Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=2)=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]
Reactant: CNc1ccc(O)cc1[N+](=O)[O-]
Reactant: N#Cc1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1ccc(Oc2ccnc(C#N)c2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 11.5 h
Yield: 76.4 %

Procedure:
A mixture of 4-chloro-2-cyano-pyridine (6.9 g, 0.05 moles), 4-methylamino-3-nitrophenol (8.4 g, 0.05 moles), and K2CO3 (10.4 g, 0.075 moles) in DMSO (80 mL) was heated to 60° C. After 11.5 h, HPLC analysis indicated complete conversion of both starting materials. After cooling to 20° C., water (240 mL) was added to the reaction mixture. The temperature rose to 40° C. before decreasing to ambient temperature. The solid was collected by filtration and washed with water (2×40 mL). The solid was then slurried in heptane (40 mL). The solid was collected and washed with heptane (40 mL). The crude product was dried in a vacuum oven at 50° C. for 16 h to afford 10.33 g (76%) of the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.5 (m, 1H), 8.2 (m, 1H), 7.9 (m, 1H), 7.7 (m, 1H), 7.5 (m, 1H), 7.2 (m, 1H), 7.1 (m, 1H), 3.0 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 165.1, 152.9, 144.4, 140.6, 134.1, 130.4, 130.1, 117.9, 117.1, 117.0, 116.5, 114.9, 29.8; APCI MS [M+H]+=271; HPLC>99% (LCAP).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.[CH3:27][CH:28]([NH2:30])[CH3:29].CCN(C(C)C)C(C)C>O1CCOCC1>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[O:18][CH:15]1[CH2:16][CH2:17][N:12]([C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]=[CH:8][C:6]3=[N:7][C:2]=2[NH:30][CH:28]([CH3:29])[CH3:27])[CH2:13][CH2:14]1
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Reactant: CC(C)N
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc2cnccc2nc1N1CCC(Oc2ccc(F)cc2F)CC1
Yield: 70.7 %

Procedure:
A solution of 3-chloro-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazine (2 g, 5.31 mmol), propan-2-amine (1.36 mL, 15.92 mmol) and DIPEA (1.85 mL, 10.62 mmol) in dioxane (10.62 mL) was heated at 95° C. overnight. After concentration, the residue was purified with silica gel column chromatography using a gradient of 0% to 100% EtOAc in heptanes to give the title compound (1.5 g, 71%) as an off-white solid. ESI-MS m/z [M+H]+ 400.00.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:22])[N:5]([CH2:19][C:20]#[CH:21])[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[CH3:2].[OH-:23].[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([C:3]1[C:4](=[O:22])[N:5]([CH2:19][C:20](=[O:23])[CH3:21])[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[CH3:2]
Reactant: [OH-]
Reactant: C#CCn1c(-c2ccccc2)nc(C(F)(F)F)c(CC)c1=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1c(C(F)(F)F)nc(-c2ccccc2)n(CC(C)=O)c1=O

Procedure:
To a stirred solution of 4.83 g (15.8 mmol) of 5-ethyl-3-propargyl-2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone (compound 46) in 50 mL of THF was added 50 mL of 10% aq NaOH. The mixture was heated at reflux for 2 h, cooled and diluted with 150 mL of ethyl acetate. The organic layer was separated, washed with 50 mL of water and 50 mL of brine and dried over MgSO4. Removal of the solvent afforded 4.74 g of 5-ethyl-3-(2-oxopropyl)-2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone (compound 179) as a white solid. 1H-NMR (CDCl3) 1.2(3H), 2.2(3H,s), 2.7(2H,q), 4.7(2H,s), 7.45(5H,m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[N:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16]Cl)[C:9]=2[CH:18]=1)=[O:4].[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[N:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:33])([F:34])[F:19])[CH:22]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:18]=1)=[O:4]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: COC(=O)c1ccc2nnn(CCCCCl)c2c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccc2nnn(CCCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)c2c1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
6-methoxycarbonyl-1-(4-chlorobutyl)-1H-benzotriazole (9.61 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 8.8 g compound (I-56) with a yield of 63.4%. ESI-MS [M+H]+: m/z 461.2.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[NH:4][N:3]=1.[C:25](Cl)(=[O:27])[CH3:26]>N1C=CC=CC=1>[CH3:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[NH:1][C:25](=[O:27])[CH3:26])(=[O:13])=[O:14])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(N)c2c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1n[nH]c2ccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)cc12

Procedure:
N-[5-(2-Methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl)-acetamide can be obtained as described in Example 28 from 0.5 g of N-(3-amino-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide, 3 ml of pyridine and 98 μl of acetyl chloride. 338 mg of N-[5-(2-methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl)-acetamide are thus obtained in the form of a white solid which decomposes at approximately 145° C. (analysis C16H16N4O5S2 % calculated C, 47.05; H, 3.95; N, 13.72; O, 19.59; S, 15.7. % found C, 46.96; H, 4.27; N, 13.23; S, 14.91).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C:8]([CH2:10][C:11]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:14][N:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[CH2:12]1)#[N:9].[CH3:46][C@@H:47]([NH2:50])[CH2:48][CH3:49]>>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[C:8]([CH2:10][C:11]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][NH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:12][N:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:50][C@H:47]([CH3:46])[CH2:48][CH3:49])=[O:21])=[CH:17][CH:16]=2)[CH2:14]1)#[N:9]
Reactant: CC[C@@H](C)N
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)cc5)C4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 19, Step 3 started from 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-azetidin-1-yl}benzoic acid and (2R)-butan-2-amine (Aldrich: Cat. #296651). LCMS (M+H)+: m/z=455.2. 1H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.99 (s, 1H), 8.76 (s, 1H), 8.50 (s, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.76 (d, 8.7 Hz, 2H), 7.68 (dd, J=3.3, 2.5 Hz, 1H), 7.14 (dd, J=3.4, 1.5 Hz, 1H), 6.59 (d, J=8.7 Hz, 2H), 4.55 (s, 2H), 4.30 (d, J=8.6 Hz, 2H), 3.89 (m, 1H), 3.75 (s, 2H), 1.58-1.39 (m, 2H), 1.10 (d, J=6.6 Hz, 3H), 0.84 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]([CH3:15])([CH3:14])[O:8][SiH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH2:6])[CH3:2].CO[CH2:19][N:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:21][Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:5]1([C:7]([CH3:15])([CH3:14])[O:8][SiH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:19][N:20]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:21]1)=[O:16])[CH3:2]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(C(=O)OCC)C(C)(C)O[SiH2]C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a cold solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-acrylic acid ethyl ester (463 mg, 1.89 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzyl-amine (540 μl, 2.11 mmol) in dichloromethane (3 ml) was added at 0° C. trifluoroacetic acid (26 μl, 0.34 mmol). The resulting solution was warmed to room temperature in two hours. The crude product was purified by column chromatography on silica get eluting with a solution of ethyl acetate in hexanes (1:10, 1:5) to give the title compound (490 mg, 69%).
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH2:14][C:12](=[O:13])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:1]([N:8]1[C:15](=[O:16])[CH:14]([C:37](=[O:38])[CH2:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:12](=[O:13])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1CC(=O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)C1C(=O)N(Cc2ccccc2)C(=O)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Yield: 88.8 %

Procedure:
To a solution of 1,3-dibenzyl barbituric acid 192 mg (0.623 mmol) in dry dichloromethane 2.0 mL under nitrogen atmosphere, added was pyridine 1.0 mL (12 mmol) and stirred at 0° C. Added was phenylacetyl chloride 96 mg (0.623 mmol, 1.00 equivalent) in dichloromethane 1.0 mL to the solution slowly during a period of 20 minutes, then stirred at room temperature for 3 hours. Added was dichloromethane 40 mL and washed the organic layer with 2 M hydrochloric acid and saturated brine, and dried over sodium sulfate. Purified was the crude product 273 mg, after removal of the solvent under the reduced pressure, by column chromatography (silica gel, eluted with dichloromethane). It obtained 1,3-dibenzyl-5-(phenylacetyl)barbituric acid 236 mg as colorless viscous oil at first (88.7% yield) and it gradually turned white plates.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OCC)=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCCCN
Reactant: CCOC(=O)c1cnc2[nH]ncc2c1OCC
Solvent: O
Product: CCCCNc1c(C(=O)OCC)cnc2[nH]ncc12

Procedure:
4-Ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester is treated with butylamine at 90° for 1 hour. After this period the mixture is cooled, diluted with water and the white crystalline precipitate is filtered off. Recrystallization from diethyl ether yields 4-butylamino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1.[C:14]([O:20][CH2:21][C:22](N)=[S:23])(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].C(OCC)(=O)C>S1(CCCC1)(=O)=O>[CH3:16][C:15]([CH3:18])([CH3:17])[C:14]([O:20][CH2:21][C:22]1[S:23][C:4]2[C:5]([N:11]=1)=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[CH:2][N:3]=2)=[O:19]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)C(=O)OCC(N)=S
Solvent: CCOC(C)=O
Solvent: O=S1(=O)CCCC1
Product: CC(C)(C)C(=O)OCc1nc2cc([N+](=O)[O-])cnc2s1
Temperature: 105 °C
Yield: 16.7 %

Procedure:
A mixture of 6 g (29.48 mmol) of 2-chloro-3,5-dinitropyridine and 7.74 g (44.22 mmol) of 2-amino-2-thioxoethyl pivalate in 50 mL of sulfolane is heated for 2 hours at 105° C. After this time, 150 mL of ethyl acetate are added to the mixture, and the organic phase is washed three times with 200 mL of water and then once with 100 mL of saturated sodium chloride solution. The organic phase is then separated out, dried over sodium sulfate and then concentrated under reduced pressure. The product obtained is purified by chromatography on a column of silica, eluting with a mixture of heptane and ethyl acetate. 1.45 g of a yellow solid are obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[O:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:10]=2)[N:6]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[O:21])[CH2:5]1.[CH2:34](N(CC)CC)C.CI.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[O:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:34])[CH2:16][CH2:15]3)[N:10]=2)[N:6]([C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[O:21])[CH2:5]1
Reactant: CON=C1C[C@@H](c2nc(C3CCNCC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Product: CON=C1C[C@@H](c2nc(C3CCN(C)CC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime (Example 12) was dissolved in dry DCM at 0° C. in presence of 1.5 equivalent of triethyl amine and treated with 1 equivalent of methyl iodide. The reaction mixture was stirred at room temperature for 12 hours. The reaction was hydrolysed and then made basic with a sodium carbonate solution (10%) and extracted with DCM. It was then dried with magnesium sulfate and solvent removal afforded a residue, which was purified by flash-chromatography using dichloromethane/methanol (98/2) as eluent to give (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(1-methyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime as a mixture of E-/Z-isomers in 50% yield (96.8% purity by HPLC).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([OH:24])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:26]([C:28]1[O:29][CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1)=[O:27]>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([OH:24])[C:14]([C:32]3[CH:31]=[CH:30][O:29][C:28]=3[CH:26]=[O:27])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2ccoc2C=O)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C=O)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 26, starting from tert-butyl 6-(benzenesulfonylmethyl)-3-bromo-2-hydroxybenzoate (Intermediate 38) and 2-formylfuran-3-boronic acid pinacol ester
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1(C)[CH:12]=[CH:11][O:10][NH:9]1)([OH:3])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:20]C1ON=C(CCCO)C=1>>[OH:3][CH2:1][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:12]=[C:11]([CH3:20])[O:10][N:9]=1
Reactant: CC1(CCCCC(=O)O)C=CON1
Reactant: Cc1cc(CCCO)no1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(CCCCCO)no1
Yield: 84 %

Procedure:
3-(5-Hydroxypentyl)-5-methylisoxazole was prepared by reduction of 3-(4-carboxybutyl)-3-methylisoxazole with lithium aluminum hydride according to the procedure of part (e) above, and was obtained in 84% yield as an oil, b.p. 115°-125° C.(0.1 mm).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[N:4]=1.[OH-].[Na+].S(OC)(O[CH3:17])(=O)=O>CCOCC.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:17])[CH:6]=[C:5]([OH:10])[N:4]=1
Reactant: COc1nc(O)cc(O)n1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1cc(O)nc(OC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
142 g (1 mol) of 2-methoxy-4,6-dihydroxypyrimidine are added while stirring to 500 cc of sodium hydroxide solution 2N and the mixture is stirred at 50° for 1 hour. Subsequently it is cooled to room temperature and 139 g (1.1 mol) of dimethyl sulphate are added dropwise while stirring; by the addition of sodium hydroxide solution 2N the pH value is kept at between 8.0 and 8.2. The mixture is stirred at 50° for a further 2 hours, cooled to room temperature and extracted with chloroform. After drying the chloroform phase over sodium sulphate the solvent is decanted in a vacuum. A white powder is obtained. After decomposition with ether/chloroform (1:1), the substance has a M.P. of 197°-201°.
Reaction SMILES: [CH:1]1([C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([O:22][CH3:23])[C:16](N(OC)C)=[O:17])=[CH:11][CH:10]=3)=[N:6][N:5]=2)[CH2:3][CH2:2]1.[Br:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][C:28]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[CH:27][C:26]=1[O:38][CH3:39]>>[Br:24][C:25]1[C:26]([O:38][CH3:39])=[CH:27][C:28]([C:33]2[O:34][C:35]([C:16](=[O:17])[CH:15]([C:12]3[CH:11]=[CH:10][C:9]([C:7]4[O:8][C:4]([CH:1]5[CH2:2][CH2:3]5)=[N:5][N:6]=4)=[CH:14][CH:13]=3)[O:22][CH3:23])=[CH:36][CH:37]=2)=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C3CC3)o2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C5CC5)o4)cc3)o2)cc(OC)c1Br
Yield: 31 %

Procedure:
2-(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide was reacted with 2-(4-bromo-3,5-dimethoxyphenyl)furan according to the procedure for the synthesis of Example 12. Purification by chromatography (EtOAc-hexanes) gave 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxyethanone as a yellow foam (0.126 g, 31% yield). MS: m/z 539.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][NH:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])([CH3:4])([CH3:3])[CH3:2].O=C1CCC(=O)N1[O:29][C:30](=O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:50]([O:49][C:47](=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30](=[O:29])[N:9]([CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)CCNCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)OCc1ccccc1
Reaction time: 42 h
Yield: 85 %

Procedure:
3-(Benzyloxycarbonylmethylamino)propionic acid tert-butyl ester (0,030 g, 0.1 mmol) and octadecanedioic acid tert-butyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0,050 mg, 0.1 mmol) was suspended in dry DMF (1 ml). HOAt (0.014 g, 0.1 mmol) and DIPEA (0.21 ml, 1.2 mmol) was added. The yellow reaction mixture was stirred under nitrogen for 42 h. The reaction mixture was concentrated. The residue was redissolved in EtOAc and washed with 0.1 N HCl (2×), water (1×), dried (Na2SO4) and concentrated to give 17-[Benzyloxycarbonylmethyl-(2-tert-butoxycarbonyl-ethyl)-carbamoyl]-heptadecanoic acid tert-butyl ester in 85% yield (55 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11](Cl)=[CH:10][C:9]=1[NH:15][C:16](=[O:34])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH:21]=1)=O)(C)(C)C.C(O)([C:38]([F:41])([F:40])[F:39])=O>C(Cl)Cl>[CH3:33][O:32][C:29]1[N:28]=[CH:27][C:26]([C:22]2[CH:21]=[C:20]([C:18]3[CH2:17][C:16](=[O:34])[NH:15][C:9]4[CH:10]=[C:11]([C:38]([F:41])([F:40])[F:39])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:31][CH:30]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Product: COc1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M46) (270 mg, 0.54 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (79 mg).
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:33]2=[O:46])[S:27][C:28]=1[C:29]([OH:31])=O.[NH2:47][CH2:48][C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:33]2=[O:46])[S:27][C:28]=1[C:29]([NH:47][CH2:48][C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1)=[O:31]
Reactant: Cc1nc(N2CCN(CCCc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CCCc3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 62 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(3-phenylpropyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 62% yield: mp 127-128° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.45 (d, J=4.2 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.22-7.07 (m, 6H), 6.51 (t, J=5.7 Hz, 1H), 4.54 (d, J=5.7 Hz, 2H), 3.98-3.92 (m, 2H), 3.49-3.43 (m, 2H), 3.31 (t, J=6.9 Hz, 2H), 2.61-2.50 (m, 5H), 1.91-1.82 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.4, 155.3, 153.6, 149.0, 148.6, 141.0, 135.8, 134.2, 128.4, 128.2, 126.1, 123.6, 116.7, 43.6, 42.1, 41.9, 41.3, 33.0, 28.7, 17.3; MS (ES+) m/z 436.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:13]=[CH:12][N:11]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:10]2[N:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=[CH:12][N:11]=2)[CH:6]=1
Reactant: Clc1nccc(N2CCOCC2)n1
Reactant: Brc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cnn(-c2nccc(N3CCOCC3)n2)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a cooled (0° C.) solution of 4-bromo-1H-pyrazole (0.74 g, 5.0 mmol) in anhydrous DMF (7 ml) was added NaH (60% dispersion in mineral oil, 0.22 g, 5.5 mmol) in a portionwise fashion over 10 minutes. The mixture was stirred like this for 30 minutes before the addition of 4-(2-chloro-pyrimidin-4-yl)-morpholine (21)(1.0 g, 5.00 mmol). The reaction was then heated under the influence of microwave radiation (120° C., 14 minutes, fixed hold time, high absorption setting). The reaction was then cooled to room temperature and water added (14 ml) which caused a precipitate to form. The solid was collected by filtration, washed with water and dried in a desiccator to give the title compound (1.44 g, 93%) in sufficiently pure form to be used without any further purification. m/z (LC-MS, ESP): 310 [M+H]+, R/T=3.08 mins.