Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]([O:19]CC)=O)[N:8]=2)=[N:2]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Mg]Br>C1COCC1>[NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])=[O:19])[N:8]=2)=[N:2]1
Reactant: COc1ccccc1[Mg]Br
Reactant: CCOC(=O)c1nc(Nc2cc[nH]n2)c2ccccc2n1
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1nc(Nc2cc[nH]n2)c2ccccc2n1
Temperature: -40 °C
Reaction time: 3 h
Yield: 17.1 %

Procedure:
To a suspension of ethyl 4-(1H-pyrazol-3-ylamino)quinazoline-2-carboxylate (0.110 g, 0.39 mmol) in THF (5 mL) under argon at −40° C. was added (2-methoxyphenyl)magnesium bromide (0.5 M solution in THF; 2.32 mL, 1.16 mmol). The mixture was stirred at −40° C. for 3 h and quenched with 0.5 N HCl (10 mL). The organic layer was separated. The aqueous layer was washed with 10% MeOH/CH2Cl2 (50 mL×2). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on preparative HPLC (Phenomenex phenylhexyl reverse phase column, eluted with gradient of solvent B=0.05% HOAc/CH3CN and solvent A=0.05% HOAc/H2O) to afford (4-(1H-pyrazol-3-ylamino)quinazolin-2-yl)(2-methoxyphenyl)methanone as a yellow solid (0.023 g, 17%). 1H NMR (300 MHz, DMSO-d6) δ 3.50 (s, 3H), 6.58 (s, 1H), 7.15 (m, 2H), 7.70-7.50 (m, 4H), 7.88 (m, 2H), 8.75 (d, 1H), 10.68 (s, 1H), 12.42 (s, 1H); LC-MS (ESI) m/z 346 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[C:33](OC(=N)C(Cl)(Cl)Cl)([CH3:36])([CH3:35])[CH3:34].B(F)(F)F.CCOCC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 6-bromo-2-(4-carboxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg) and 2,2,2-trichloroacetoimidate tert-butyl ester (400 mg) in methylene chloride (6 ml) was added dropwise a catalytic amount of boron trifluoride diethyl etherate at room temperature and the mixture was stirred for 1 hr. To the reaction mixture was added 10% aqueous potassium carbonate solution, and the mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) and the obtained crystals were washed with methanol to give the title compound (260 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH2:21])[CH3:9])[CH:7]=1
Reactant: [BH3-]C#N
Reactant: COc1cc(Cl)cc(C(C)=O)c1OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: COc1cc(Cl)cc(C(C)N)c1OC
Temperature: 25 °C
Reaction time: 36 h
Yield: 56.2 %

Procedure:
To a stirred solution of 1-(5-chloro-2,3-dimethoxy-phenyl)-ethanone (3.6 g, 16.8 mmol) and ammonium acetate (12.9 g, 168 mmol) in absolute methanol (50 mL) was added sodium cyanoborohydride (0.738 g, 11.8 mmol) in one portion. The resulting solution was stirred at room temperature for 36 h. Concentrated HCl was added until pH<2. The methanol was then evaporated, and the resulting white residue was dissolved in H2O (50 mL) and washed with diethyl ether (2×50 mL). The aqueous phase was then basified with powdered KOH to pH>10, saturated with NaCl, and extracted with dichloromethane (4×10 mL). The combined dichloromethane extracts were dried over Na2SO4, filtered, and evaporated to the crude compound which was purified by silica gel column (1% NH4OH/8% methanol/dichloromethane) to afford 1-(5-chloro-2,3-dimethoxy-phenyl)-ethyl amine (1.43 g, 40%): 1H NMR (400 MHz, CDCl3): δ 6.98 (d, 1 H), 6.78 (d, 1 H), 4.39 (m, 1 H), 3.86 (s, 3 H), 3.83 (s, 3 H), 1.35 (d, 3 H).
Reaction SMILES: I[C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)#[CH:14].C(N(CC)CC)C.CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[N:18]1[CH:19]=[CH:20][C:15]([C:13]2[O:12][C:3]3=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]3[CH:14]=2)=[CH:16][CH:17]=1
Reactant: C#Cc1ccncc1
Reactant: Oc1ncc(C(F)(F)F)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)(F)c1cnc2oc(-c3ccncc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
A mixture of 0.29 g of 3-iodo-5-(trifluoromethyl)pyridin-2-ol, 0.35 g of 4-ethynylpyridine, 20 mg of dichlorobis(triphenylphosphine)palladium(II), 0.30 g of triethylamine, 15 mg of copper(I) iodide and 5 ml of DMF was stirred under a nitrogen atmosphere at room temperature for 2 hours. To the reaction mixture were added water, then t-butyl methyl ether, and the mixture was filtered through Celite (registered trademark). The filtrate was separated, and the organic layer was dried over sodium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel preparative thin-layer chromatography to obtain 33 mg of 2-(pyridin-4-yl)-5-trifluoromethyl-furo[2,3-b]pyridine (hereinafter, referred to as “Present Active Compound 13”).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:27]([C:31]([F:34])([F:33])[F:32])[O:28]2)=[CH:23][CH:22]=1.[CH2:40]([CH:42]([CH2:45][CH3:46])[CH2:43]O)[CH3:41].N(C(OCC)=O)=NC([O-])=O>C1COCC1>[CH2:40]([CH:42]([CH2:45][CH3:46])[CH2:43][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:27]([C:31]([F:34])([F:32])[F:33])[O:28]2)=[CH:23][CH:22]=1)[CH3:41]
Reactant: CCC(CC)CO
Reactant: CCOC(=O)C1=Cc2ccc(O)cc2OC1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2ccc(OCC(CC)CC)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The polymer bound PPh3 was suspended in THF for 15 min. Ethyl 7-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 1a, Step 1 (2.0 g, 6.94 mmole) and 2-ethyl-1-butanol (1.3 mL, 10.35 mmole) were added to above slurry and the mixture was stirred at r.t. for 15 min. Ethyl azodicarboxylate (1.6 mL, 10.35 mmole) was added to above mixture dropwise and the mixture was stirred at room temperature overnight. LCMS indicated product formation and that there was a trace amount of starting material present. The polymer was filtered off through celite pad and the pad was washed with ether. The filtrate was concentrated and the product mixture was suspended in hexane. The suspension was filtered and the filtrate was evaporated and dried in vacuo to afford yellow oil, (2.37 g, 92%): LCMS m/z 394.95 (M+Na). This ester was of suitable purity to use without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:14][C:15]([CH:17]=[CH2:18])=O>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5]([C:17]([CH3:18])=[CH:15][CH:14]=[N:8]2)=[CH:6][CH:7]=1
Reactant: C=CC(C)=O
Reactant: Cc1cccc(N)c1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc2c(C)ccnc2c1
Temperature: 12 °C

Procedure:
A solution of 3-methyl-phenylamine (1 eq), in 1,4-dioxane is stirred and cooled to approximately 12° C. Sulfuric acid (2 eq.) is slowly added and heated at reflux. Methylvinyl ketone (1.5 eq) is added dropwise into the refluxing solution. The solution is heated for 1 h after addition is complete. The reaction solution is evaporated to dryness and dissolved in methylene chloride. The solution is adjusted to pH 8 with 1 M sodium carbonate and extracted with three times with water. The residue is chromatographed on SiO2 (70/30 hexane/ethylacetate) to yield the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)=[O:16].[CH3:24][CH:25]([CH3:41])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:30]=1)=[O:27]>>[F:23][C:19]1[CH:18]=[C:17]([C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:38]2[CH2:39][CH2:40][CH:35]([C:31]3[CH:30]=[C:29]([NH:28][C:26](=[O:27])[CH:25]([CH3:24])[CH3:41])[CH:34]=[CH:33][CH:32]=3)[CH2:36][CH2:37]2)[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCCl)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using K2CO3 instead of Na2CO3 and NaI instead of KI and 6-chloro-1-(3-fluorophenyl)-1-hexanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 439.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[C:15](=[CH:16][CH2:17][C:18]([OH:25])([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C@H:12]1[OH:26])C.COCCOC.[OH-].[K+].[Na+].[Cl-]>C(OCC)C.O>[OH:26][C@@H:12]1[CH2:13][CH2:14][C:15](=[CH:16][CH2:17][C:18]([OH:25])([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@H:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCCCCC(C)(O)CC=C1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: COCCOC
Product: CCCCCC(C)(O)CC=C1CC[C@@H](O)[C@@H]1CCCCCCC(=O)O

Procedure:
A mixture of 250 mg. 9β,15-dihydroxy-15-methyl-12-prostenoic acid ethyl ester (as mixture of the two 15-epimers), 20 ml. 1,2-dimethoxyethane, 0.3 g. KOH and 5 ml. water is stirred for 12 hours at room temperature, diluted with 40 ml. diethyl ether and saturated with NaCl. The organic phase is separated, washed twice with 15 ml. amounts of H2O and dried over MgSO4. Solvent is removed to obtain, as oily residue, 9β,15-dihydroxy-15-methyl-12-prostenoic acid as mixture of the 15-epimers.
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[N:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].C([N:19]=[C:20]=[N:21]C1C=NC=CC=1)(C)(C)C>>[C:20]([N:21]=[C:7]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[NH:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])#[N:19]
Reactant: CC(C)(C)N=C=Nc1cccnc1
Reactant: CC(C)(C)CN=C=Nc1cccnc1
Product: CC(C)(C)CNC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure of Example 1, but substituting N-neopentyl-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the N"-cyano-N-neopentyl-N'-3-pyridylguanidine was obtained with a melting point of 214.0°-215.0° C.
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22]([NH:25][N:26]1[CH:30]([CH2:31][CH2:32][C:33](O)=[O:34])[C:29](=[O:36])[O:28][CH2:27]1)(=[O:24])=[O:23].N1C=CC=CC=1.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>C(Cl)Cl.C1COCC1>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22]([NH:25][N:26]1[CH:30]([CH2:31][CH2:32][CH:33]=[O:34])[C:29](=[O:36])[O:28][CH2:27]1)(=[O:23])=[O:24]
Reactant: O=C(O)CCC1C(=O)OCN1NS(=O)(=O)c1ccc2ccccc2c1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=CCCC1C(=O)OCN1NS(=O)(=O)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.4 ml (18.2 mmol) of dry dimethylformamide were introduced into 50 ml of methylene chloride and, at 0° C. under an inert gas atmosphere, 2.0 ml (28.2 mmol) of oxalyl chloride in 70 ml of methylene chloride were added dropwise. The mixture was stirred at 0° C. for 30 min and then the solvent was removed under reduced pressure. The remaining white salt (highly hygroscopic) was suspended in 120 ml of THF/acetonitrile (1:1) and cooled to -30° C. To this were added dropwise 5.6 g (16 mmol) of 3-[3-(2-naphthalenesulfonylamino)oxazolidin-5-on-4-yl]propionic acid together with 1.07 ml (16 mmol) of pyridine in 30 ml of THF, and the mixture was then stirred at -20° C. for 20 min. The mixture was subsequently cooled to -75° C., 307 mg of cuprous iodide were added, then a solution of 5.6 g (21.8 mmol) of lithium tri-tert-butoxyaluminum hydride in 20 ml of THF was slowly added dropwise, and the mixture was stirred at this temperature for 1 h. Quenching was then carried out at -75° C. with 30 ml of 2N hydrochloric acid and, after the mixture had warmed to room temperature, the solvent was removed under reduced pressure, the residue was taken up in methylene chloride, the Cu salts were removed by filtration, and the organic phase was washed three times with water, dried over magnesium sulfate and concentrated under reduced pressure. 5.4 g of slightly impure 3-[3-(2-naphthalenesulfonylamino)oxazolidin-5-on-4-yl]propanal were obtained which were rapidly processed further because of the low stability.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.O=[C:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH3:47])[C:42]=2[O:48][CH3:49])[CH2:36][CH2:35]1.O>COCCOC.CCCCCC.CS(C)=O>[CH:2](=[C:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH3:47])[C:42]=2[O:48][CH3:49])[CH2:36][CH2:35]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1c(NC2CCC(=O)CC2)ccnc1C
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COc1c(NC2CCC(=Cc3ccccc3)CC2)ccnc1C

Procedure:
7.8 g of benzyltriphenylphosphonium bromide in 50 ml of ethylene glycol dimethyl ether are deprotonated at 10° to 20° C. using 11 ml of 1.6 molar butyllithium solution in hexane. After 30 minutes 1.3 g of 4-(4-oxocyclohexylamino)-3-methoxy-2-methylpyridine are added dropwise in 10 ml of DMSO. After 5 hours at 40° to 50° C. the mixture is poured into water and extracted with methylene chloride. The product is purified by column chromatography on silica gel (eluent: ethanol). 0.6=41%; m.p.: 120° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12](=[O:20])[CH2:13]/[CH:14]=[CH:15]/[CH2:16][C:17](O)=[O:18]>>[C:1]1([CH2:7][CH2:8][NH:9][C:17]([CH2:16]/[CH:15]=[CH:14]/[CH2:13][C:12]([O:11][CH3:10])=[O:20])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C/C=C/CC(=O)O
Reactant: NCCc1ccccc1
Product: COC(=O)C/C=C/CC(=O)NCCc1ccccc1

Procedure:
The sub-title compound was prepared from benzeneethanamine and E-hex-3-enedioic acid monomethyl ester using the procedure of Example 6(a) mp 69°-70°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([N+:22]([O-])=O)=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)#[N:2]>[H][H].[Pd]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([NH2:22])=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: [H][H]
Reactant: N#Cc1ccc(CC(=O)N2CCc3ccc([N+](=O)[O-])cc3C2)cc1
Agent: [Pd]
Product: N#Cc1ccc(CC(=O)N2CCc3ccc(N)cc3C2)cc1

Procedure:
Prepared analogously to Example 1b from 2-[(4-cyanophenyl)-acetyl]-7-nitro-1,2,3,4-tetrahydro-isoquinoline and hydrogen/palladium.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](I)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])[CH3:2].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(I)c2nc(-c3ccccc3)sc2c1OCc1ccccc1
Reactant: C1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(N2CCCCC2)c2nc(-c3ccccc3)sc2c1OCc1ccccc1
Temperature: 130 °C
Yield: 15.8 %

Procedure:
A mixture of 7-benzyloxy-4-iodo-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (165 mg, 0.32 mmole), piperidine (95 μl, 0.96 mmole) and triethylamine (89 μl, 0.64 mmole) in ethanol (1.6 ml) was heated at 130° C. in a CEM microwave synthesizer for 30 min before it was cooled to room temperature, concentrated and purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a green oil (24 mg). MS: (+) m/z 474.55 (M+1).
Reaction SMILES: [C:1]1([P:7]([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[N+:15]([C:3]1[CH:2]=[C:1]([P:7]([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=1)([O-:17])=[O:16]
Reactant: OP(O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc(P(O)O)c1

Procedure:
reacting benzenephosphonous acid in a sulfuric acid medium under nitrating conditions by the dropwise addition of nitric acid at a temperature of about 0° C. to about 5° C. to form m-nitrobenzenephosphonous acid in a reaction mixture;
Reaction SMILES: [CH2:1]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].[CH3:18][CH:19]1[CH2:24][C:23](=[O:25])[O:22][C:21](=[O:26])[CH2:20]1.[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([C:7]1[N:8]([C:23](=[O:25])[CH2:24][CH:19]([CH3:18])[CH2:20][C:21]([OH:26])=[O:22])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: CCCCCCc1cc2ccccc2[nH]1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCCCc1cc2ccccc2n1C(=O)CC(C)CC(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of 2-hexyl-1H-indole in DMSO was added KOH at RT and was stirred for 30 minutes. Then to this mixture, 4-methyl-dihydro-pyran-2,6-dione was added and stirred for 3 hours. The reaction was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][C:8]([C:10]1[CH:19]=[CH:18][C:13]2[S:14][C:15]([CH3:17])=[CH:16][C:12]=2[CH:11]=1)=[O:9]>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]([C:10]1[CH:19]=[CH:18][C:13]2[S:14][C:15]([CH3:17])=[C:16]([Cl:4])[C:12]=2[CH:11]=1)=[O:9]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1ccc2sc(C)cc2c1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2sc(C)c(Cl)c2c1

Procedure:
Sulphuryl chloride (3.38 g) was added dropwise to a stirred solution of 2-methylbenzo[b]thiophene-5-carboxylic acid methyl ester (5.15 g) in chloroform (50 ml). The resulting solution was heated under reflux for 2 hours, cooled, washed with water, dried (Na2SO4) and evaporated. The residue was crystallised from methanol/water to give 3-chloro-2-methylbenzo[b]thiophene-5-carboxylic acid methyl ester, 3.00 g, m.p. 85°-86°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a mixture of 4-(4-ethoxycarbonyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (10 g, 29.9 mmol) in ethanol (200 mL was added 1 N sodium hydroxide (100 mL). The reaction mixture was stirred at 70° C. overnight. The solvent was removed under vacuum and the residue washed twice with ethyl acetate, acidified to pH 6 with 5 N HCl, filtered, and concentrated to dryness to provide the title compound (8 g, 87% yield) as a white solid. 1H NMR (d6-DMSO, 400 MHz) δ (ppm) 7.74 (m, 2H), 6.92 (m, 2H), 3.90 (m, 2H), 3.42 (m, 2H), 3.25 (m, 4H), 1.38 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([CH3:11])[CH:3]=1.[Br:12]Br>C(O)(=O)C.O>[Br:12][C:3]1[C:4]([CH3:11])=[N:5][CH:6]=[C:7]([C:2]=1[OH:1])[C:8]([OH:10])=[O:9]
Reactant: BrBr
Reactant: Cc1cc(O)c(C(=O)O)cn1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ncc(C(=O)O)c(O)c1Br
Temperature: 60 °C
Reaction time: 5 h
Yield: 98.1 %

Procedure:
4-Hydroxy-6-methylnicotinic acid 19 (95.6 g, 0.625 mol) was dissolved in acetic acid (950 ml) and water (190 ml), and bromine (39 ml, 0.750 mol) was added over 15 minutes. After the solution was stirred at 60° C. for 5 hours, the solvent was distilled off under reduced pressure, methanol (200 ml) was added and, crystals were collected by filtration. The solution was distilled off under reduced pressure, methanol was added again to the residue, and crystals were collected by filtration. A total of 142.2 g (98%) of 5-bromo-4-hydroxy-6-methylnicotinic acid 20 was obtained as a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[C:19]([NH2:21])=[O:20].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](OC)=O)=[CH:25][CH:24]=1.[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[NH:21][C:19](=[O:20])[C:3]3[C:4]([CH2:17][CH3:18])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=3[N:1]=2)=[CH:25][CH:24]=1
Reactant: CCCCCCC(CCC)n1nc(CC)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CC)c2c(=O)[nH]c(Cc3ccc(Br)cc3)nc21
Yield: 43.5 %

Procedure:
10 mg (0.034 mmol) of 5-amino-3-ethyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.087 mmol) of methyl 4-bromophenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 7 mg (67%) of a solid, Rf=0.69 (dichloromethane/methanol=15:1).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:8][CH:9]=[CH:10][N:11]=2)[CH2:3]1.Cl[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[N:2]1[CH2:5][CH:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:8][CH:9]=[CH:10][N:11]=2)[CH2:3]1
Reactant: Oc1ccccc1-c1nccnc1C1CNC1
Reactant: Clc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccccc1-c1nccnc1C1CN(c2ccc3ccccc3n2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
To a solution of 2-(3-azetidin-3-yl-pyrazin-2-yl)-phenol hydrochloride (275 mg, 1 mmol) and 2-chloro-quinoline (163 mg, 1 mmol) in DMF (10 mL) was added Cs2CO3 (650 mg, 2 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (30 mL×2). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by ISCO silica gel column (10% to 80% EtOAc in petroleum ether) to give 2-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenol (56 mg, 0.16 mmol, yield 16%).