Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=1>C(O)=O>[CH:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(N)ccn1
Solvent: O=CO
Product: COC(=O)c1cc(NC=O)ccn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
A mixture of formic acid (20 g.) and acetic anhydride (41.3 g.) was stirred for 30 minutes at 50° C. and thereto was added methyl 4-amino-2-pyridinecarboxylate (11 g.) at ambient temperature, and then the mixture was stirred for 2 hours at 70°-75° C. After the removal of the solvent from the reaction mixture, the residue was recrystallized from ethanol (160 ml.) to give a pale yellow powder of methyl 4-formamido-2-pyridinecarboxylate (8.3 g.), mp. 185° to 186.5° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[NH:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])C.[OH-].[K+].Cl.O>C(O)C>[F:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:18][C:17]2=1
Reactant: CCOC(=O)C1CCc2[nH]c3ccc(F)cc3c2C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCc2[nH]c3ccc(F)cc3c2C1
Temperature: 42.5 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
6-Fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid ethyl ester (80 g, 0.3 mol) was dissolved in 1 L of ethanol solution of KOH (28 g, 0.5 mol). The resulting mixture was stirred under nitrogen at 40-45° C. until completion of hydrolysis (TLC, HPLC) in 3 hrs. To the cooled solution were added 0.5 L of 1N aqueous HCl and 0.5 L of water; the resulting mixture was concentrated under reduced pressure. The target compound crystallized out of the aqueous solution when ethanol boiled out; 71.2 g (99%) of the title compound were obtained after drying.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.C([Li])CCC.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([B:18]([OH:23])[OH:19])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1B(O)O
Reaction time: 0.67 h
Yield: 66.1 %

Procedure:
A round-bottom flask was charged with 2-chloro-3′-fluoro-4-iodo-5-methoxy-1,1′-biphenyl (1.68 g, 4.63 mmol), triisopropyl borate (1.399 ml, 6.02 mmol), and THF (23.17 ml). The flask was cooled in a dry ice-acetone bath for 10 min, then n-butyllithium (2.5 M in hexane) (2.409 ml, 6.02 mmol) was added drop wise over 1 min. After 40 min, a solution of 2 N aq. NaOH (25 mL) was added. The resulting biphasic mixture was stirred for 10 min, and then partitioned between water and ether. The layers were separated, and the ethereal layer was extracted with water (2×). The combined aq. extracts were washed with ether, and the ethereal layer was back-extracted with water. The combined aq. layers were acidified with 3N aq. HCl (50 mL), and the aq. mixture was extracted with DCM (3×). The combined DCM-layers were dried over sodium sulfate, filtered, and concentrated to give (2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)boronic acid (0.859 g, 3.06 mmol, 66.1% yield) as an oily solid. m/z (ESI) 281.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:3]=1[O:4][C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH3:25][N:26]=[C:27]=[O:28]>C1C=CC=CC=1>[CH3:25][NH:26][C:27]([N:8]1[CH2:7][CH2:6][C:5]([O:4][C:3]2[C:17]([F:24])=[C:18]([F:23])[C:19]([F:22])=[C:20]([F:21])[C:2]=2[F:1])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:9]1)=[O:28]
Reactant: CN=C=O
Reactant: Fc1c(F)c(F)c(OC2(c3ccccc3)CCNCC2)c(F)c1F
Solvent: c1ccccc1
Product: CNC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
A solution of 5.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine in 50 ml of benzene was treated with a solution of 0.9 g of methyl isocyanate in 20 ml of benzene over a period of ten minutes. The reaction mixture was then stirred at ambient temperature for two hours. Evaporate of the volatiles afforded a solid which was purified by means of high pressure liquid chromatography (silica gel; elution with 50% ethyl acetate/dichloromethane) to yield 4.0 g (69%) of 1-(N-methylamino)carbonyl-4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine, m.p. 87°-89° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[N:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C)C=O>[S:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:25]([N:19]2[CH2:20][CH2:21][N:22]([C:7]([C:6]3[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=3[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:23][CH2:24]2)=[N:26]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nsc3ccccc23)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (CA=87691-88-1) in dimethylformamide. The crude material was purified by HPLC (Zorbax XDB, reversed phase, water/acetonitrile) to yield the title compound as a white foam. MS (m/e): 460.3 (M+H+)
Reaction SMILES: CO.O1[CH2:8][CH2:7][O:6][CH2:5]C1.Cl.[Cl:10]C1[N:16]=[CH:15][N:14]=[C:13]([N:17]2[C:21](=[O:22])[C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][NH:18]2)C=1>C1COCC1>[ClH:10].[CH3:5][O:6][C:7]1[N:16]=[CH:15][N:14]=[C:13]([N:17]2[C:21](=[O:22])[C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][NH:18]2)[CH:8]=1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Reactant: C1COCCO1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-n2[nH]cc(-n3ccnn3)c2=O)ncn1

Procedure:
0.3 ml (6.6 mmol) methanol are initially introduced into 15 ml dioxane. 1.3 ml (2.7 mmol) of a 2 M solution of the phosphazene base P2-tert-butyl in THF are added slowly, while stirring, and the mixture is stirred at RT for 15 min 350 mg (1.3 mmol) of the compound from Example 52A are subsequently added and the mixture is reacted in a single mode microwave (CEM Explorer) at 150° C. for 2 h. A further 2 ml (49.2 mmol) methanol are then added and the mixture is reacted again in a single mode microwave (CEM Explorer) under the same conditions for 2 h. After cooling, the reaction mixture is concentrated and the residue is purified via preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined and the mixture is concentrated on a rotary evaporator. The residue is dried under a high vacuum and 3 ml of a 4 N solution of hydrogen chloride in dioxane is subsequently added. The mixture is stirred at RT for 30 min and the solid is then filtered off and dried under a high vacuum.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25]([CH3:29])([CH3:28])[C:26]#N)[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH:30]S(O)(=O)=O>O1CCCC1.O>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25]([CH3:29])([CH3:28])[CH:26]=[O:30])[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C#N)c1cccc(OCc2ccccc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C=O)c1cccc(OCc2ccccc2)c1
Temperature: 16.5 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Diisobutylaluminum hydride (300 mL, 0.3 mol of a 1.0 M solution in hexanes) was added dropwise to a cooled (15° C., ice-bath) solution of nitrile II (59.9 g, 0.24 mol) in anhydrous tetrahydrofuran (250 mL). The reaction temperature was maintained at 15-18° C. during the addition. The reaction was then allowed to warm to room temperature and stirred for an additional 2 hours. The reaction was hydrolyzed by addition of a cold solution of conc. H2SO4 (35.5 mL) in water (117.5 mL) with the temperature maintained at <30° C. The resultant mixture was stirred for a further 2 hours, then filtered, and the filtrate extracted with diethyl ether (2×250 mL), washed with water (300 mL), brine (300 mL), dried and concentrated under reduced pressure to give crude aldehyde III as a light-yellow oil (59.82 g, 98%) which was used without further purification. M+1=255.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=[C:12]([Br:19])[CH:11]=1)([CH3:9])[CH3:8])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:19][C:12]1[CH:11]=[C:10]([C:7]([CH3:9])([CH3:8])[CH2:6][C:5]([C:20]([F:23])([F:21])[F:22])([OH:24])[CH2:4][OH:3])[C:18]2[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(Br)cc2c1OCC2)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CC(O)(CO)C(F)(F)F)c1cc(Br)cc2c1OCC2
Yield: 72.5 %

Procedure:
To a solution of the 2.28 g (5.36 mmol) of the above 4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester in 30 mL of dry THF was added 705 mg (18.57 mmol) of lithium aluminum hydride in several portions. The mixture foamed and became slightly exothermic and was then warmed at reflux for 1.5 hours. The mixture was then cooled and cautiously quenched with water dropwise, dried over magnesium sulfate, filtered through diatomaceous earth, and concentrated in vacuo to afford 1.82 g of crude product as a white solid. Trituration with hexanes followed by filtration afforded 1.49 g (72%) of 4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentane-1,2-diol as a white solid, m.p. 124° C.-128° C.
Reaction SMILES: [C:1]1(=[N:13]O)[C:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1.[OH2:15]>>[C:1]1(=[O:15])[C:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2][NH:13]1
Reactant: ON=C1CCc2oc3ccccc3c21
Reactant: O
Product: O=C1NCCc2oc3ccccc3c21

Procedure:
A mixture of 2,3-dihydro-1H-cyclopent a[b]benzofuran-1-one oxime (1.0g) and polyphosphoric acid (ca.2 ml) was heated at 110° for 5h. Water (100 ml) was added and the suspension was extracted with ethyl acetate (3×50 ml). The combined extracts were dried and evaporated to give a solid (ca.325 mg) which was purified by FCC eluting with System B (1:1) to give the title compound, m.p. 158°-161°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:14][CH2:15][CH2:16][CH3:17].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:14]([O:12][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=1)[CH2:15][CH2:16][CH3:17]
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1cc(C)c([N+](=O)[O-])c(C)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
Formation of compound (c): A mixture of 3,5-dimethyl-4-nitrophenol (b) (2 g, 12 mmol), bromobutane (1.6 mL, 15 mmol), K2CO3 (2.1 g, 15 mmol) in DMF (6 mL) was stirred at 60° C. for 6 hours. The reaction mixture was poured into 50 mL of H2O and extracted with ether (3×50 mL). The combined ether layer was washed with H2O and subsequently with brine, dried over Na2SO4, filtered and concentrated to give compound (c), 4-butoxy-2,6-dimethyl-nitrobenzene (2.6 g, 97% yield) as a dark brown oil. 1H-NMR in CDCl3.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Cl:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]([CH3:15])[N:7]=1.C(=O)=O.[Cl-].[NH4+]>C1COCC1>[Cl:5][C:6]1[N:7]=[C:8]([CH3:15])[CH:9]=[C:10]2[CH:2]=[CH:1][NH:12][C:11]=12
Reactant: C=C[Mg]Br
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc2cc[nH]c2c(Cl)n1
Reaction time: 18 h
Yield: 44 %

Procedure:
Vinylmagnesium bromide solution (1 M in THF, 111 mL, 111 mmol) was added dropwise at −78° C. to a solution of 2-chloro-3-nitro-6-picoline (6.19 g, 35.2 mmol) in THF (200 mL). The dry ice cooling bath was replaced by an ice/NaCl cooling bath, and the reaction mixture was allowed to reach RT over 18 h, then the reaction mixture was carefully treated with 20% aq. ammonium chloride solution (210 mL). The reaction mixture was extracted with ethyl acetate, the organic layer was dried (MgSO4), and evaporated. Chromatography of the residue (SiO2, heptane/ethyl acetate gradient) afforded the title compound (2.58 g, 44%). Orange solid, MS (EI) 166.1 (100, M+).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2Cl)[CH2:5][CH2:4]1.[CH3:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.CC#N>O>[F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:27]([CH3:26])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:5][CH2:4]1
Reactant: CNc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reactant: CNCc1ccc(F)cc1
Solvent: O
Solvent: CC#N
Product: CNc1cc(N(C)Cc2ccc(F)cc2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (60 mg, 0.158 mmol), N-methyl-N-(4-fluorobenzyl)amine (24 μL, 0.18 mmol) and MeCN (1 mL) is irradiated in a microwave oven for 45 min at 160° C., and after cooling diluted with water. The mixture is extracted with EtOAc, the combined organic phases are dried with Na2SO4, filtered and concentrated and directly used in the next step. Yield: 80 mg.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].CN1CCOCC1.ClC(OCC(C)C)=O.[C:21]([O:25][C:26](=[O:35])[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH2:34])([CH3:24])([CH3:23])[CH3:22]>ClCCl>[C:21]([O:25][C:26](=[O:35])[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:1](=[O:5])[CH:2]=[CH2:3])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: C=CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To a solution of acrylic acid (2.50 g, 34.7 mmol) in dichloromethane (80 mL) at 0 degrees Celsius was added N-methyl-morpholine (4.73 g, 46.8 mmol), followed by isobutyl chloroformate (6.37 g, 46.8mmol). After 30 minutes, a solution of (2-amino-phenyl)-carbamic acid tertbutyl ester (5.80 g, 27.8 mmol) in dichloromethane (50 mL) was added dropwise to the refluxing reaction mixture over 30min. After the reaction was completed (2 hours later), the reaction mixture was allowed to cool down to room temperature, poured into ice water, and extracted with dichloromethane (30 mL×3). The organic layer was washed with water, dilute sodium bicarbonate solution, 0.1M HCl, water, and brine in turn. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/petroleum ether=1/4 (v/v) to obtain the desired product (2.5g, 34%). MS: calc'd 263 (MH+), exp 263 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH:38][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=2)=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:25][CH:24]=1
Reactant: COC(=O)CCN
Reactant: CCCCCC=C(c1ccc(C(=O)O)cc1)c1ccc(OC)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC=C(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[1-(3-bromo-4-methoxy-phenyl)-hept-1-enyl]-benzoic acid (380 mg, 0.94 mmol) in methylene chloride (9 mL) are added triethyl amine (0.39 mL, 2.81 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (197 mg, 1.41 mmol) and EDCI (541 mg, 2.81 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving the titled compound (321 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:14]([OH:18])[C:15]#[C:16][CH3:17].[H-].[Na+].O>O1CCCC1>[CH2:14]([O:18][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1)[C:15]#[C:16][CH3:17]
Reactant: CC#CCO
Reactant: Clc1cc(-c2ccccc2)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC#CCOc1cc(-c2ccccc2)ncn1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
In 5 ml of tetrahydrofuran were dissolved 186 mg of 4-chloro-6-phenylpyrimidine and 82 mg of 2-butyn-1-ol, to which 47 mg of sodium hydride (60% in oil) was added with stirring at room temperature, followed by further stirring for 3 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 190 mg of 4-(2-butynyloxy)-6-phenylpyrimidine (the present compound (38)), m.p.: 59.6° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]2[N:6]=[CH:7][CH:8]=[N:9][C:10]=2[CH:11]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(Br)cc2nccnc12
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc2nccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
As shown in step 6-vi of Scheme 6, a solution of 7-bromoquinoxalin-5-ol (2.0 g, 8.89 mmol) in DCM (20 mL) was added imidazole (1.82 g, 26.7 mmol) and tert-butyldimethylsilyl chloride (1.34 g, 1.65 mL, 8.89 mmol). The reaction mixture was stirred overnight at RT, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 20% EtOAc/hexanes gradient) to provide 7-bromo-5-((tert-butyldimethylsilyl)oxy)quinoxaline (compound 1018) as a colorless oil: 1H-NMR (300 MHz, CDCL3) δ 8.69 (q, J=1.8 Hz, 2H), 7.80 (d, J=2.1 Hz, 1H), 7.22 (d, J=2.1 Hz, 1H), 0.96 (s, 9H), 0.81 (s, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[C:12](=[O:19])[C:11]3[CH2:20][CH:21]([CH3:23])[O:22][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8].[I-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[O:19][CH:21]([CH3:23])[CH2:20][C:11]=3[C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1Cc2c(n(-c3ccc(Cl)c(Cl)c3)c3ncccc3c2=O)O1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC1Cc2c(c3cccnc3n(-c3ccc(Cl)c(Cl)c3)c2=O)O1
Temperature: 0 °C

Procedure:
To a solution of 9-(3,4-dichlorophenyl)-3,9-dihydro-2-methyl-furo[2,3-b][1,8]naphthyridin-4(2H)-one (125 mg.) (prepared as in example 2) in dimethylacetamide (20 ml.) in an atmosphere of nitrogen was added sodium iodide (250 mg.). The solution was refluxed for 4 hrs., and it was poured over ice-water, filtered, dried and recrystallized from isopropanol to yield the desired product, m.p. 273°-274° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:10])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([SH:10])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(S)cc1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(S)cc1Cl
Temperature: 0 °C
Reaction time: 20 h
Yield: 97.9 %

Procedure:
324 mg of said di(3-chloro-4-methoxyphenyl)disulfide was dissolved in 10 ml of ethanol, followed by addition of 106 mg of sodium borohydride. The mixture was stirred over 2 hours at room temperature. The solution thus reacted was made weakly acidic by addition of dilute hydrochloric acid. The product was extracted twice with ethyl acetate. The organic layer was washed with saturated salt water and then dried over sodium sulfate anhydride. The solvent was distilled out under reduced pressure. The resulting crude product was purified by flash column chromatography (hexane:ethyl acetate=15:1), whereby 239 mg of 3-chloro-4-methoxybenzenethiol was obtained. 231 mg of the resulting 3-chloro-4-methoxybenzenethiol was dissolved in 4 ml dichloromethane, followed by cooling to 0° C. 4 ml of boron tribromide in dichloromethane was added dropwise under stirring. The mixture was stirred for 2 hours under cooling on ice and then for 20 hours at room temperature. Subsequently, under cooling on ice, water was added to the solution thus reacted, and the product was extracted twice with chloroform. The organic layer was washed with saturated salt water and dried over sodium sulfate anhydride. The solvent was distilled out, whereby 208 mg of crude 3-chloro-4-hydroxybenzenethiol was obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1>C(O)(=O)C>[NH:16]1[CH:17]=[CH:18][C:14]([NH:13][C:1]2[NH:2][C:6](=[O:7])[C:5]3[C:4]([CH:3]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[N:15]1
Reactant: Nc1cc[nH]n1
Reactant: N#CCc1ccccc1C(=O)O
Solvent: CC(=O)O
Product: O=c1[nH]c(Nc2cc[nH]n2)cc2ccccc12
Temperature: 130 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
2-Cyanomethyl-benzoic acid (1.61 g, 0.01 mol), 3-amino-pyrazole (1 g, 0.01 mol), acetic acid (15 ml), were sealed in a bottle (20 ml). The mixture was heated at 130° C. for 20 minutes under microwave irradiation. The mixture was concentrated and the residue was dissolved in 5 ml MeOH. The solution was added dropwise to 200 ml water. After stirred for 1 hour, solid was collected and dried to give product (1.8 g, 75% yield). LC-MS: 227 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[C:10]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: Clc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: OC1(c2cccc(Cl)c2)CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
3-Chlorophenylmagnesium bromide (3.4 mL, 3.4 mmol) was added to a cooled (−10° C.) solution of cyclohexanone (0.3 g, 3.1 mmol) in anhydrous tetrahydrofuran slowly over 30 min. After complete addition, the reaction mixture was slowly warmed to room temperature, stirred for 18 hours. Again cooled (−5° C.), than quenched with sat. ammonium chloride solution over 30 min. The reaction mixture was extracted with ethyl acetate, dried, filtered and concentrated to afford 550 mg of 1-(3-chlorophenyl)cyclohexanol.