Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=1[CH3:43]>[Cu]I.CS(C)=O>[CH3:43][C:34]1[CH:35]=[C:36]([C:39]([F:40])([F:41])[F:42])[CH:37]=[CH:38][C:33]=1[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:18][CH:19]=1
Reactant: Cc1cc(C(F)(F)F)ccc1Br
Reactant: Nc1ncccc1-c1ccc(O)cc1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: Cc1cc(C(F)(F)F)ccc1Oc1ccc(-c2cccnc2N)cc1
Temperature: 130 °C
Reaction time: 5 h
Yield: 52.9 %

Procedure:
Copper(I) iodide (102 mg) was added to a mixture of picolinic acid (66.1 mg), 4-(2-aminopyridin-3-yl)phenol (500 mg), tripotassium phosphate (1710 mg), 1-bromo-2-methyl-4-(trifluoromethyl)benzene (770 mg) and DMSO (8 mL). The mixture was stirred at 130° C. under nitrogen for 5 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Water was added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (489 mg) as a yellow solid.
Reaction SMILES: C(OP(OCC)([CH:6]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=O)C.C=O.[C:21](=O)([O-])[O-].[K+].[K+].O>C(OCC)C>[CH3:15][CH:13]([CH3:14])[CH2:12][C:6](=[CH2:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(CC(C)C)P(=O)(OCC)OCC
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: C=C(CC(C)C)C(=O)OCC
Yield: 63.3 %

Procedure:
A mixture of 19 g (67.9 mmol) of ethyl 2-(diethoxyphosphinyl)-4-methylpentanoate, 27 ml (360.3 mmol) of formaldehyde and 28 g (202.6 mmol) of potassium carbonate is maintained at reflux for 3 hours. A mixture of water and diethyl ether is added. The aqueous phase is extracted with diethyl ether. The combined organic phases are washed with water, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is distilled under reduced pressure. 6.7 g of product are recovered in the form of an oil (yield=63.3%).
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](CN4CCOCC4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.COC1C=CC=CC=1C=O>>[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[O:4][CH3:3])[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Reactant: O=C(O)C(F)(F)F
Agent: COc1ccccc1C=O
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1ccccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 96 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-methoxybenzaldehyde were reacted to produce the title compound (96%). 1H NMR (d-chloroform): 13.89 (br s, 1H) 8.31 (dd, J=1.8 Hz, 1H), 8.10 (d, J=9 Hz, 1H), 7.84 (s, 1H), 7.46 (m, 1H), 7.10 (t, J=8 Hz, 1H), 7.04 (d, J=8 Hz, 1H), 6.49 (m, 1H), 6.43 (m, 1H), 6.07 (br s, 1H), 5.60 (br s, 1H), 5.39 (t, J=8 Hz, 1H), 4.15 (s, 3H), 3.16 (s, 1H), 3.01 (s, 1H), 2.73 (d, J=9 Hz, 1H), 2.33 (d, J=9 Hz, 1H), 1.67 (d, J=9 Hz, 1H). MS: 411.04 (M+H). HPLC retention time: 2.58 minutes (G Method).
Reaction SMILES: Br[C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:15](=[O:16])[CH:10]3[CH2:11][O:12][CH2:13][CH2:14][N:9]3[C:3]=2[N:4]=1
Reactant: O=C(NC1CCOCC1)C1COCCN1c1nc(Cl)ncc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CCOCC1
Temperature: 120 °C
Yield: 76.1 %

Procedure:
To a 5 mL microwave vial were added 4-(5-bromo-2-chloropyrimidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)morpholine-3-carboxamide (PREPARATION x54, 320 mg, 0.789 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (34.2 mg, 0.059 mmol), palladium(II) acetate (8.85 mg, 0.039 mmol), and potassium phosphate, tribasic (234 mg, 1.104 mmol). The vessel was sealed, evacuated, and refilled with nitrogen. To the vessel were added dioxane (2 mL) and tert-butanol (0.500 mL), and the mixture was heated in a microwave to 120° C. for 6 hours. The reaction mixture was subsequently partitioned between saturated brine and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by normal phase column chromatography (SiO2, 50-100% EtOAc gradient in hexanes over 20 minutes) to give the title compound (195 mg, 76%).
Reaction SMILES: [CH:1]([C:4]1[NH:12][C:11]2[C:10](=O)[NH:9][C:8](=[O:14])[N:7]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:6]=2[N:5]=1)([CH3:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23].[OH-].[Na+]>N1C=CC=CC=1>[CH:1]([C:4]1[NH:12][C:11]2[C:10](=[S:23])[NH:9][C:8](=[O:14])[N:7]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)c1nc2c([nH]1)c(=O)[nH]c(=O)n2Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(C)c1nc2c([nH]1)c(=S)[nH]c(=O)n2Cc1ccncc1
Temperature: 5 °C
Yield: 136.5 %

Procedure:
1.19 g of 8-isopropyl-3-(4-picolyl)-xanthine and 1.07 g of phosphorus pentasulfide were heated under reflux in 25 ml of pyridine for 4 hours. After cooling to 5° C., 5.28 ml (10.6 mM) of 2N NaOH were added. The solid was filtered off and washed with pyridine. The filtrate was evaporated to dryness, the residue suspended in water and the solid collected, redissolved in 40 ml of 1N NaOH, treated with 0.2 g of charcoal, filtered and neutralized to pH 7.5. The solid was collected, washed and dried to give the title compound (0.99 g) as a white solid mp 310-14° C. (decomposition);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[C:20][Si](C)(C)C)[CH:15]=[CH:14][C:13]=2[C:12]2=[N:25][N:26]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:27]([NH:28][CH:29]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]3)=[C:11]2[N:10]=1.O>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[CH:20])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:25][N:26]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:45])([CH3:44])[CH3:46])[C:27]([NH:28][CH:29]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]3)=[C:11]2[N:10]=1
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)n(COCC[Si](C)(C)C)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)n(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A 30 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 74 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-2-{[2-(trimethylsilyl)ethoxy]methyl}-7-trimethylsilanylethynyl-2H-pyrazolo[4,3-c]isoquinoline in 5 ml of THF, 0.22 cm3 of tetrabutylammonium fluoride is added, and the mixture is stirred at RT for 30 min. It is poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (40-63 μm), eluting with a mixture of DCM and AcOEt (85/15 by vol.), to give 47 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-2-{[2-(trimethylsilyl)ethoxy]methyl}-7-ethynyl-2H-pyrazolo[4,3-c]isoquinoline (lemon yellow solid). MS (E/I): m/z=611 (M+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[NH2:15][C:16]1[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:15][C:16]2[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=2)=[O:14])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N)s1
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)s1
Yield: 54.3 %

Procedure:
In the same manner as that of Example 2, 4,5-diisopropylfuran-2-carboxylic acid (42 mg, 0.214 mmol) was condensed with methyl 5-aminothiophene-2-carboxylate (50 mg, 0.318 mmol), and the resultant was purified by silica gel chromatography (2% methanol-chloroform) to obtain methyl 5-[(4,5-diisopropylfuran-2-carbonyl)amino]thiophene-2-carboxylate (39 mg, 54%) as pale yellow prisms.
Reaction SMILES: [CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.N1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:22]=[CH:21]\[CH2:20]/[CH:19]=[CH:18]\[CH2:22]/[CH:21]=[CH:20]\[CH2:19][CH2:18][CH2:4][CH2:3][C:14]([O:10][CH2:9][CH2:8][O:7][CH2:6][N:5]1[C:4]2[NH:11][C:12]([NH2:16])=[N:13][C:14](=[O:15])[C:3]=2[N:2]=[CH:1]1)=[O:15]
Reactant: c1ccncc1
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21

Procedure:
Acyclovir (ACV, 0.5 g, 2.22 mmol, used as a dry white powder) was suspended in anhydrous pyridine (10 ml) and to the mixture stirred under dry nitrogen was added GLA acid chloride (0.788 g, 2.664 mmol). The reaction mixture was stirred overnight at room temperature after which period TLC indicated conversion to the required product. The pyridine was removed in vacuo and the residual syrup was dissolved in chloroform. This was introduced into a column of silica gel (30 g) pre-equilibrated in chloroform:ethanol (30:1, v:v). Elution with chloroform followed by chloroform:ethanol (30:1), (20:1) and finally (15:1), gave the required product, AK-5, as a TLC homogeneous semisolid. Yield, 48% (0.517 g, 1.065 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:11]1C2C=CC=CC=2C=[C:12]1C=O>>[CH3:1][C:2]1[C:10]2[O:9][C:8]([CH:12]=[O:11])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2ccoc12
Reactant: O=Cc1cc2ccccc2o1
Product: Cc1cccc2cc(C=O)oc12

Procedure:
c. 7-Methyl-benzofuran-2-aldehyde was prepared by formylating 7-methyl-benzofuran according to the same method as used for the preparation of benzofuran-2-aldehyde. The product thus obtained has the following ion peaks in its mass spectrum: 160 (100%), 159 (62%) and 131 (33%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[CH:27][CH:28]=3)[N:10]=2)[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)cn3nc(N)nc23)cc1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cc(F)cn4n3)cc2)CC1

Procedure:
[6-Fluoro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 6-fluoro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(4-bromo-phenyl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as an orange solid (23% yield). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.45 (s, 1H), 8.26 (d, J=8.0 Hz, 2H), 8.11 (d, J=7.7 Hz, 2H), 7.58 (d, J=9.0 Hz, 1H), 7.48 (dd, J=11.5 Hz, 7.8 Hz, 2H), 6.98 (d, J=7.9 Hz, 2H), 6.76 (s, 1H), 3.27 (bm, 4H), 3.12 (s, 3H), 2.62 (bm, 4H), 2.38 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:16][C:17]1[NH:22][C:21](=[O:23])[C:20]([CH:24]([NH:26][C:27](=[O:41])[CH:28]([CH:38]([OH:40])[CH3:39])[CH2:29]/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:25])=[N:19][N:18]=1.C(N(CC)CC)C>>[C:38]([CH:28]([CH2:29]/[CH:30]=[CH:31]/[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:27]([NH:26][CH:24]([C:20]1[C:21](=[O:23])[NH:22][C:17]([CH2:16][C:15]2[CH:42]=[CH:43][C:44]([O:45][CH3:46])=[C:13]([O:12][CH3:11])[CH:14]=2)=[N:18][N:19]=1)[CH3:25])=[O:41])(=[O:40])[CH3:39]
Reactant: COc1ccc(Cc2nnc(C(C)NC(=O)C(C/C=C/c3ccccc3)C(C)O)c(=O)[nH]2)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(Cc2nnc(C(C)NC(=O)C(C/C=C/c3ccccc3)C(C)=O)c(=O)[nH]2)cc1OC

Procedure:
Analogously to Example 40A, 320 mg (2.50 mmol) of oxalyl chloride, 390 mg (5.00 mmol) of dimethyl sulphoxide, 800 mg (1.63 mmol) of (4E)-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-2-(1-hydroxyethyl)-5-phenyl-4-pentenamide and 1.82 g (18.0 mmol) of triethylamine are reacted to give (4E)-2-acetyl-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]-ethyl}-5-phenyl-4-pentenamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:19]1([CH3:26])[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:26])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(-c2ccncc2)nc1Cl
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cnc(-c2ccncc2)nc1Oc1ccccc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 7.9 %

Procedure:
A suspension of 0.6 g (2 28 mmol) 4-chloro-2-pyridin-4-yl-pyrimidine-5-carboxylic acid ethyl ester, 0.27 g (2 50 mmol) o-cresol and 2.97 g (9.10 mmol) Cs2CO3 in 15 ml acetonitrile was stirred for 17 h at RT. The suspension was poured into 150 ml H2O and extracted three times with 90 ml ethyl acetate. The combined organic phases were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/MeOH 100:1) to give 0.74 g (97%) 2-pyridin-4-yl-4-o-tolyloxy-pyrimidine-5-carboxylic acid ethyl ester as a yellow solid, MS (EI): 335.1 (M+).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH-].[K+].Cl.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.C>CS(C)=O.C(OCC)(=O)C.O>[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=[O:9])=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccccc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
A solution of salicylaldehyde (5 g, 40.9 mmol) in DMSO (75 mL) was treated with crushed potassium hydroxide (5.4 g, 81.8 mmol) and allowed to stir at room temperature for 1 hour. This was then treated with 4-picolyl chloride hydrochloride (6.8 g, 40.9 mmol) and the dark mixture allowed to stir overnight. The mixture was poured into water and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with 5% NaOH, three times with water then with brine. Drying over MgSO4 and removal of the solvent under reduced pressure gave the crude product. This was taken up in ethyl acetate, treated with charcoal, filtered, and the solvent removed under reduced pressure to give 5.42 g (62.1%) of the product as an oil; MS-CI 214 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].Cl.[NH2:13][N:14]=[CH:15]N1C=CC=N1>O1CCOCC1>[NH2:13][N:14]=[CH:15][NH:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: NN=Cn1cccn1
Reactant: NCC(=O)NC1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: NN=CNCC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
A round-bottomed flask is charged with 15 g of 2-amino-N-(cyclohexyl)-acetamide, 14,6 g 1-aminoiminomehtylpyrazole hydrochloride and 100 ml of dioxane. After 18 h stirring at reflux, the reaction medium is cooled to room temperature and precipitate which has formed is filtered off with suction. 16 g of a white solid are obtained.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[S:15][C:14]([C:16]([OH:18])=[O:17])=[C:13]([N:19]([C@H:29]4[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]4)[C:20]([C@H:22]4[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]4)=[O:21])[CH:12]=3)=[CH:7][CH2:6]2)[O:4]CC1.Cl>C1COCC1.C(Cl)Cl>[OH:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([N:19]([C:20]([C@H:22]2[CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][CH2:27]2)=[O:21])[C:13]2[CH:12]=[C:11]([C:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH:7]=3)[S:15][C:14]=2[C:16]([OH:18])=[O:17])[CH2:30][CH2:31]1
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCC4(CC3)OCCO4)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCC(=O)CC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Temperature: 40 °C

Procedure:
To a solution of 5-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (428 mg, 0.85 mmol) in THF (5 mL) was added 3N HCl (2.5 mL), and the mixture was heated at 40° C. for 5 h. Then it was diluted with CH2Cl2 (70 mL) and washed with brine and water. Organic fraction was dried over Na2SO4, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 0-10% MeOH in CH2Cl2 to give 278 mg (71%) of 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4-oxo-cyclohex-1-enyl)-thiophene-2-carboxylic acid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:38]([C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)[C:39]2=[O:40])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccc(Cl)cc3)CC2)c1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and 4-chlorophenyl isocyanate to give the title compound as a colorless solid. MS: 552.7 ([M+H]+)
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O-]CCCC.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([N:27]2[C:31](Cl)=[N:30][N:29]=[CH:28]2)[CH:24]=[CH:25][CH:26]=1>CN(C)C=O>[F:33][C:20]([F:19])([F:34])[C:21]1[CH:22]=[C:23]([N:27]2[C:28]([O:13][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:29][N:30]=[CH:31]2)[CH:24]=[CH:25][CH:26]=1
Reactant: Oc1ccccc1
Reactant: FC(F)(F)c1cccc(-n2cnnc2Cl)c1
Agent: CC(C)(C)[O-]
Agent: CCCC[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(-n2cnnc2Oc2ccccc2)c1
Temperature: 75 °C

Procedure:
0.8 g of potassium tert-butoxide was added to a solution of 0.53 g of phenol in 10 ml of dry dimethyl formamide. When all the butoxide had dissolved, a solution of 1.4 g of 25B in 10 ml of dry dimethylformamide (10 ml) was added and the stirred mixture was heated to 75° C. for 90 minutes. The reaction mixture was poured into a large excess of ice-water, the solid product filtered off and recrystallized from hexane/ethyl acetate to give 25, as a solid, m.p.: 83°-85° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[N:20]2[C:21]3[C:16]([O:17][CH2:18][CH2:19]2)=[C:15]([F:22])[CH:14]=[CH:13][C:12]=3[N:11]=1)[CH3:9])(C)(C)C.FC1C=CC2=C3C=1OCCN3C(C(NC(=O)C)C)=N2.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:22][C:15]1[CH:14]=[CH:13][C:12]2=[C:21]3[C:16]=1[O:17][CH2:18][CH2:19][N:20]3[C:10]([CH:8]([NH2:7])[CH3:9])=[N:11]2
Reactant: CC(NC(=O)OC(C)(C)C)c1nc2ccc(F)c3c2n1CCO3
Agent: CC(=O)NC(C)c1nc2ccc(F)c3c2n1CCO3
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)c1nc2ccc(F)c3c2n1CCO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To an ice-cooled solution of the mixture of [1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)ethyl]carbamic acid tert-butyl ester and N-[1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)ethyl]acetamide from the previous step in DCM (15 mL) was added TFA (3 mL) and the mixture was stirred at RT for 2 h. Toluene was added and volatiles were removed under reduced pressure, the resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. Purification by column chromatography (Si—PCC, gradient 2-8% 2M NH3/MeOH in DCM) afforded the title compound as a light brown gum (185.6 mg, 65%, 2 steps). LCMS (Method B): RT 1.54 min [M+H]+ 222
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[C:19]([CH3:20])[C:14]=2[O:13][C:12](=[O:22])[CH:11]=1>C(Cl)Cl.N1C=CC=CC=1.O>[NH2:9][C:10]1[C:15]2[CH:16]=[CH:17][C:18]([O:21][C:6]([C:2]3[NH:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[C:19]([CH3:20])[C:14]=2[O:13][C:12](=[O:22])[CH:11]=1
Reactant: O=C(Cl)c1ccc[nH]1
Reactant: Cc1c(O)ccc2c(N)cc(=O)oc12
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1c(OC(=O)c2ccc[nH]2)ccc2c(N)cc(=O)oc12

Procedure:
A solution of pyrrole-2-carboxylic acid chloride (0.065 gm) in methylene chloride (0.5 ml) was added to a suspension of 4-amino-7-hydroxy-8-methyl-benzopyran-2-one (0.095 gm) in pyridine (2 ml). The suspension was heated at 70 for 10 mins. to obtain a homogeneous solution. The reaction mixture was then diluted with water, filtered and the solid was crystallized form dimethylformamide/water to afford the title compound. MS: m/e 284 (M.+).
Reaction SMILES: C(OC(N1CCC([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[CH:28]=[CH:27][O:26][CH:25]=3)[CH:15]=2)CC1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[O:26]1[CH:27]=[CH:28][C:24]([CH2:23][N:16]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:22]3[C:14]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:17]3)=[CH:15]2)=[CH:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cn(Cc3ccoc3)c3ncccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc2c(c1)c(N1CCCCC1)cn2Cc1ccoc1

Procedure:
Over a solution of 1.4 g (3.7 mmol) of 4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester in 10 ml of dichloromethane, 2.85 ml of trifluoroacetic acid were carefully added. The crude mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude residue was dissolved in 10 ml of ethyl acetate and washed with saturated aqueous solution of sodium carbonate and brine. After drying over sodium sulphate, filtering and removing the solvent under reduced pressure, 0.62 g (60% of yield) of the expected product were obtained.