Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][OH:14])=O)(C)(C)C.ClC1C=C(OC[C@@H]2CCCN2C(OC(C)(C)C)=O)C=NC=1.C(O[C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[CH2:48]O)=O)(C)(C)C>>[CH3:48][C:44]1[C:45]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:46][CH:47]=[CH:41][N:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Cl)c1
Product: Cc1ncccc1OC[C@H]1CCCN1

Procedure:
Replacing (S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol of Example 15 with (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (Aldrich Chemical Co.), and following the procedure of steps 15a and 15b, the title compound was prepared. The MS and 1H NMR spectra were similar to compound 15a.
Reaction SMILES: COC(C1CC(=O)[N:7](C2C=CC(O)=CC=2)[CH2:6]1)=O.FC1C=CC(C)=C(C=1)CBr.C[O:29][C:30]([CH:32]1[CH2:36][C:35](=[O:37])[N:34]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]3[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][C:47]=3[CH3:53])=[CH:40][CH:39]=2)[CH2:33]1)=O>C(O)C>[CH3:6][NH2:7].[CH3:6][NH:7][C:30]([CH:32]1[CH2:36][C:35](=[O:37])[N:34]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]3[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][C:47]=3[CH3:53])=[CH:40][CH:39]=2)[CH2:33]1)=[O:29]
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3cc(F)ccc3C)cc2)C1
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Agent: Cc1ccc(F)cc1CBr
Solvent: CCO
Product: CN
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3cc(F)ccc3C)cc2)C1

Procedure:
The title compound is prepared by alkylation of the (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester with 5-fluoro-2-methylbenzyl bromide giving the (RS)-1-[4-(5-fluoro-2-methyl-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid [71% of theory, MS: m/e=358 (M+H)+] which, thereupon, by treatment with methylamine in ethanol at 60° C. during 4 h yields the (RS)-1-[4-(5-fluoro-2-methyl-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide. Yield: 53% of theory as a colorless solid. MS: m/e=357 (M+H)+.
Reaction SMILES: O1CCCC1.[CH3:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:9].[Br:24]Br.C(=O)([O-])O.[Na+]>CCCCCC.C(OCC)(=O)C>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH:7]([Br:24])[CH3:6])=[CH:11][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(Br)C(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To 100 mL of a tetrahydrofuran solution of 24.00 g (100 mmol) of 4-benzyloxypropiophenone, a hexane solution (20 mL) of 23.973 g (1.5 equivalents) of bromine was gradually added at 20° C., followed by 1 hour of stirring. To the resulting solution, 50 mL of a saturated sodium hydrogen carbonate solution and 100 mL of ethyl acetate were added to conduct extraction. The organic layer was washed with 30 mL of a 20 wt % sodium thiosulfate aqueous solution, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvents. A colorless, oily substance was obtained as a result. To this substance, 200 mL of hexane was added to precipitate crystals. White crystals (31.12 g; isolation yield: 95%) of 1-[4-(benzyloxy)phenyl]-2-bromo-1-propanone were obtained as a result.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].Cl.[CH3:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][SH:27])[CH2:20][CH2:19]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[OH2:9].[ClH:10].[ClH:10].[C:1]1([NH:7][C:8](=[SH:27][CH2:26][CH2:25][CH2:24][N:21]2[CH2:20][CH2:19][N:18]([CH2:17][C:16]3[CH:15]=[CH:14][C:13]([CH3:12])=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:9].[OH2:9].[C:1]1([NH:7][C:8](=[SH:27][CH2:26][CH2:25][CH2:24][N:21]2[CH2:20][CH2:19][N:18]([CH2:17][C:16]3[CH:15]=[CH:14][C:13]([CH3:12])=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].[ClH:10]
Reactant: Cc1ccc(CN2CCN(CCCS)CC2)cc1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(CN2CCN(CCC[SH]=C(O)Nc3ccccc3)CC2)cc1
Product: O
Yield: 48.2 %

Procedure:
The procedure described in Example 2 was followed, using 1.4 g of phenyl isocyanate, 4.0 g of 3-[4-(4-methylbenzyl)piperazin-1-yl]propanethiol dihydrochloride, 1.2 g of triethylamine and 50 ml of methylene chloride, to give 1.1 g (20% of theory) of N-phenyl-S-{3-[4-(4-methylbenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride sesquihydrate as a white crystalline solid, M.p. 255°-258° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[N:17]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:29][CH:28]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: Nc1ccc(CN2CCCCC2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(CN2CCCCC2)cc1
Temperature: 115 °C
Yield: 84.6 %

Procedure:
6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (100 mg, 0.350 mmol) and 4-piperidin-1-ylmethyl-phenylamine (67 mg, 0.35 mmol) are suspended in 5 ml of dimethylformamide. Mixture is heated at 115° C. for 2 hours forming a homogeneous mixture. Mixture is cooled to room temperature and concentrated on high vacuum to yield an orange oil. Residue is taken up in ethyl ether causing an orange solid to form. Mixture is filtered, and residue washed with 50 ml of ethyl ether to afford the product as an orange solid (130 mg, 0.296 mmol, 85%); 1H NMR (DMSO-d6) δ 1.37-1.52 (m, 6H), 2.25-2.36 (m, 4H), 3.40 (s, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.39 (dd, J=1.6, 8.4 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.89 (d, J=8.4 Hz, 1H), 8.44 (d, J=1.6 Hz, 1H), 8.92 (d, J=12.8 Hz, 1H), 11.39 (s, 1H), 12.50 (d, J=12.7 Hz, 1H).
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1F)[C:10]#[N:11].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:10]#[N:11]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)c(F)c1
Temperature: 100 °C
Reaction time: 5.5 h
Yield: 99.2 %

Procedure:
To a DMF (20 mL) solution of 3,4-difluorobenzonitrile (3.00 g), morpholine (2.82 g) and potassium carbonate (5.97 g) were added, and the reaction solution was allowed to be warmed to 100° C. and agitated for 5.5 hours. Water and ethyl acetate were added to the reaction solution after confirming disappearance of the starting materials, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and 4.41 g of the title compound was obtained by condensing under reduced pressure. The physical properties of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4](Cl)[N:3]=1.N.[OH-].[Na+].FC1C=CC2N=C[N:20](C3N=C4C(NC(=O)N4C4CCOCC4)=C(C(N4CCCCC4)=O)N=3)C=2C=1>O>[ClH:8].[Cl:8][C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH2:20])[C:5]=1[NH2:9]
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Reactant: O=C(c1nc(-n2cnc3ccc(F)cc32)nc2c1[nH]c(=O)n2C1CCOCC1)N1CCCCC1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cl
Product: Nc1nc(N)c(N)c(Cl)n1
Temperature: 25 °C
Yield: 87 %

Procedure:
6-chloropyrimidine-2,4,5-triamine hydrochloride was prepared as described in WO 94/07892. 2,5-Diamino-4,6-dichloropyrimidine (10.8 g, 60.3 mmol) and concentrated aqueous ammonia (30 mL) were heated together in a sealed tube at 105° C. for 18 h, then cooled to room temperature. 2.34 g NaOH in water (10 mL) was added and the excess ammonia stripped out by concentrating to a low volume. Dilute HCl 2N (35 mL) and water (10 mL) were added and heated to dissolve, cooled to crystallize, then filtered to give the desired 6-chloropyrimidine-2,4,5-triamine hydrochloride (87% yield). MS (EI) m/z 160.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.Cl.[NH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[N:22][CH:21]=[CH:20]2)=[O:15].CCN(C(C)C)C(C)C.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH:23]1[C:24]2[C:19](=[CH:18][C:17]([NH:16][C:14](=[O:15])[CH2:13][NH:12][CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=3)=[CH:26][CH:25]=2)[CH:20]=[CH:21][N:22]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: NCC(=O)Nc1ccc2cnccc2c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNCc1cccc(Cl)c1)Nc1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To m-chlorobenzaldehyde in MeOH was added 2-amino-N-(isoquinolin-6-yl)acetamide dihydrochloride (from Example 40) and the pH was adjusted to 5 with DIPEA. The mixture was stirred at room temperature for 2 hours, then NaCNBH3 was added and the pH was adjusted to ˜5.0 with acetic acid. The mixture was stirred 12 hours, quenched with Na2CO3(sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated to give N-(isoquinolin-6-yl)-2-(3-chlorobenzylamino)acetamide (E59).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[OH-].[K+].C(=O)=O.[CH2:31]1[O:33][CH:32]1CO>>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([O:24][CH2:25][CH:32]3[O:33][CH2:31]3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: OCC1CO1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Product: COC12C(CO)C3=C(C(=O)C(C)=C(OCC4CO4)C3=O)N1CC1NC12
Product: NC(=O)O
Yield: 33 %

Procedure:
A solution of mitomycin A (100 mg or 0.286 mmole) in 4 ml of glycidol was stirred at room temperature and under nitrogen for 45 minutes with 500 mg of a 1.6% solution of KOH in glycidol. The reaction mixture was decomposed with excess dry ice while immersing the flask into a water bath at room temperature. The crude reaction product was chromatographed on a silica gel column using first CHCl3 -MeOH 9.5:0.5, which elutes glycidol and pink by-products, and then CHCl3 -MeOH 9:1, which elutes the product. The product was further purified by preparative thin layer chromatography on silica gel with a mixture of CHCl3 and methanol 9:1 as the solvent. Thus, there was obtained 712 mg (33%) of the desired product, which gave indefinite decomposition on heating and provided the following compound analysis:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[NH2:24][CH:25]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:26]([O:28][CH3:29])=[O:27].[O:37]1CCC[CH2:38]1>>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:38]([NH:24][CH:25]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[C:26]([O:28][CH3:29])=[O:27])=[O:37])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(N)c1ccc(F)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(NC(=O)NC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Amino-1-benzylpiperidine (460 mg, 2.42 mmol) in tetrahydrofuran (15 mL) was added to a solution of p-nitrophenylchloroformate (487 mg, 2.42 mmol) and diisopropylethylamine (430 uL, 2.42 mmol) in tetrahydrofuran (5 mL) at 0° C. After 1 h, additional diisopropylethylamine was added (860 uL, 4.84 mmol) along with methyl amino(4-fluorophenyl)acetate (443 mg, 2.42 mmol). The reaction was warmed to room temperature and stirred overnight. The mixture was filtered, concentrated and redissolved in ethyl acetate. The ethyl acetate layer was washed with 1N sodium hydroxide (3×), saturated sodium bicarbonate solution, water, brine, and dried over sodium sulfate. The crude product was purified by column chromatography (silica gel, 0 to 5%/methanol in methylene chloride gradient elution), giving the title compound (700 mg). MS 400.29 (M+1)
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][S@:5](=[O:29])[C@@H:6]2[C@H:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16](=[O:28])[N:7]2[C:8]=1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].O.[Cl-].[NH4+].[Mg]>CN(C)C=O.C(OCC)(=O)C>[CH2:2]=[C:3]1[C@H:8]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[N:7]2[C:16](=[O:28])[C@@H:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:6]2[S@@:5](=[O:29])[CH2:4]1
Reactant: CC(C)(C)OC(=O)C1=C(CBr)C[S@](=O)[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=C1C[S@](=O)[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a stirred solution of 480 mg (1 mmole) of tertbutyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenylacetamido-3-cephem-4-carboxylate in 12.5 ml of dimethylformamide was added 2.5 ml of water, 1 g of ammonium chloride and 500 mg of magnesium powder at 0° C. After stirring for 2 hours at 0° C. 100 ml of ethyl acetate was added. After filtration the diluted reaction mixture was subsequently washed with water, 1N hydrochloric acid, brine, and dried with magnesium sulfate. After treating the dried solution with diethylether and n-hexane the title product was filtered off, washed with n-hexane and dried, yielding 382 mg of tert-butyl (1S,4R,6R,7R)-3-methylene-1-oxo-7-phenylacetamido-cepham-4-carboxylate.
Reaction SMILES: [CH:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[OH-].[Na+].O1CCOCC1>[CH:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1=NOC(C2CCCCC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1=NOC(C2CCCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 5-cyclohexyl-4,5-dihydroisoxazole-3-carboxylate (0.1 g; 0.44 mmol) was dissolved in a mixture of sodium hydroxide (5 mL, 1M in water) and dioxane (2 mL). The reaction mixture was stirred vigorously at room temperature overnight and concentrated under reduced pressure. The resulting solution was acidified and extracted with ethyl acetate, dried and concentrated under reduced pressure and the crude material was used without further purification.
Reaction SMILES: [N-:1]=[C:2]=[S:3].[Na+].[N:5]1C=CC=CC=1.CS(O[N:16]=[C:17](Cl)[C@H:18]1[CH2:22][O:21][C:20]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:19]1)(=O)=O.CC1C(OC2C(N)=NC=C(SC3C=CC=CN=3)C=2)=CC=C(C)N=1>C(#N)C>[O:19]1[C:20]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:21][CH2:22][CH:18]1[C:17]1[N:1]=[C:2]([NH2:5])[S:3][N:16]=1
Reactant: [N-]=C=S
Reactant: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Reactant: c1ccncc1
Agent: Cc1ccc(Oc2cc(Sc3ccccn3)cnc2N)c(C)n1
Agent: [Na+]
Solvent: CC#N
Product: Nc1nc(C2COC3(CCCCC3)O2)ns1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
To a solution of sodium isothiocyanate (0.24 g, 3.0 mmol) in acetonitrile (30 mL) was added pyridine (0.51 g, 6.5 mmol) followed by (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (0.77 g, 2.6 mmol) and the reaction was stirred at 60° C. for 20 minutes, followed by addition of 3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (0.70 g, 2.2 mmol) and the reaction was stirred overnight at 60° C. The reaction was concentrated in vacuo and the residue partitioned between EtOAc and 2 M NaOH. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The material was purified over silica gel (30% EtOAc in CH2Cl2) to afford (S)-N-(3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl-1,2,4-thiadiazol-5-amine (0.50 g, 0.91 mmol, 42% yield).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=3[O:26][CH3:27])=[CH:14][C:13]2=[O:28])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30]N(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[OH:61][C@@H:62]([CH2:92]O)[CH2:63][N:64]1[CH:68]=[CH:67][C:66]([NH:69]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:65]1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=3[O:26][CH3:27])=[CH:14][C:13]2=[O:28])[C:9]([NH:69][C:66]2[CH:67]=[CH:68][N:64]([CH2:63][C:62]([OH:61])([CH3:92])[CH3:30])[N:65]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)O)C2)c1OC
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1OC
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 41.4 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,3-dimethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (150 mg, 0.39 mmol) in dichloromethane (8 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (225 mg, 1.2 mol) and N,N-diisopropylethylamine (254 mg, 2.0 mol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (180 mg, 1.2 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 60 mg, 0.39 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-2-[4-(2,3-dimethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (85 mg, 42%) as a light brown sticky solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.82-1.09 (m, 2H), 1.15 (br. s., 3H), 1.16 (br. s., 3H), 1.18-1.32 (m, 3H), 1.60-1.96 (m, 8H), 3.68 (s, 1H), 3.84 (s, 3H), 3.90 (s, 3H), 3.94 (s, 2H), 4.10 (d, J=17.9 Hz, 1H), 4.26 (d, J=17.9 Hz, 1H), 4.89 (dd, J=8.8, 6.8 Hz, 1H), 4.97 (s, 1H), 6.69 (d, J=2.1 Hz, 1H), 6.78 (d, J=8.3 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H), 7.05 (t, J=8.3 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 8.64 (s, 1H).
Reaction SMILES: O.[NH:2]1[C:10](=[O:11])[C:8](=O)[C:6](=[O:7])[NH:5][C:3]1=[O:4].S(=O)(=O)(O)O.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Hg]>[C:17]1([CH3:23])[CH:22]=[CH:21][C:20]([C:8]2([C:20]3[CH:21]=[CH:22][C:17]([CH3:23])=[CH:18][CH:19]=3)[C:10](=[O:11])[NH:2][C:3](=[O:4])[NH:5][C:6]2=[O:7])=[CH:19][CH:18]=1
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Hg]
Solvent: O
Product: Cc1ccc(C2(c3ccc(C)cc3)C(=O)NC(=O)NC2=O)cc1

Procedure:
In a 500 cc. 3-necked flask fitted with a reflux condenser, a mercury seal stirrer and a thermometer in a well, were placed 16 g. of alloxan monohydrate and 60 g. of sulfuric acid, sp.gr. 1.84. Then 75 cc. of toluene were added through the reflux condenser and the mixture heated in an oil-bath, with stirring for four and one-half hours at 75°-80°. After this time the reaction mixture was cooled, most of the toluene later decanted, and the sirupy sulfuric acid later poured into 150 cc. of cold water. The precipitated material was filtered and washed in a beaker with 100 cc. of water and refiltered. After drying in a vacuum this material was dissolved in 160 cc. of boiling glacial acetic acid, filtered and allowed to crystallize.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.O>[CH2:24]([O:31][C:32]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C1Cc2ccc(N)cc2NC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1Cc2ccc(NC(=O)OCc3ccccc3)cc2NC1=O

Procedure:
To a suspension of ethyl 7-amino-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxylate (2.0 g) in THF(40 ml) was added aqueous sodium carbonate (4.5 g in 40 ml) and cooled, to which benzylchloroformate (1.8 ml) was added dropwise. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried, and concentrated. The precipitated crystals were washed with hexane to obtain the entitled compound (3.07 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(O)C>[C:11]1([C:2]2[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)c1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)c1cncc(-c2ccccc2)c1

Procedure:
A mixture of 5-Bromo-3-acetylpyridine (2 g, 10 mmol), phenylboronic acid (1.5 g, 12 mmol), trans-dibromobis(triphenylphosphine) palladium (II) (0.4 g, 0.5 mmol), toluene (60 ml), ethanol (20 ml) and 2M aqueous sodium carbonate (40 ml) was refluxed for 1 hour under a nitrogen atmosphere. The mixture was diluted with ethyl acetate and the organic phase was washed with water and brine, dried and evaporated. The crude product was chromatographed on silica gel eluting with a gradient of 0-100% EtoAc in hexane to afford the: 5-(Phenyl)-3-acetylpyridine as a solid. 2 g (10 mmol, 100%). TLC Rf 0.3 (1:1 hexane/EtOAc); MS: 198.5 (M+H); 1H NMR (DMSO) δ 9.12 (dd, J=2.2 Hz, 2H), 8.50 (t, J=2.1 Hz, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.54 (t, J=7.7 Hz, 2H), 7.49 (t, J=7.7 Hz, 1H), 3.02 (s, 3H); 13C NMR δ 197.51, 151.30, 148.12, 136.14, 135.51, 134.05, 133.34, 132.00, 129.91, 129.78, 129.19, 127.64, 27.14.