Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCCl.CN([CH:8]=[O:9])C.P(Cl)(Cl)(Cl)=O.[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([O:22][CH3:23])=[O:21]>ClC(Cl)C>[CH:8]([C:19]1[NH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=1)=[O:9]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc[nH]1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1ccc(C=O)[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.5 %

Procedure:
To 1,2-dichloroethane (40 mL) was added DMF (13.6 mL, 176 mmol). The mixture was cooled to 0° C. and phosphorus oxychloride (16.4 mL, 176 mmol) was added dropwise over 5 min. The resulting solution was stirred for 15 min. To the solution at 0° C. was added dropwise methyl 1H-pyrrole-2-carboxylate (20 g, 160 mmol) in dichloroethane (80 mL) (about 1 h). The cooling bath was removed, and the reaction mixture was heated to reflux for about 1 h and was then cooled to rt. EtOAc (250 mL) in ice water (400 mL) was added and the organic layer was separated. The aqueous layer was neutralized with NaHCO3 solution, and then extracted with EtOAc (4×100 mL). The organic layer and the combined organic extracts were washed with dilute NaHCO3 solution, brine, dried (Na2SO4) and filtered. Silica gel was added, the solvent removed and the silica gel-imbedded material was purified by flash chromatography (0-50% EtOAc/Heptane) to afford a major product, methyl 5-formyl-1H-pyrrole-2-carboxylate (16.3 g) and a minor product, methyl 4-formyl-1H-pyrrole-2-carboxylate (6.94 g). Combined yield: 23.3 g (95%).
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.[N:31]12[C:37](=[O:38])[CH2:36][CH:35]1[CH2:34][C:33](=O)[CH:32]2[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>C(Cl)Cl>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([O:10][C:33]2[CH2:34][CH:35]3[N:31]([C:37](=[O:38])[CH2:36]3)[C:32]=2[C:40]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:41])(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OCc3ccccc3)N3C(=O)CC3C2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 66.8 %

Procedure:
p-Toluenesulfonic anhydride (326 mg, 1 mμol) and N,N-diisopropylethylamine (192 μl, 1.1 mμol) are added to an ice-cold, stirring solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (259 mg, 1 mμol) in anhydrous methylene chloride (10 ml). The resulting solution is stirred in the cold and under a nitrogen atmosphere for 2.5 hours. The solution is diluted with methylene chloride (20 ml), washed with water (10 ml), 1M pH3 phosphate buffer (10 ml) and 5% aqueous sodium bicarbonate (2×10 ml) dried with magnesium sulfate, filtered, and evaporated under vacuum to a semi-solid. This material is triturated with ice-cold ethyl acetate (2×2 ml) and diethyl ether (2×5 ml) to provide benzyl 3-(p-toluenesulfonyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (276 mg, 67%) as a white powder. Recrystallization from methylene chloride-diethyl ether gives analytically pure product as small white needles: mp 103°-105°; IR (CH2Cl2) 1786, 1723, 1382, and 1190 cm-1 ; NMR (CDCl3) 8 2.44 (s, 3, ArCH3) 3.03 (dd, 1, J=3.0 and 17.0, H6β), 3.16 (dd, 1, J=8.5 and 18.7, H4a), 3.32 (dd, 1, J=10.0 and 18.7, H4b), 3.55 (dd, 1, J=5.5 and 17.0, H6α), 4.21 (m, 1, H5), 5.14 (ABq, 2, J=12, CH2Ar), 7.35 (S, 5, ArHN, 7.26 and 7.75 (two d's, 4, J=9, ArH); UV(dioxane) 283 (ε6600) and 277 (ε6500) nm.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.BrC1C=CC(C(C2OC3C=CC=CC=3C=2)=O)=CC=1>>[C:6]([C:8]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)(=[O:7])[C:5]1[CH:4]=[CH:3][CH:2]=[CH:18][CH:17]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cc2ccccc2o1
Agent: O=C(c1ccc(Br)cc1)c1cc2ccccc2o1
Product: O=C(c1ccccc1)c1cc2ccccc2o1

Procedure:
2-(4-chlorobenzoyl)benzo[b]furan and 2-(4-bromobenzoyl)-benzo [b]furan: ibid., Ghelardoni, M.; Pestellini, V.; Musante, C.: Gazz. Chim. Ital. 99, 1273 (1969);
Reaction SMILES: B(Br)(Br)Br.C1[O:27][C:26]2[CH:25]=[CH:24][C:9]([CH:10]=[C:11]3[CH2:20][CH2:19][C:18]4[C:13]([CH3:22])([CH2:14][CH2:15][C:16](=[O:21])[CH:17]=4)[C:12]3=[O:23])=[CH:8][C:7]=2[O:6]1.C(=O)([O-])[O-].[K+].[K+].CO>ClCCl.O>[OH:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=1[OH:27])[CH:10]=[C:11]1[CH2:20][CH2:19][C:18]2[C:13]([CH3:22])([CH2:14][CH2:15][C:16](=[O:21])[CH:17]=2)[C:12]1=[O:23]
Reactant: CC12CCC(=O)C=C1CCC(=Cc1ccc3c(c1)OCO3)C2=O
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC12CCC(=O)C=C1CCC(=Cc1ccc(O)c(O)c1)C2=O

Procedure:
A solution of boron tribromide (0.28 ml, 0.003 mole) in dichloromethane (15.1) was added to a well stirred solution of 2-(3,4-methylenedioxybenzylidene)-3,4,8,8a-tetrahydro-8a-methyl-1,6(2H,7H)-naphthalenedione (9) (0.3 g, 0.001 mole) in dichloromethane (20 ml) containing potassium carbonate (1.0 g) at -78° C. under nitrogen. After 10 minutes the mixture was treated with methanol (1 ml) and poured into water. The organic phase was separated and dried (Na2SO4). The solvent was removed and the product was chromatographed on silica gel using ether as eluant. The title compound was obtained as a yellow crystalline solid (0.05 g, 17%) m.p. 193°-5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][CH2:14][CH2:15][C:7]1=[C:6]2[CH:16]=O.C([O-])(=O)C.[NH4+].[N+:23]([CH2:26][CH3:27])([O-:25])=[O:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][CH2:14][CH2:15][C:7]1=[C:6]2[CH:16]=[C:26]([N+:23]([O-:25])=[O:24])[CH3:27]
Reactant: CC[N+](=O)[O-]
Reactant: COc1ccc2c(c1)c(C=O)c1n2CCCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc2c(c1)c(C=C(C)[N+](=O)[O-])c1n2CCCC1
Temperature: 25 °C

Procedure:
A stirred solution of 2-methoxy-6,7,8,9-tetrahydro-pyrido[1,2-a]indole-10-carboxaldehyde and ammonium acetate in nitroethane is heated to 100° C. for 1 h, cooled to room temperature and partitioned between ethyl acetate and water. The combined organic extracts are washed (water, brine), dried (sodium sulfate) and concentrated in vacuo to give the product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:18][NH2:19]>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:18][N:19]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1N
Reactant: NN
Solvent: O
Product: COc1ccc(C2=NNC(=O)CC2)cc1N
Yield: 95 %

Procedure:
This was prepared in 95% yield by reaction of 3-(3-amino-4-methoxybenzoyl)-propionic acid with hydrazine hydrate in ethanolic solution at reflux temperature for 5 hours. It had m.p. 218°-220°C after crystallisation from ethanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]([CH3:33])[CH:22]2[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]2)[CH3:10])[C:5]([C:34]#[N:35])=[C:4]([CH3:36])[N:3]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>ClCCl>[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38].[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]([CH:22]2[CH2:23][NH:24][CH2:25]2)[CH3:33])[CH3:10])[C:5]([C:34]#[N:35])=[C:4]([CH3:36])[N:3]=1
Reactant: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N(C)C2CN(C(=O)OC(C)(C)C)C2)c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N(C)C2CNC2)c1C#N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Crude tert-butyl (S)-3-((5-(1-((2-amino-5-cyano-6-methylpyrimidin-4-yl)amino)ethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)(methyl)amino)azetidine-1-carboxylate was dissolved in dichloromethane (1 mL). To this solution was added TFA (0.462 mL, 6.00 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. The solvent was removed with a stream of nitrogen and the crude product was purified by preparative HPLC (acid mode, 1-25% ACN/water gradient) to give a TFA salt of the title compound as a clear film (5.9 mg, 19% over two steps). 1H NMR (400 MHz, CD3OD) δ ppm 1.73-1.82 (m, 3H), 2.49-2.56 (m, 3H), 2.82-2.89 (m, 3H), 3.94-4.08 (m, 4H), 4.19-4.33 (m, 3H), 4.46-4.57 (m, 1H), 5.97-6.09 (m, 1H), 6.70-6.77 (m, 1H), 7.85-7.94 (m, 1H), 8.32-8.47 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C20H25N9, 392. found 392.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]=[C:3]1[CH2:14][CH3:15]>C(OCC)(=O)C.C(O)C.Cl.[Pd]>[CH3:1][N:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]=[C:3]1[CH2:14][CH3:15]
Reactant: CCOC(=O)C=Cc1cnc(CC)n1C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cnc(CC)n1C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
A mixture of ethyl β-(1-methyl-2-ethyl-imidazol-5-yl)acrylate (2.1 g, 10.1 mmol) and 1.1 g of 10% Pd/C in ethyl acetate/ethanol/HCl (1M in ethyl acetate; 50 ml/8 ml/8 ml) was hydrogenated under hydrogen (50 psi) for 2 h. The mixture was filtered through celite, the residue was washed with ethylene chloride/methanol (5:1, 2×), and the combined organic layer was concentrated in vacuo. The residue was basified with aqueous sodium bicarbonate solution, extracted with methylene chloride (4×), and the combined organic layer was dried over sodium sulfate and concentrated in vacuo. Upon chromatographic purification of the residue on 20 cm silica column (methylene chloride/methanol 50/1 - 15/1), 1.9 g (90%) of ethyl 3-(1-methyl-2-ethyl-imidazol-5-yl)propionate was isolated as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C:16]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6]3.[N:25]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH:29]=[N:28][CH:27]=[N:26]1.C(N(CC)CC)C>CS(C)=O>[N:25]1([CH2:30][CH2:31][CH2:32][NH:33][C:10]2[C:9]3[O:14][CH2:15][C:16]4([CH2:17][CH2:18][CH2:19][CH2:20]4)[N:7]4[C:8]=3[C:3]([C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6]4)=[C:2]([NH2:1])[C:11]=2[F:12])[CH:29]=[N:28][CH:27]=[N:26]1
Reactant: NCCCn1cncn1
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3C1(CCCC1)CO2
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c(F)c(NCCCn2cncn2)c2c3c1c(=O)c(C(=O)O)cn3C1(CCCC1)CO2
Yield: 18.1 %

Procedure:
A solution of 8-amino-9,10-difluoro-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]-quinoline-3,1′-cyclopentane]-6-carboxylic acid (13 mg, 0.04 mmol) and 3-(1H-1,2,4-triazol-1-yl)propan-1-amine (5 mg, 0.04 mmol) and 5.5 μL triethylamine in DMSO (0.3 mL) was stirred at 90° C. for 24 h. The reaction mixture was cooled and freeze-dried overnight. The crude product was taken up in ACN and purified by prep HPLC to yield 10-(3-(1H-1,2,4-triazol-1-yl)propylamino)-8-amino-9-fluoro-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]quinoline-3,1′-cyclopentane]-6-carboxylic acid (3.2 mg, 18%) as a yellow solid. MS (EP) m/z: 443 (M++1). (Calcd. For C21H23FN6O4, 442.18).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=4[F:34])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl>[CH2:42]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][C:25]=4[F:34])=[C:17]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1
Reactant: BrCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Nc2ncnc3c2cnn3C2CCN(Cc3ccccc3)CC2)c(F)c1

Procedure:
[1-(1-Benzyl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-(2-fluoro-4-methanesulfonylphenyl)-amine was prepared according to General Procedure F by the reaction of 4-[4-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 1) with trifluoroacetic acid in dichloromethane followed by reaction with benzyl bromide (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.87-1.90 (m, 2H), 2.13-2.24 (m, 4H), 2.93-2.97 (m, 2H), 3.54 (s, 2H), 4.67-4.72 (m, 1H), 7.25-7.35 (m, 5H), 7.78-7.81 (m, 1H), 7.88-7.91 (m, 1H), 8.20-8.24 (m, 1H), 8.38-8.41 (m, 2H), 11.71 (s, 1H). Mass spectrum MH+=481.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:24])[CH:3]=1.[C:25]1([CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1N=CN=C(NC(N2CCCC2)=O)C=1.C(OCC)(=O)C>[F:24][C:4]1[CH:3]=[C:2]([NH:1][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:36])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])[CH:8]=1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c(F)c1
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCCC3)ncn2)c(F)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 12 %

Procedure:
To a solution of morpholine-4-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (54 mg) in N,N-dimethylformamide (1.0 ml) was added a solution of phenylacetyl isocyanate in hexane (0.972 ml, Production Example 1), followed by stirring at room temperature for 25 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to 1:2, ethyl acetate, ethyl acetate:methanol=20:1 to 10:1). Fractions containing the target compound were concentrated to give a solid, which was suspended in ethyl acetate. The solid was filtered off, washed with ethyl acetate, and dried under aeration to provide the titled compound (9.5 mg, 12%) as colorless powder.
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].[F:5][C:6]([F:30])([F:29])[C:7]1[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[N:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10]>C(O)C>[OH:4][NH:3][C:23]([C:20]1[N:21]=[N:22][C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:9](=[O:10])[C:8]3[CH:25]=[CH:26][CH:27]=[CH:28][C:7]=3[C:6]([F:30])([F:29])[F:5])[CH2:16][CH2:15]2)=[CH:18][CH:19]=1)=[NH:24]
Reactant: NO
Reactant: N#Cc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N=C(NO)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Sodium metal (0.116 g, 4.98 mmol) was added to ice cold ethanol (10 mL). When all the sodium metal dissolved, hydroxylamine hydrochloride (0.346 g, 4.98 mmol) was introduced in one portion. The suspension was stirred at room temperature for 15 minutes and a solution of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]-pyridazine-3-carbonitrile (0.900 g, 2.49 mmol) in ethanol (2 mL) was then added. The mixture was further stirred at room temperature overnight. The solvent was removed in vacuo and the residue was suspended in ethyl acetate (10 mL) and filtered through celite. The filtrate was concentrated and the product was purified by column chromatography. The title compound was obtained as a pale yellow syrup in 55% yield (0.54 g). 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J=9.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.70-7.52 (m, 2H), 7.35 (d, J=7.4 Hz, 1H), 6.95 (d, J=9.5 Hz, 1H), 5.53 (s, 2H), 4.10-3.95 (m, 1H), 3.98-3.82 (m, 1H), 3.82-3.60 (m, 4H), 3.32 (t, J=5.1 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 157.5, 147.5, 142.1, 132.2, 130.2, 127.3, 125.1, 123.2, 110.8, 44.2, 42.6, 42.3, 39.1 MS (ES+) m/z 395.3 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH2:28][C:25]2[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccncc1
Reactant: c1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(Cc2ccc(OC[C@H]3CCCN3Cc3ccncc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
To a solution of Example 1 (0.25 g, 0.82 mmol) in dichloromethane (2 mL) was added 4-picolyl chloride hydrochloride (0.13 g, 0.79 mmol) and triethylamine (0.29 mL, 2.08 mmol). The resulting mixture was stirred at ambient temperature overnight. The crude product was extracted into dichloromethane and washed with water followed by brine. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.11 g, 45%); 1H NMR (400 MHz, CDCl3); δ 1.70-1.81 (m, 3H), 2.03 (m, 1H), 2.27 (m, 1H), 2.94-3.03 (m, 2H), 3.49 (d, J=14.4 Hz, 1H), 3.86 (m, 1H), 3.92 (s, 2H), 3.94 (m, 1H), 4.19 (d, J=14.4 Hz, 1H), 6.79 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 7.15-7.20 (m, 3H), 7.26-7.29 (m, 4H), 8.51 (m, 2H); MS (m/z) 359.5 (M+1); LC (99.7%); HPLC (91.6%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:38]([C:41]1[CH:42]=[C:43]([N:47]=[C:48]=[O:49])[CH:44]=[CH:45][CH:46]=1)(=[O:40])[CH3:39]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:48]([NH:47][C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([C:38](=[O:40])[CH3:39])[CH:42]=2)=[O:49])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Reactant: CC(=O)c1cccc(N=C=O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1cccc(NC(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 17 h
Yield: 31.1 %

Procedure:
In a dry flask (3R,4R)-4-amino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (56 mg, 0.133 mmol) was dissolved in tetrahydrofuran (2 mL) and triethylamine (24 μL, 0.172 mmol) and 3-acetylphenylisocyanate (22 μL, 0.160 mmol) were added. The reaction mixture was stirred for 17 hours. One-half of the original reaction mixture (1 mL) was concentrated in vacuo then purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (24 mg, 62%). 1H NMR (400 MHz, DMSO, 120° C.), δ: 8.32 (s, 1H), 7.91 (t, 1H, J=2), 7.58 (m, 1H), 7.48 (m, 1H), 7.33 (t, 1H, J=8), 7.15 (m, 2H), 6.99 (m, 2H), 5.98 (d, 1H, J=10), 4.04 (bd, 1H, J=13), 3.89 (bm, 4H), 3.20 (bs, 2H), 2.96 (m, 2H), 2.86 (m, 2H), 2.50 (s, 3H), 2.46 (m, 2H), 1.90 (m, 1H), 1.62 (bm, 4H), 1.43 (2s, 9H), 1.20 (m, 1H). HRMS (ESI), C32H42FN4O5 m+/z: calc.=581.3139, found=581.3141.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:7][C:8]=1[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH3:20])=[CH:15][CH:14]=1)=[O:12])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Br[CH2:41][C:42]([O:44]CC)=[O:43]>CN(C)C=O.O>[CH:1]([C:4]1[N:5]=[C:6]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=2)[S:7][C:8]=1[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:20])[CH2:41][C:42]([OH:44])=[O:43])=[CH:15][CH:14]=1)=[O:12])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CNc1ccc(C(=O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CCC(=O)c1ccc(N(C)CC(=O)O)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 122.6 %

Procedure:
The obtained 3-[4-Isopropyl-2-[4-(trifluoromethyl)phenyl]thiazol-5-yl]-1-(4-methylaminophenyl)propan-1-one (40 mg, 0.0931 mmol) and diisopropylethylamine (80 μL, 0.462 mmol) were dissolved in anhydrous dimethylformamide (2 mL). Ethyl bromoacetate (66 mg, 0.393 mmol) was added to the solution. The mixture was stirred at 110° C. for 16 hours. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate to remove the solvent. The obtained residue was purified by silica gel column chromatography with hexane/chloroform (7:3, v/v) to give the desired compound (56 mg) as yellow crystalline product (yield 47%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[F:15][C:16]([F:22])([F:21])[CH2:17][CH2:18][CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[O:14]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:19][CH2:18][CH2:17][C:16]([F:22])([F:21])[F:15])=[CH:7][CH:6]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: OCCCC(F)(F)F
Reactant: COC(=O)CC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CC(=O)c1ccc(OCCCC(F)(F)F)cc1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of methyl 3-(4-hydroxyphenyl)-3-oxopropanoate (7.8 g, 40.2 mmol) and 4,4,4-trifluorobutan-1-ol (5.15 g, 40.2 mmol) in CH2Cl2 (201 mL) at 0° C. was added triphenylphosphine (12.6 g, 48.2 mmol). The mixture was stirred for a few min, and then DIAD (9.37 mL, 48.2 mmol) was added. The reaction was stirred at 0° C. for 30 min, then warmed to rt and stirred for 3 days. The reaction was loaded directly onto a 300 g silica gel column and eluted with EtOAc in hexanes. Fractions containing the product were combined and concentrated to provide Intermediate 14A (9.9 g, 80%) as a colorless solid. 1H NMR (500 MHz, CDCl3) δ 2.03-2.13 (m, 2H), 2.26-2.39 (m, 2H), 3.75 (s, 3H), 3.96 (s, 2H), 4.09 (t, J=6.05 Hz, 2H), 6.92-6.96 (m, 2H), 7.86-7.97 (m, 2H).