammonium hydroxide. The mixture was extracted with methylene chloride (3×100 mL). The organic layer was washed with water (3×80 mL), dried over anhydrous sodium sulfate, filtered and solvent removed under vacuum. The crude oil was column chromatographed on a Biotage (40% ethyl acetate-hexane/hexane). The product-containing fractions were concentrated under vacuum to give 0.56 g (86%) of the title compound as a clear oil. MS ES m/e 378 (M+H)+; 1H NMR (500 MHz, DMSO-D6): 2.74-2.78 δ (M, 3H), 2.96 δ (d J=6.7 Hz, 2H), 3.21 δ (t, J=6.4 Hz, 2H), 4.4 δ (s, 1H), 7.15-7.17 δ (m, 2H), 7.24-7.29 δ (m, 5H), 7.38-7.418 δ (m, 5H), 7.47 δ (d, J=8.4 Hz, 1H), 8.07 δ (s, 1H), 11.37 δ (br, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][OH:16].[F:17][C:18]1[C:26](O)=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C>[F:17][C:18]1[C:26]([O:16][CH2:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:6][C:2]=2[CH3:1])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21]
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: Cc1sc(-c2ccccc2)nc1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1sc(-c2ccccc2)nc1CCCOc1ccc(F)c(C(N)=O)c1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
3-(5-Methyl-2-phenyl-thiazol-4-yl)-propan-1-ol To a solution of 3-(5-methyl-2-phenyl-thiazol-4-yl)-propan-1-ol (0.219 g, 1.0 mmol) in 5 ml of anhydrous DMF, 2,6-difluoro-3-hydroxybenzamide (0.173 g, 1.0 mmol), PPh3 (0.262 g, 1.0 mmol) and diisopropyl azodicarboxylate (0.202 g, 1.0 mmol) was added. The reaction mixture was stirred at 80° C. for overnight under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400μ) using ethyl acetate/hexane (35:65) as the eluent to provide the title compound as white solid (0.050 g, 13%). 1H NMR (DMSO-d6, 400 MHz): δ 2.44 (broad s, 3H), 3.14 (t, 2H, J=6.4 Hz), 4.35 (t, 2H, J=6.4 Hz), 7.04 (dt, 1H, J=9.2 Hz (o-coupling), 7.22-7.28 (m, 1H), 7.43-7.49 (m, 3H), 7.83-7.86 (m, 3H), 8.10 (s, 1H); MS ES+(375.15), HPLC (method 5) Rt=10.67 min.
Reaction SMILES: C(N(CC)CC)C.[N-]=[N+]=[N-].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(C(O)=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C[N:34]([CH:36]=[O:37])C>>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][C:21]([N:34]=[C:36]=[O:37])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:13])([CH3:14])[CH3:12]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Agent: [N-]=[N+]=[N-]
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N=C=O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (5.02 mL, 36.1 mmol) and diphenylhosphoryl azide (4.24 mL, 19.7 mmol) are added to a solution of 1-(tert-butoxycarbonyl)-4-phenyl-4-piperidinecarboxylic acid (5.0 g, 16.4 mmol) in dry DMF (50 mL) under nitrogen at ambient temperature. The mixture is stirred at ambient temperature for 2 h, and then heated to 60° C. for 3 h. The mixture is slightly cooled and concentrated in vacuo. Water (75 mL) is added to the remanence followed by extraction with ethyl acetate (2×75 mL). Combined organic fractions are washed with brine (3×50 mL), dried (MgSO4) and evaporated to dryness. The crude mixture is purified by silica gel chromatography eluting with ethyl acetate-heptane (1:4). This furnishes 4.8 g (98%) of the wanted 1-(tert-butoxycarbonyl)-4-isocyanato-4-phenyl-piperidine as a clear oil. LC/MS (m/z) 203.2 (M-boc+H+); tR=3.64 min. 1H NMR (CDCl3) 1.49 (s, 9H); 1.92 (bd, 2H); 2.02 (dt, 2H); 3.15 (bt, 2H); 4.17 (bs, 2H); 7.26 (dd, 1H); 7.39 (dt, 2H); 7.44 (dd, 2H).
Reaction SMILES: CC(C)(S([NH:6][C:7]1([C:11]2[S:15][C:14]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[CH:26]=[CH:27][N:28]=[C:22]4[CH:21]=3)=[O:17])=[CH:13][CH:12]=2)[CH2:10][O:9][CH2:8]1)=O)C.Cl.O1CCOCC1>CO>[NH2:6][C:7]1([C:11]2[S:15][C:14]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[CH:26]=[CH:27][N:28]=[C:22]4[CH:21]=3)=[O:17])=[CH:13][CH:12]=2)[CH2:10][O:9][CH2:8]1
Reactant: CC(C)(C)S(=O)NC1(c2ccc(C(=O)NCc3ccn4ccnc4c3)s2)COC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(c2ccc(C(=O)NCc3ccn4ccnc4c3)s2)COC1
Reaction time: 2 h

Procedure:
5-(3-(1,1-Dimethylethylsulfinamido)oxetan-3-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)thiophene-2-carboxamide (432 mg, 1 mmol) in 10 ml methanol was treated with 4N aqueous HCl in dioxane (0.75 ml, 3 mmol) and the mixture was stirred for 2 hours. Concentration provided the title compound.