Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=O)(C)(C)C.[C:16]([Li])(C)(C)C.CI.Cl>C1COCC1.CCCCC>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:16])[C:9]=1[NH2:8]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1F
Reactant: [Li]C(C)(C)C
Agent: Cl
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1cccc(F)c1N
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
A solution of 8.15 g (38.5 mmol) of N-t-butoxycarbonyl-2-fluoroaniline in 30 ml of dry THF was coled to -70° C., and 46.3 ml (93 mmol) of 2.0M t-butyllithium in pentane was added dropwise at a rate sufficient to maintain the temperature below -65° C. When the addition was complete the reaction mixture was stirred at -70° C. for 15 minutes, warmed to -20° C. and stirred for 2.5 hours. A solution of 6.8 g (30 mmol) of methyl iodide in THF was added and the reaction was allowed to warm to room temperature. The reaction mixture was partitioned between ether and water, and the organic layer was washed with saturated aqueous NaCl and dried (MgSO4). Evaporation at reduced pressure gave a yellow solid which was added to 25 ml of 3N HCl and heated at reflux for 3 hours. After cooling to room the pH of the solution was adjusted to pH 7, and the solution was extracted twice with methylene chloride. The combined organic phases were washed with water and dried (MgSO4). Evaporation at reduced pressure gave a yellow oil which was Kugelrohr distilled to yield 3.8 g (80%) of the desired product as a liquid, bp 91°-93° C. (0.1 mm). IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:38][CH2:39][CH:40]1[CH2:44][CH2:43][CH2:42][N:41]1[CH2:45][CH3:46]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:45]([N:41]1[CH2:42][CH2:43][CH2:44][CH:40]1[CH2:39][NH:38][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH:13]=1)[CH3:46]
Reactant: COc1ccc(C(=O)O)cc1OC/C=C(\C)CCC=C(C)C
Reactant: CCN1CCCC1CN
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CCCC1CNC(=O)c1ccc(OC)c(OC/C=C(\C)CCC=C(C)C)c1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
3-geranyloxy-4-methoxybenzoic acid(1.52 g) was dissolved in chloroform (50 ml) and triethylamine (1.4 ml), and then diphenylphosphinic chloride(1.0 ml) was added thereto while being cooled with ice. After being stirred for 15 minutes, the mixture, with 2-aminomethyl-1-ethylpyrrolidine(0.7 ml) added thereto, was stirred for 1.5 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1), thereby yielding 1.47 g(71%) of the aimed compound.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.C([Br:19])(=O)C>C1(C)C=CC=CC=1>[Br:19][CH:2]1[CH2:3][C:4](=[O:5])[N:13]([C:12]2[CH:14]=[CH:15][C:9]([F:8])=[CH:10][CH:11]=2)[C:1]1=[O:7]
Reactant: CC(=O)Br
Reactant: Nc1ccc(F)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C1CC(Br)C(=O)N1c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
29.4 g. (0.3 mole) maleic acid anhydride were dissolved in 300 ml. toluene and a solution of 33.3 g. (0.3 mole) 4-fluoroaniline in 100 ml. toluene added thereto at 30° C. The hemi-anilide rapidly precipitated out. For the completion of the reaction, the mixture was heated for 2 hours to 100° C., then cooled, the precipitated product filtered off, washed and dried. The yield of hemi-anilide was quantitative. The hemianilide was suspended in acetic acid ethyl ester and 43 g. (0.35 mole) acetyl bromide added thereto. The reaction was carried out by stirring at 30° C. (2 hrs.) and by subsequent 2 hours heating to reflux, thereafter the solvent was distilled off and the residue crystallised. The yield amounted to 69.2 g. (corresponding to 85.5% of theory). The product displayed a melting point of 154° C.
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]([NH:15]C(=O)OC(C)(C)C)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:23]>ClCCl.O1CCOCC1.C(OCC)C>[ClH:23].[ClH:23].[N:1]1([CH2:7][C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:15])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H](CN1CCOCC1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: N[C@H](CN1CCOCC1)c1ccccc1
Reaction time: 18 h
Yield: 90 %

Procedure:
A solution of 11.58 g (0.0378 mol) of tert-butyl (1S)-2-morpholin-4-yl-1-phenylethylcarbamate in 100 mL of dichloromethane was treated with 120 mL of HCl 4M in dioxane and stirred for 18 hours. The mixture was diluted with diethylether and the product filtered (9.48 g, 90% yield).
Reaction SMILES: [N:1]1(C2C=CC(NC3C4N(C=CN=4)C(C4C=C5C(=CC=4)C(=O)NC5)=CN=3)=CC=2)CCOCC1.Br[C:34]1[N:39]2[CH:40]=[CH:41][N:42]=[C:38]2[C:37]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:55][CH2:54][N:53]([CH:56]([CH3:58])[CH3:57])[CH2:52][CH2:51]3)=[CH:46][CH:45]=2)=[N:36][CH:35]=1.CC1(C)C(C)(C)OB([C:67]2[CH:68]=[C:69]([C:72]([NH2:74])=[O:73])[O:70][CH:71]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH3:1].[CH:56]([N:53]1[CH2:54][CH2:55][N:50]([C:47]2[CH:48]=[CH:49][C:44]([NH:43][C:37]3[C:38]4[N:39]([CH:40]=[CH:41][N:42]=4)[C:34]([C:67]4[CH:68]=[C:69]([C:72]([NH2:74])=[O:73])[O:70][CH:71]=4)=[CH:35][N:36]=3)=[CH:45][CH:46]=2)[CH2:51][CH2:52]1)([CH3:58])[CH3:57]
Reactant: CC1(C)OB(c2coc(C(N)=O)c2)OC1(C)C
Reactant: O=C1NCc2cc(-c3cnc(Nc4ccc(N5CCOCC5)cc4)c4nccn34)ccc21
Reactant: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)N1CCN(c2ccc(Nc3ncc(-c4coc(C(N)=O)c4)n4ccnc34)cc2)CC1
Product: N
Yield: 36 %

Procedure:
In the same way as described for Compound 178, step 4, using, 5-bromo-imidazo[1,2-a]pyrazin-8-yl-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-amine (0.08 g, 0.19 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-furan-2-carboxylic acid amide (0.092 g, 0.39 mmol), 1.5M Na2CO3 (1.02 mL, 1.53 mmol) and Pd(PPh3)4 (0.055 g, 0.47 mmol) in dioxane (4 mL). Purification using silica gel column chromatography, eluting with DCM followed by 97:3 DCM:NH3 (7M in MeOH), affords the title compound (30.2 mg, 36%).
Reaction SMILES: [OH-:1].[Na+].[C:3]([C:5]1[C:10]2[CH2:11][C:12](=NN)[C:13]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:14]=3[S:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)#N.[OH2:23]>C(O)COCCO>[C:3]([C:5]1[C:10]2[CH2:11][CH2:12][C:13]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:14]=3[S:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)([OH:23])=[O:1]
Reactant: [OH-]
Reactant: O
Reactant: N#Cc1cccc2c1CC(=NN)c1ccc(F)cc1S2
Agent: [Na+]
Solvent: OCCOCCO
Product: O=C(O)c1cccc2c1CCc1ccc(F)cc1S2
Reaction time: 2 h

Procedure:
To 1.0g of sodium hydroxide dissolved in 15ml of diethylene glycol was added 1.0g of 9-cyano-3-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one hydrazone and the resulting mixture was heated with stirring at 190°-200° C for 2 hours. After cooling, water was added to the mixture, which was extracted with benzene. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was chromatographed over silica gel, and eluted with ethyl acetate-benzene (1:10), and there was obtained the crude product. Recrystallization from methanol afforded 102mg of 9-carboxy-3-fluoro-10,11-dihydrodibenzo[b,f]thiepin having a melting point of 209°-211° C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:18][C:19]1([CH:34]=O)[CH2:23][CH:22]2[CH:24]([CH3:33])[C:25]([N+:30]([O-:32])=[O:31])=[C:26]([CH3:29])[C:27]([CH3:28])=[C:21]2[O:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C.O>[N+:30]([C:25]1[CH:24]([CH3:33])[CH:22]2[CH2:23][C:19]([CH2:18][N:15]3[CH2:16][CH2:17][N:12]([C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[CH:4][N:3]=[CH:2]5)=[CH:11][CH:10]=4)[CH2:13][CH2:14]3)([CH3:34])[O:20][C:21]2=[C:27]([CH3:28])[C:26]=1[CH3:29])([O-:32])=[O:31]
Reactant: c1cn(-c2ccc(N3CCNCC3)cc2)cn1
Reactant: CC1=C2OC(C)(C=O)CC2C(C)C([N+](=O)[O-])=C1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CC1=C2OC(C)(CN3CCN(c4ccc(-n5ccnc5)cc4)CC3)CC2C(C)C([N+](=O)[O-])=C1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
0.7 g of 1-(4-imidazol-1-ylphenyl)-piperazine and 0.7 g of 2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-aldehyde were dissolved in 20 ml of methylene chloride and 1 ml of acetic acid as a catalyst was added, followed by stirring at room temperature for 30 minutes. To the resulting reaction solution, 1.2 g of sodium triacetoxyborohydride was added, followed by stirring at room temperature for 30 minutes. After the completion of the reaction, the reaction solution was poured into water, neutralized with an aqueous saturated sodium hydrogen carbonate solution and then extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, 1.3 g of the objective product was obtained.
Reaction SMILES: [N:1]([CH:4]([C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)[CH2:5][CH2:6][OH:7])=[N+]=[N-]>[Pd].C(OCC)(=O)C>[NH2:1][CH:4]([C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=1)[CH2:5][CH2:6][OH:7]
Reactant: [N-]=[N+]=NC(CCO)c1ccc(C(F)(F)F)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NC(CCO)c1ccc(C(F)(F)F)nc1
Reaction time: 8 h

Procedure:
A mixture of 3-azido-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (7.29 g, 29.6 mmol), ethyl acetate (320 mL), and 10% Pd—C (3.2 g) was stirred under H2 (1 atm) overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo to yield the title product.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([Cl:10])=[O:9])=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.Cl>CCOCC.O1CCOCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:9])=[CH:4][CH:3]=1.[ClH:10].[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)Cl
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN1CCN(C(=O)C(C)(C)Oc2ccc(Br)cc2)CC1

Procedure:
1-(2-(4-Bromophenoxy)-2-methylpropanoyl)-4-methylpiperazine was prepared in accordance to the procedure described in Example 29(a) from 2-(4-bromophenoxy)-2-methylpropanoyl chloride and 1-methylpiperazine (5.3 mL, 17.5 mmol). This compound (2.37 g, 6.95 mmol) was dissolved in Et2O and HCl in dioxane (4M, 2.26 mL) was added dropwise with stirring. The precipitate was filtered off and dried to yield the sub-title compound (2.5 g, 95%).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][C:37]([Cl:44])=[N:38][C:39]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:46]1([CH2:52][CH2:53][O:54][NH2:55])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.ClCCl>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[C:35]2[N:36]=[C:37]([Cl:44])[N:38]=[C:39]([NH:55][O:54][CH2:53][CH2:52][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]=2[N:41]=[CH:42]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NOCCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OC[C@H]1O[C@@H](n2cnc3c(NOCCc4ccccc4)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 65.6 %

Procedure:
9-(2,3,5-Tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.0 g, 3.2 mmol), O-(2-phenylethyl)hydroxylamine hydrochloride (0.70 g, 4.0 mmol) and diisopropylethylamine (0.95 g, 7.4 mmol) were dissolved in 1,4-dioxan (40 ml) and heated at reflux for 3 days. After cooling the reaction mixture was diluted with dichloromethane (50 ml) and washed with water (2×30 ml). The organic phase was dried (MgSO4). Flash chromatography on a silica gel column, eluting with heptane/ethyl acetate (1/1) gave the desired product as a foam (1.54 g, 66%), 1H NMR (DMSO-d6)γ 3.05 (2H, t, --OCH2 --), 4.19 (2H, t,--CH2Ph), 4.70 (1H, dd, H-5'a), 4.80 (1H, dd, H-5'b), 4.90 (1H, dd, H-4'), 5.22 (1H, t, H-3'), 6.39 (1H, t, H-2'), 6.59 (1H, d, H-1'), 8.51 (1H, s H-8).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:13]1=O)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C(=O)NC(=O)NC1=O.COC(OC)(C)C>CC(C)=O>[CH3:1][O:2][CH2:3][C@H:4]1[C@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C@H:13]2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5]1
Reactant: COCC(Nc1ccccc1)=C1CCN(C(=O)OCc2ccccc2)C1=O
Agent: O=c1[nH]c(=O)[nH]c(=O)[nH]1
Solvent: CC(C)=O
Solvent: COC(C)(C)OC
Product: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 20 mL Schlenk flask were charged [Rh(cod)2]OTf (6.4 mg) [mw. 468.34, 0.0136 mmol, s/c 50] and (2S,4S)-3,5-xylyl-skewphos (9.0 mg) [mw. 552.71, 0.0163 mmol], and the system was substituted with argon. Deaeration-treated dehydrated acetone (5 mL) was added by argon pressure supply. Under an argon atmosphere, the mixture was stirred at room temperature for 1 hr. Separately, into a 120 mL stainless autoclave were charged benzyl 3-(2-methoxy-1-(phenylamino)ethylidene)-2-oxopyrrolidine-1-carboxylate (250.0 mg) [mw. 366.41, 0.682 mmol] and cyanuric acid (88.0 mg) [mw. 129.08, 0.682 mmol], and the system was substituted with argon. The catalyst in the Schlenk flask was added into the autoclave by argon pressure supply. A mixture of 2,2-dimethoxypropane (244 μL) [mw. 104.15, 2.05 mmol] and deaeration-treated dehydrated acetone (3 mL) added by argon pressure supply in the Schlenk flask was added into the autoclave by argon pressure supply. Furthermore, the inside of the Schlenk flask was washed with dehydrated acetone (2 mL), and the washing was added into the autoclave by argon pressure supply. Hydrogen was filled therein to 6 MPa, and the mixture was stirred at a reaction temperature of 60° C. for 16 hr. The reaction mixture was allowed to cool to room temperature and depressurized. The reaction mixture was subjected to high performance liquid chromatography and area percentage and optical purity of the resultant product, (3aR,4R,9bR)-benzyl 4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate, were determined to find production at a ratio of 95%. The optical purity was 22% ee.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:15]=[CH:14]C=1C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([OH:34])[CH3:33].N.C1(P([N:50]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:15]=[CH:14][C:33]=1[C:32]([NH2:50])=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Yield: 48.3 %

Procedure:
A solution of 2-(benzylamino)-4-(4-benzoylpiperazin-1-yl)benzoic acid (80 mg, 0.2 mmol), 2 M ammonia ethanol solution (0.60 ml, 1.2 mmol), tiethylamine (0.08 ml, 0.57 mmol) and diphenylphosphoryl azide (0.045 ml, 0.2 mmol) in 15 ml THF was stirred for 16 hours. The run was quenched with 1 ml water and all the solvents were evaporated under vacuum. 2-(benzylamino)-4-(4-bezoylpiperazin-1-yl)benzamide (40 mg, 40%) was obtained by flash column chromatograph (60% ethyl acetate in hexanes), and its hydrochloride was made by bubbling HCL gas in ether solution. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 3.28-3.670 (br, 8H), 4.43 (s, 2H), 5.00 (s, 1H), 6.06 (s, 1H), 6.24 (d, J=8.2 Hz, 1H), 7.00 (s, 1H), 7.12-7.65 (m, 13H), 7.67 (d, J=8.8 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 43.5, 46.0, 95.3, 102.7, 127.0, 127.3, 128.3, 128.4, 128.5, 128.6, 129.6, 132.4, 136.0, 139.3, 151.7, 154.2, 167.0, 168.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](C(O)=O)[CH:3]=1.C([N:13](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl>C(O)(C)(C)C.O1CCOCC1.O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:13])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: CCN(CC)CC
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: Nc1cc(Cl)ccn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-pyridinecarboxylic acid (5.95 g) in tert-butanol (89.25 mL) were added triethylamine (6.32 mL) and diphenylphosphoryl azide (8.95 mL). The mixture was stirred at 100° C. for overnight. To the solution was added water and the mixture was extracted with EtOAc and washed with water and brine. The extract was dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized with EtOAc to give a white solid. The solid was dissolved in dioxane (50 mL). To the solution was added 4M HCl in dioxane (90 mL) and the mixture was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure to give 4-chloro-2-pyridinamine hydrochloride (3.02 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][N:12](C)C=O>>[CH3:11][NH:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: CNc1ncccc1[N+](=O)[O-]
Yield: 80 %

Procedure:
25 g (0.16M) of 2-chloro-3-nitropyridine is dissolved in 200 ml dimethylformamide. For three hours monomethylamine is bubbled into the solution. The mixture is heated to reflux overnight. After the solvent is removed the oily residue is triturated with water and the solid is collected and air dried. The crude material is recrystallized from hexane to give 19.5 g (80% yield) of title compound, melting point 62°-3° C.
Reaction SMILES: [CH:1]([C:4]1[C:8](=[O:9])[O:7][CH2:6][C:5]=1[N:10]1[CH2:14][CH2:13][C:12]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[C:11]1=[O:27])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]([C:4]1[C:8](=[O:9])[O:7][CH2:6][C:5]=1[N:10]1[CH2:14][CH2:13][C:12]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:11]1=[O:27])([CH3:3])[CH3:2]
Reactant: CC(C)C1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(4-isopropyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (195 mg, 0.515 mmol) in methylene chloride was added trifluoroacetic acid at rt and the resulting solution was stirred at rt for 1 h. After removing the volatiles the residue was dissolved in methylene chloride and treated with hydrogen chloride (2 mL, 4 N in dioxane) and concentrated again to give 2-(4-isopropyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one as hydrogen chloride salt. LCMS: (M+1)+: 279.16.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]([C:29]4[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:36])[N:23]=[CH:24][C:25]=3[CH:26]([CH3:28])[CH3:27])=[CH:15][C:14]=2[CH3:37])[CH3:12])[CH:5]=1.[OH-:39].[Li+].[O:41]1[CH2:46]COCC1>>[Cl:35][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:36])[C:29]=1[N:22]1[C:21]([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([CH:11]([S:10][C:6]3[CH:5]=[CH:4][C:9]([C:46]([OH:41])=[O:39])=[CH:8][CH:7]=3)[CH3:12])=[C:14]([CH3:37])[CH:15]=2)=[C:25]([CH:26]([CH3:28])[CH3:27])[CH:24]=[N:23]1
Reactant: [OH-]
Reactant: C1COCCO1
Reactant: COC(=O)c1cccc(SC(C)c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)c1
Agent: [Li+]
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C(C)Sc1ccc(C(=O)O)cc1
Temperature: 50 °C

Procedure:
To an ambient temperature solution of 3-(1-{4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-ethylsulfanyl)-benzoic acid methyl ester (10 mg, 0.0176 mmol) in dioxane (2 mL) is added a solution of lithium hydroxide (26 μL, 0.052 mmol, 2.0N in water). The reaction mixture is heated to 50° C. The reaction mixture is concentrated and the residue is partitioned between Et2O and water. The aqueous layer pH is adjusted to approximately 4 and is extracted with a second portion of Et2O. The combined organic layers are washed with water, dried (MgSO4), filtered and concentrated to yield the title compound (10 mg, quant). ES/MS m/e (35Cl) 556.3 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][O:10][C:12](=[O:13])[O:11]2)=[CH:6][CH:7]=1
Reactant: OCC(O)c1ccc(Br)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1OCC(c2ccc(Br)cc2)O1
Temperature: 40 °C
Yield: 56.6 %

Procedure:
1-(4-bromophenyl)ethane-1,2-diol (0.15 g, 0.69 mmol) was dissolved in 7 mls of dry acetonitrile, followed by the addition of carbonyldiimidazole (0.17 g, 1.04 mmol). This mixture was warmed to 40° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with saturated ammonium chloride solution, water, dried over sodium sulfate and concentrated under reduced pressure. 10 g Sep Pak purification (1:1 EtOAc:Hexanes) afforded 0.095 g of 4-(4-bromophenyl)-1,3-dioxolan-2-one (57%) as a white solid.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8].[C-:13]#[N:14].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]([OH:8])[C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1
Reactant: [C-]#N
Reactant: O=Cc1cccc(OC(F)F)c1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC(O)c1cccc(OC(F)F)c1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To 3-difluoromethoxybenzaldehyde (1.77 g, 10 mmol) in ethyl acetate (25 mL) was added a solution of KCN (2.0 g) and NaHSO3 (3.2 g) dissolved in H2O (25 mL). It was left stirring overnight before it was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 131A (1.85 g, 92% yield) as an oil.