Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH2:11][CH:10]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[C:14]([CH2:20][C:21]#[N:22])[C:13]=2[CH3:23])[CH2:9][C:8](=[O:24])[C:7]=1[C:25](=[O:28])[CH2:26][CH3:27].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S>[OH:5][C:6]1[CH2:11][CH:10]([C:12]2[C:13]([CH3:23])=[C:14]([CH2:20][C:21]#[N:22])[C:15]([CH3:19])=[C:16]([C:1](=[O:3])[CH3:2])[C:17]=2[CH3:18])[CH2:9][C:8](=[O:24])[C:7]=1[C:25](=[O:28])[CH2:26][CH3:27]
Reactant: CC(=O)Cl
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CC#N)c2C)CC1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)C1=C(O)CC(c2c(C)c(CC#N)c(C)c(C(C)=O)c2C)CC1=O
Temperature: 0 °C

Procedure:
Acetyl chloride (1.34 g, 17.0 mmol) was added to an ice cooled mixture of 3-hydroxy-2-propionyl-5-(3-cyanomethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (2.65 g, 8.15 mmol) and aluminium chloride (4.15 g, 33.4 mmol) in carbon disulfide (100 ml). The mixture was refluxed for 4 h, cooled and added cautiously to 10% hydrochloric acid (50 ml) and ice (50 ml). The organic solvent was allowed to evaporate from the mixture then the aqueous layer was extracted with ethyl acetate, the organic extracts were washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product was chromatographed on silica gel (elution with an increasing gradient of ethyl acetate in methylene chloride). After an initial fraction of unreacted starting material, 3-hydroxy-2-propionyl-5-(3-acetyl-5-cyanomethyl-2,4,6-trimethyl phenyl)cyclohex-2-en-1-one was obtained as a colourless solid (1.5 g, 50%), which was characterized by proton magnetic resonance spectroscopy (CDCl3 ; δ in ppm): 1.12 (3H,t); 2.23 (3H,s); 2.25 (3H,s); 2.47 (6H,s); 2.4-4.1 (7H,m); 18.08 (1H,s).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)O1.Br[C:17]1[CH:18]=[C:19]2[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][N:23](C3CCCCO3)[C:20]2=[CH:21][N:22]=1>>[C:26]1([C:25]2[C:19]3[C:20](=[CH:21][N:22]=[C:17]([C:9]4[CH:14]=[N:13][CH:12]=[CH:11][N:10]=4)[CH:18]=3)[NH:23][N:24]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)OB(c2cnccn2)OC1(C)C
Reactant: Brc1cc2c(-c3ccccc3)nn(C3CCCCO3)c2cn1
Product: c1ccc(-c2n[nH]c3cnc(-c4cnccn4)cc23)cc1
Yield: 28 %

Procedure:
Following the procedures in Example 204, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine and 5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted and the product was deprotected to give 214 as a yellow solid (22 mg, 28%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 9.26 (s, 1H), 8.97 (s, 1H), 8.76 (s, 1H), 8.67 (d, 1H), 8.05 (t, 2H), 7.61 (t, 2H), 7.48 (t, 1H). ESI MS m/z=274 (M+1)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1)([O-])=O.O.Cl>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CCOC(=O)N1CCN(c2ccncc2[N+](=O)[O-])CC1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)N1CCN(c2ccncc2N)CC1
Yield: 95.1 %

Procedure:
A mechanically stirred solution of ethyl 4-(3-nitro-4-pyridinyl)-1-piperazinecarboxylate (10 g, 35.7 mmol) and iron filings [40 mesh](21.7 g, 389 mmol) in a mixture of 50 mL of ethanol, 7 mL of water and 0.36 mL of concentrated HCl was heated to reflux for 4 h. The hot solution was filtered and concentrated in vacuo to give of ethyl 4-(3-amino-4-pyridinyl)-1-piperazinecarboxylate (8.5 g, 95%). An analytical sample was obtained by recrystallization from ethyl acetate in hexanes: mp 141°-142° C. Anal. Calcd for C12H18N4O2 : C, 57.58; H, 7.25; N, 22.38. Found: C, 57.43; H, 7.19; N, 22.24.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C:10]=2[CH:11]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.[NH4+]>>[C:16]1([N:22]2[CH2:27][CH2:26][N:25]([C:2]3[N:3]=[N:4][C:5]4[C:6]5[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=5[CH2:8][CH2:9][C:10]=4[CH:11]=3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1cc2c(nn1)-c1ccccc1CC2
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: [NH4+]
Product: c1ccc(N2CCN(c3cc4c(nn3)-c3ccccc3CC4)CC2)cc1
Temperature: 130 °C
Reaction time: 48 h
Yield: 88.1 %

Procedure:
A mixture of comprising about 0.01 mol of 3-chloro-5,6-dihydrobenzo[h]cinnoline, about 0.05 mol of 1-phenylpiperazine and about 0.01 mol of ammonium hydrochloride was prepared in about 15 ml of 1-BuOH. The mixture was stirred at 130° C. for 48 h, and then the solvent was removed under reduced pressure. The remaining residue was then extracted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4. Removal of solvent followed by recrystallization from 95% ethanol yielded bright yellow crystals, yield 88.1%; HPLC: 96.0% purity; HRMS calculated 342.1839, found 342.1831; 1H NMR (CDCl3): δ 8.474 (d, J=7.5, 1H), 7.222-7.400 (m, 4H), 7.012 (d, J=10, 2H), 6.925 (t, J=6.5, 3=7.5, 1H), 6.824 (S, 1H), 3.900 (s, 4H), 3.370 (d, J=4.5, 4H), 2.932 (s, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]([C:7]1[O:11][N:10]=[C:9]([CH2:12][S:13][CH3:14])[N:8]=1)[CH3:6].I([O-])(=O)(=O)=[O:25].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]([C:7]1[O:11][N:10]=[C:9]([CH2:12][S:13]([CH3:14])=[O:25])[N:8]=1)[CH3:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSCc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CS(C)=O)no1
Yield: 100.4 %

Procedure:
To a solution of 0.95 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-methylthiomethyl-1,2,4-oxadiazole in 150 ml of ethanol was added a solution of 1.36 g of sodium metaperiodate in 50 ml of water. After stirring with reflux for 9 hours, the reaction mixture was cooled, diluted with water and extracted with chloroform. The extracts were washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed over silica gel using chloroform to yield 1.0 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-methylsulfinylmethyl- 1,2,4-oxadiazole. It was recrystallized from ethyl acetate-diisopropyl ether to give colorless needles, m.p. 71°-72° C. (decomp.).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:39])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:23]5[S:30][CH:29]=[CH:28][C:24]=5[N:25]([CH3:27])[N:26]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:39])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:23]5[S:30][CH:29]=[CH:28][C:24]=5[N:25]([CH3:27])[N:26]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccsc34)nc12)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4ccsc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
To a solution of 2-(1-methyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (131 mg, 0.23 mmol) in CH2Cl2 (2 mL) was added TFA (0.75 mL). The reaction mixture was stirred at room temperature for 5 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with 0% to 10% MeOH/CH2Cl2 to afford 83 mg (83%) of 2-(1-methyl-1H-thieno[3,2-c]pyrazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white solid. MS (M+Na)+=457; mp=310-320° C.; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.93 (br. s., 1H), 9.07 (s, 1H), 8.46 (d, J=11.0 Hz, 1H), 8.19 (d, J=7.9 Hz, 1H), 7.82 (d, J=5.3 Hz, 1H), 7.32 (d, J=5.3 Hz, 1H), 4.42-4.77 (m, 3H), 4.13-4.21 (m, 1H), 4.12 (s, 3H), 3.97-4.08 (m, 1H), 3.76-3.89 (m, 1H), 1.51 (dd, J=6.8, 2.6 Hz, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][C:14]3[CH:18]=[CH:17][S:16][C:15]=3[C:19]([NH2:21])=[O:20])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1>O1CCOCC1.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>[CH3:22][O:23][C:24]1[C:29]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([CH2:13][C:14]4[CH:18]=[CH:17][S:16][C:15]=4[C:19]([NH2:21])=[O:20])[N:10]=[CH:9]3)=[CH:4][CH:3]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: NC(=O)c1sccc1Cc1cn(-c2ccc(I)cc2)cn1
Reactant: COc1ncccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COc1ncccc1-c1ccc(-n2cnc(Cc3ccsc3C(N)=O)c2)cc1
Temperature: 100 °C

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (0.044 g, 0.1 mmol), 2-methoxypyridine-3-ylboronic acid (0.016 g, 0.11 mmol) and Pd(PPh3)2Cl2 (0.007 g, 0.01 mmol) in p-dioxane (0.7 mL) was purged with Argon for 5 min. A degassed aqueous solution of Na2CO3 (IM, 0.3 mL) was added. After being heated at 100° C. for 2 h, the mixture was cooled to room temperature, and purified by preparative HPLC to yield 5-chloro-N-((1-(4-(2-methoxypyridin-3-yl)phenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (MS 425.0, 427.0 (M+H), Cl pattern).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=1>>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([C:22]([C:21]1[CH:20]=[N:19][C:18]([NH2:17])=[CH:26][CH:25]=1)=[O:23])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)N1C2CCCC1CNC2
Product: CC(C)(C)OC(=O)N1C2CCCC1CN(C(=O)c1ccc(N)nc1)C2
Yield: 71.8 %

Procedure:
Following general amide formation method 1, 3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (170 mg, 0.751 mmol, 1.1 eq) was combined with 6-amino-nicotinic acid (94 mg, 0.683 mmol, 1.0 eq) which gave 3-(6-amino-pyridine-3-carbonyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (170 mg) in 72% yield. 1H NMR (400 MHz, CDCl3-d) δ ppm 1.50 (s, 9H) 1.55-1.72 (m, 2H) 1.74-1.98 (m, 4H) 3.20 (qd, J=7.41, 4.55 Hz, 3H) 3.65-3.82 (m, J=13.20, 6.66, 6.66, 4.29 Hz, 2H) 4.18 (br. s., 1H) 4.28 (br. s., 1H) 4.66 (br. s., 1H) 4.85 (br. s., 1H) 6.58 (d, J=8.59 Hz, 1H) 7.57 (dd, J=8.59, 2.02 Hz, 1H) 8.04 (s, 1H) 8.16 (d, J=2.02 Hz, 1H) MS m/z 291.4 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([F:18])[C:10]=1[Cl:19])C1C=CC=CC=1.BrB(Br)Br>C(Cl)Cl>[Cl:19][C:10]1[C:11]([F:18])=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Cl)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(O)c(Cl)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
A 0° C. solution of 1-(benzyloxy)-2-chloro-3-fluoro-4-nitrobenzene (45 g, 160 mmol) in DCM (200 mL) was treated drop-wise with tribromoborane (7.9 g, 320 mmol) over 0.5 h, stirred at 0° C. for 2 h, treated with satd. NaHCO3 and was washed with brine. The organic layer was dried over Na2SO4 and concentrated to afford 2-chloro-3-fluoro-4-nitrophenol (25 g, 82%). 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1 H), 6.95 (m, 2 H), 4.67 (brs, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]=[C:9]=[S:10])=[O:7].[CH2:11]([O:13][CH2:14][C:15]1[N:16]([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]=[C:19]([NH2:25])[C:18]=2[N:26]=1)[CH3:12]>>[NH2:25][C:19]1[C:18]2[N:26]=[C:15]([CH2:14][O:13][CH2:11][CH3:12])[N:16]([CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([C:9]([NH:8][C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[O:7])=[S:10])[CH2:31][CH2:30]3)[C:17]=2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]=1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Reactant: O=C(N=C=S)c1ccco1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(C(=S)NC(=O)c2ccco2)CC1

Procedure:
Using the method of Examples 54-65, 2-furoylisothiocyanate was reacted with 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 485.2357.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1ccc(F)cc1
Reaction time: 4.5 h
Yield: 90.9 %

Procedure:
A mixture of 4-fluorocinnamic acid (300.0 g, 1.8 mol, Aldrich) and 5% palladium on carbon (9.0 g) in ethanol (3 L) was hydrogenated at atmospheric pressure and room temperature for 4.5 h. The mixture was filtered through Celite (diatomaceous earth) and the filtrate was concentrated in vacuo to give 275.1 g (91%) of 3-(4-fluorophenyl)propionic acid as a white solid: m.p., 86°-88° C.;
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[NH:15][CH:16]=[CH:17][N:18]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[CH:32](I)([CH3:34])[CH3:33]>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:32]([CH3:34])[CH3:33])[CH:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)OCCn1cc(-c3ncc[nH]3)nc1-2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1ccnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reaction time: 18 h

Procedure:
To a solution of 9-bromo-2-(1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.237 g, 0.716 mmol) and Cesium Carbonate (0.280 g, 0.859 mmol) in N,N-Dimethylformamide (4.74 mL, 61.2 mmol) was added Isopropyl iodide (0.0859 mL, 0.859 mmol). The reaction was stirred 18 h at 50 C. The reaction was quenched with water then extracted EtOAc 2×. The crude product was purified to give 9-bromo-2-(1-isopropyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. MS: (ESI+)=373.1
Reaction SMILES: [C:1]([O:10]CC)(=[O:9])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]1(=O)[CH2:18]CCC[CH2:14]1.CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[CH2:7]([O:6][C:4](=[O:5])[C:3](=[C:13]([CH3:18])[CH3:14])[CH2:2][C:1]([OH:10])=[O:9])[CH3:8]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)C(CC(=O)O)=C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a solution of of 17.4 g (0.1 mol) diethyl succinate and 9.8 g (0.1 mol) cyclohexanone in 100 ml tert-butanol was added 11.2 g (0.1 mol) potassium tert-butoxide in one portion. The mixture was allowed to stir at room temperature for 30 min. 10 ml of water were added and the solvent was removed under reduced pressure. The residue was dissolved in 100 ml water and transferred into a separation funnel. The solution was extracted twice with 50 ml ethyl acetate to remove neutral impurities, acidified with 6M HCl and extracted again twice with 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 18.5 g (82%) of a thick yellow oil. 1H-NMR: 86% conjugated, 14% deconjugated product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH3:13])[C:9]([O:11]C)=[O:10].[OH-].[Na+].C(O)(=O)C>C(O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)[C@@H](C)OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@@H](OC1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
In ethanol (510 ml) was dissolved methyl (2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionate (42.7 g), to which was added, under ice-cooling, a 2N solution of sodium hydroxide (170 ml), followed by stirring for one hour at room temperature. The reaction mixture was cooled with ice, to which was added a 26% aqueous solution of acetic acid (120 ml), followed by extraction with dichloromethane (200 ml) three times. Dichloromethane layers were combined, washed with a saturated aqueous sodium chloride solution (100 ml) twice, and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to leave (2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionic acid (32 g) as a colorless waxy product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][C:51]([C:53]1[S:54][C:55]2[CH2:56][NH:57][CH2:58][CH2:59][C:60]=2[N:61]=1)=[O:52]>CN(C=O)C>[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][C:51]([C:53]1[S:54][C:55]2[CH2:56][N:57]([C:12](=[O:14])[CH2:11][NH:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:58][CH2:59][C:60]=2[N:61]=1)=[O:52]
Reactant: O=C(O)CNc1ccc2c(c1)OCO2
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=O)CNc1ccc3c(c1)OCO3)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of (Benzo[1,3]dioxol-5-ylamino)-acetic acid. (1.0 mmol) in dry DMF (10 mL), were added 1-hydroxybenzotriazole (1.2 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2 mmol) and N-methylmorpholine (2.0 mmol). Solution was cooled to 0° C. N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide. obtained in step VIII of Example 1 was then added and mixture was stirred at room temperature overnight. Reaction mixture was concentrated, diluted with water, extracted with dichloromethane, washed with brine solution, and dried over anhydrous Na2SO4. Concentrated and purified by column chromatograph to obtained the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:23][CH2:22][CH2:21][C@H:9]1[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])=O)(C)(C)C.C(OCC)(=O)C.[ClH:30]>CCOCC>[ClH:30].[C:15]1([CH2:14][CH2:13][NH:12][C:10](=[O:11])[C@@H:9]2[CH2:21][CH2:22][CH2:23][NH:8]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(NCCc1ccccc1)[C@@H]1CCCN1

Procedure:
A solution of 1-(tert-butyloxycarbonyl)-N-(2-phenylethyl)-L-prolinamide (2.46 g.) in ethyl acetate-hydrogen chloride (3.9 N, 30 ml.) was stirred for 20 minutes at room temperature, then diluted with ether (to about 200 ml.). The solvents were decanted from the resulting gum, which was triturated with ether, affording crystalline N-(2-phenylethyl)-L-prolinamide hydrochloride (1.91 g., m.r. 147°-150° ).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5](Br)[N:6]=1.C([Li])CCC.[CH2:13]([Sn:15](Br)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]>CCOCC>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([Sn:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:13][CH3:14])[N:6]=1
Reactant: Cc1nc(Br)cs1
Reactant: CC[Sn](Br)(CC)CC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC[Sn](CC)(CC)c1csc(C)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (1.6M, 3.3 mL, 5.35 mmol) was added to a solution of 2,4-dibromothiazole (1.0 g, 4.12 mmol) in anhydrous ether (10 mL) stirred at −78 ° C. under nitrogen. After 20 minutes, methyl trifluromethanesulfonate (878 mg, 5.35 mmol) was added, then the reaction mixture was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched and washed with water, washed with brine, dried through MgSO4, and then the solvent was evaporated to give a brown oily residue of 2-methyl-4-bromo-thiazole (900 mg). Under nitrogen, the 2-methyl-4-bromo-thiazole (430 mg, 2.42 mmol) dissolved in anhydrous ether (5 mL) then cooled to −78° C. under nitrogen. n-Butyllithium (1.6M, 1.7 mL, 2.66 mmol) was added, followed, after 10 min by triethylstannyl bromide (760 mg, 2.66 mmol). The solution was then warmed to room temperature, and stirred for another 1 h. The mixture was quenched, and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give the sub-title compound give as a brown oily residue (655 mg), which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=4[NH:14][C:13]3=[O:22])[CH:10]=1)[N:7]([CH3:23])[C:6]([CH3:24])=[C:5]2[CH3:25].[C:26]([O:32][CH3:33])(=[O:31])[CH:27]=[CH:28][CH2:29][CH3:30].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C>[CH3:33][O:32][C:26](=[O:31])[CH2:27][CH:28]([N:14]1[C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[N:7]([CH3:23])[C:6]([CH3:24])=[C:5]3[CH3:25])[C:13]1=[O:22])[CH2:29][CH3:30]
Reactant: CCC=CC(=O)OC
Reactant: Cc1ccc2c(c1)[nH]c(=O)n2Cc1cc(Cl)cc2c(C)c(C)n(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCC(CC(=O)OC)n1c(=O)n(Cc2cc(Cl)cc3c(C)c(C)n(C)c23)c2ccc(C)cc21
Temperature: 120 °C
Yield: 77.7 %

Procedure:
To a solution of 1-(5-Chloro-1,2,3-trimethyl-1H-indol-7-ylmethyl)-5-methyl-1,3-dihydro-benzimidazol-2-one (40 mg, 0.11 mmol) in DMA (2 mL) were added Methyl 2-pentenoate (26 mg, 0.23 mmol) and K2CO3 (31 mg, 0.23 mmol). The reaction mixture was heated to 120° C. for 20 min in a microwave. When the reaction was completed, the reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 4:1 Hexane:ethyl acetate to afford 40 mg of the desired product. LCMS (ESMS): m/z 468.36 (M+H+).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[CH:26]=[CH:25][C:11]2[S:12][CH2:13][CH2:14][N:15]([S:16]([C:19]3[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=3)(=[O:18])=[O:17])[C:10]=2[CH:9]=1)=[O:7])(=O)[CH3:2].C1CCN2C(=NCCC2)CC1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:2][C:1]1[O:7][C:6]([C:8]2[CH:26]=[CH:25][C:11]3[S:12][CH2:13][CH2:14][N:15]([S:16]([C:19]4[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=4)(=[O:17])=[O:18])[C:10]=3[CH:9]=2)=[N:5][N:4]=1
Reactant: CC(=O)NNC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cn(C)cn1)CCS2
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nnc(-c2ccc3c(c2)N(S(=O)(=O)c2cn(C)cn2)CCS3)o1
Yield: 66.7 %

Procedure:
To a solution of N′-acetyl-4-(1-methyl-1H-imidazol-4-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbohydrazide (25 mg, 63 μmol) in THF (1 mL) was added DBU (14 mg, 95 μmol) and Burgess reagent (75 mg, 316 μmol). The reaction vial was capped subjected to microwave irradiation (150° C., 10 min). LCMS analysis of the reaction mixture indicated that the starting material had been consumed. The reaction was diluted with saturated aqueous NaHCO3 (1 mL) and EtOAc (2 mL). The organic layer was removed and the aqueous layer was extracted with EtOAc (2 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography with a gradient elution of hexanes with 10-60% EtOAc to provide 2-methyl-5-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-1,3,4-oxadiazole (16 mg, 42 μmol, 67% yield). LCMS (+ESI) m/z=377.8 [M+H]+; 1H-NMR (CDCl3) δ 8.05 (m, 2H), 7.9 (d, 2H), 7.8 (d, 2H), 7.4-7.5 (m, 3H), 7.25 (d, 1H), 7.1 (dd, 1H), 6.75 (d, 1H), 3.5 (t, 2H), 3.1 (t, 2H).