Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.O.[NH2:11][NH2:12].[OH-].[K+]>>[NH:11]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1)[NH2:12]
Reactant: NN
Reactant: OCc1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NNc1ccc(CO)cn1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
220.0 g (1.5 mol) (6-chloropyridin-3-yl)methanol [Evans et al., Organic Letters 2001, 19, 3009-3012] are initially introduced into 746 ml (767.1 g, 15.3 mol) hydrazine hydrate and the mixture is stirred at a bath temperature of 150° C. for 5 h. The reaction mixture is concentrated in vacuo, the residue is taken up in 500 ml water and 86.0 g (1.5 mol) potassium hydroxide are added. The mixture is stirred for 15 min, the water is then removed almost completely on a rotary evaporator and the residues of water are distilled off azeotropically with toluene several times. The oily residue is stirred in ethanol, the mixture is cooled to approx. 10° C., the potassium chloride which has precipitated out is filtered off, the filtrate is concentrated, diethyl ether is added to the residue and the mixture is stirred. Finally, the product is filtered off, the residue on the filter is washed with diethyl ether and the crystals are dried in vacuo.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][CH:4]=[CH:3]1.P(Br)(Br)[Br:15]>CN(C=O)C.O>[Br:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: N#Cc1ccc2[nH]ccc(=O)c2c1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2nccc(Br)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of (b) (12 g, 70.5 mmol) in DMF (75 ml) was added dropwise phosphorous tribromide (8 ml, 84.6 mmol) over five minutes (slightly exothermic). The reaction was allowed to cool to room temperature and was then diluted with ice water (100 ml) and stirred 1 hour then diluted with additional water (300 ml). The product was filtered off, washed with water and air dried to provide 14.3 g of product (87%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C1(C)C=CC(S(O[CH2:17][C@H:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O>[CH3:23][C:20]1([CH3:24])[O:19][C@@H:18]([CH2:17][N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)[CH2:22][O:21]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](Cn2cc(I)cn2)O1
Temperature: 100 °C
Yield: 95.9 %

Procedure:
A mixture of 4-iodopyrazole (1.40 g, 7.21 mmol), (R)-(−)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl p-toluenesulfonate (2.27 g, 7.93 mmol), Cs2CO3 (3.52 g, 10.8 mmol) and DMF (10 mL, 100 mmol) was heated to 100° C. for 16 hrs. The reaction mixture was diluted with EtOAc, washed with water (2×), dried with sodium sulfate, filtered and concentrated in vacuo to a solid which was purified using a Teledyne ISCO Combiflash® Rf system [0→20% EtOAc/Heptane] to afford 2.13 g of the title compound (96%). 1H NMR (400 MHz, CDCl3) d 7.55 (s, 1H), 7.52 (s, 1H), 4.43 (dd, J=4.8, 6.1 Hz, 1H), 4.24-4.28 (m, 2H), 4.08 (dd, J=6.3, 8.8 Hz, 1H), 3.76 (dd, J=6.1, 8.6 Hz, 1H), 1.39 (s, 3H), 1.34-1.37 (m, 3H). MS (ESI): m/z 309.01 [M+H]+. UPLC: tR=1.26 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](O)=[O:14])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)cn1
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cn(-c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Fluoro-phenyl)-1H-imidazole-4-carboxylic acid is dissolved in THF. Borane tetrahydrofuran complex in THF is added dropwise. The reaction is refluxed for 2 h and stirred at room temperature overnight. The reaction mixture is then cooled to 0° C. and methanol is added dropwise. The solvents are evaporated and the residue is taken up in HCl and refluxed for 2 h. The reaction mixture is then cooled to 0° C. and sodium hydroxide solution is added dropwise. The desired compound [1-(4-fluoro-phenyl)-1H-imidazol-4-yl]-methanol is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]>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>[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:32]=[CH:31][C:30]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])=[CH:4][CH:3]=3)=[CH:29][CH:28]=2)[CH2:25][CH2:26]1)=[O:23])[CH3:20]
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C@@H:25]([CH3:34])[C@H:26]([OH:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+]>CO.C1COCC1>[OH:33][C@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@@H:25]([NH:24][CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:6]=1)[CH3:34]
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H](C)[C@H](O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
{2′-[((1S,2R)-2-Hydroxy-1-methyl-2-phenyl-ethylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester (0.021 g, 0.04 mmol) in MeOH (0.33 mL) and THF (0.4 mL) was treated with 1N aqueous NaOH (0.1 mL) and stirred at room temperature for 4 hours. Analytical LCMS showed that some starting material was still present, so additional 1N aqueous NaOH (0.05 mL) was added, and the reaction was stirred at room temperature overnight. Analytical LCMS showed that starting material still remained, so additional 1N aqueous NaOH (0.1 mL) was added, and the reaction was stirred for 4 hours. After work-up with CH2Cl2 and 1N aqueous HCl, the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][OH:10].O>C1C=CC=CC=1>[CH3:9][O:10][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: ClCc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: COCc1ccccc1
Yield: 93 %

Procedure:
To a solution of 1.57 g (10 mmol) of benzyl chloride in 40 ml of benzene, 5.57 g (15 mmol) of the tris(dimethylamino)[tris(dimethylamino)phosphoranilideneamino]phosphonium salt of methanol, said salt having had been synthesized in a similar manner as in Example 1, were added at 0° C., followed by a reaction at room temperature for 3 hours. Water (50 ml) was then added to the reaction mixture to terminate the reaction. An organic layer was separated, washed successively with 20 ml of water and 20 ml of a saturated aqueous solution of sodium chloride, and then concentrated to dryness. The resulting liquid compound was distilled, whereby benzyl methyl ether, the target compound, was obtained as a colorless liquid compound in an amount of 1.13 g. Its yield was 93%.
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[CH2:7]=[C:8]([CH3:10])[CH3:9].Cl>ClCCl>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([OH:1])[CH2:9][C:8]([CH3:10])=[CH2:7]
Reactant: C=C(C)C
Reactant: O=CC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: C=C(C)CC(O)C(Cl)(Cl)Cl
Reaction time: 20 h
Yield: 95.2 %

Procedure:
To the optically-active catalyst of Example 1 (a) (total product) under nitrogen was added a solution of chloral (3.3 ml, 33.8 mmole) in dichloromethane (dried over calcium hydride) (30 ml). After cooling the solution to 0°-5° C., isobutene gas (2.84 g, 50 mmole) was bubbled through the mixture over about 1 min. At this stage the temperature of the mixture was not allowed to rise above 20° C. After stirring the mixture at 10°-15° C. for up to 20 h, it was poured into 10% hydrochloric acid (30 ml). After shaking the phases, the aqueous layer was separated and extracted with fresh dichloromethane (2×30 ml). The combined organic extracts were washed with water (30 ml) and dried (MgSO4). Concentration of the extract gave a red oil (6.55 g, 95%) which was distilled to give the product as a colourless oil, with physical characteristics identical to those reported in the literature.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])([O-])=O.O.O.Cl[Sn]Cl>CCO>[NH2:1][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]
Reactant: N#Cc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(Oc2ccccc2N)c1
Yield: 98.9 %

Procedure:
A solution of 3-(2-nitrophenoxy)benzonitrile (1.21 g, 5 mmol, 1.0 equiv) in 30 mL of EtOH was treated with SnCl2.2H2O (3-38 g, 3 equiv) at reflux for 4 h. The volatile was evaporated and the residue was redissolved in EtOAc, washed with saturated aqueous NaHCO3 and 1N NaOH. The organic layer was dried over MgSO4, filtered and evaporated to give 3-(2-aminophenoxy)benzonitrile (1.04 g, 99%). MS found for C13H11N2O (M+H)+: 211.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(O)O.C(N(CC)CC)C>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:2]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH:3]=1)=[O:6]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(C)c(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(-c2ccc(C(=O)O)cc2)c1
Temperature: 100 °C
Yield: 71.3 %

Procedure:
A stirred solution of methyl 3-bromo-4-methylbenzoate (2.6 g, 0.011 mole) in dry DMF (20 ml) under argon was treated with 4-boronobenzoic acid (1.85 g, 0.011 mole) and tetrakis (triphenylphosphine) palladium(0) (400 mg), followed by triethylamine (4.68 ml, 0.046 mole). The mixture was heated at 100° C. for 18 hours, then concentrated in vacuo. The residue was treated with ethyl acetate and extracted with 10% NaHCO3 solution. The basic extract was acidified with dil. HCl and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a light orange solid (2.12 g, 85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:7][CH2:6][CH:5]([CH2:8][CH2:9]O)[CH2:4][O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:32][CH2:9][CH2:8][CH:5]1[CH2:6][O:7][C:2]([CH3:11])([CH3:1])[O:3][CH2:4]1
Reactant: CC1(C)OCC(CCO)CO1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCBr)CO1
Temperature: 0 °C

Procedure:
To a solution of compound 32 (84 g, 0.528 mol) in dry DMF (500 mL) was added triphenylphosphine (207 g, 0.79 mol) with vigorous stirring until it becomes a clear solution. The mature was cooled to 0° C. and added CBr4 (260 g, 0.79 mol) portion wise over a period of 30 min and allowed to stir at RT for 5 h. The reaction mixture was cooled to 0° C., added saturated NaHCO3 solution (200 mL) and extracted with hexane (4×200 mL). The combined organic layer was dried, concentrated under vacuum and the crude title compound (117 g) was used for next reaction without any purification. TLC: Pet. ether/EtOAc, 7:3, Rf=0.6
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[CH2:13](O)[CH2:14][OH:15].C(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1([C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[O:15][CH2:14][CH2:13][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(OCC)OCC
Solvent: ClCCl
Product: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1
Temperature: 25 °C

Procedure:
P-Nitroacetophenone (1.65 g, 10 mmol), ethylene glycol (5 ml, 89 mmol), triethyl orthoformate (2.96 g, 20 mmol), and p-toluenesulfonic acid (0.086 g, 0.5 mmol) were combined in methylene chloride (4 ml). The solution was heated with an oil bath (50°-70° C., 6 hrs), cooled to room temperature, and poured into excess 10% sodium hydroxide solution. The phases were separated and the aqueous phase was extracted twice with methylene chloride. The combined organic phase was washed three times with water and dried with anhydrous sodium sulphate. Evaporation of the solvent left a light yellow product (1.78 g) with mp. 69°-71° C., (lit. 73°-75° C., see J. Pharm. Sci. 57, 784 (1968)).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.Br[C:40]1[CH:41]=[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:43]=[N:44][CH:45]=1.CCCCCCC>C1(C)C=CC=CC=1>[F:20][C:17]([F:18])([F:19])[C:15]1[CH:14]=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:40]3[CH:41]=[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:43]=[N:44][CH:45]=3)[N:7]=[CH:8]2)[CH:16]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1cncc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.503 g, 0.7 mmol), commercially available 5-bromo-pyridine-3-sulfonic acid amide (0.183 g, 0.77 mmol), tetrakis(triphenyl-phosphine)palladium (0.040 g, 0.030 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (258 mg, 72%). MS (ISP) 514.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: Ic1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)c1ccccc1
Yield: 90 %

Procedure:
Following General Procedure A (90° C., 30 hours), diethyl malonate (240 mg, 1.5 mmol) is coupled with iodobenzene (112 μL, 1.0 mmol) to give 90% diethylphenylmalonate.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4]Cl.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]>COCCOC.C(O)C>[Cl:1][CH2:2][C:3]1[N:13]=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[CH:4]=1
Reactant: O=C(CCl)CCl
Reactant: Nc1ccccn1
Solvent: CCO
Solvent: COCCOC
Product: ClCc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 1,3-dichloropropan-2-one (1.40 g, 11 mmol) in 1,2-dimethoxyethane (5 mL), pyridin-2-amine (0.94 g 10 mmol) was added. The solid dissolved immediately and a white precipitate was observed. The mixture was stirred at room temperature for 1 h, and then was cooled to 0° C. for 20 min. The resulting mixture was filtered to give a white solid. The precipitate was suspended in ethanol (EtOH) (40 mL) and heated at reflux to render a clear solution. After refluxing for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and saturated aqueous NaHCO3 solution was added to adjust the pH to ˜7.0. A white suspension formed during the course of addition. The resulting mixture was stirred for 20 min and then filtered to give the title compound as a white solid (0.5 g, 30% yield). ESI MS: m/z 167 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J=6.8 Hz, 1H), 7.97 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.23 (t, J=7.6 Hz, 1H), 6.88 (t, J=6.4 Hz, 1H), 4.82 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2)[CH3:2].[Br:13]Br>>[Br:13][C:5]12[CH2:11][CH:9]3[CH2:8][CH:7]([CH2:12][C:3]([CH2:1][CH3:2])([CH2:10]3)[CH2:4]1)[CH2:6]2
Reactant: BrBr
Reactant: CCC12CC3CC(CC(C3)C1)C2
Product: CCC12CC3CC(CC(Br)(C3)C1)C2
Yield: 90.3 %

Procedure:
1-Bromo-3-ethyladamantane was prepared from 1-ethyladamantane (K. Gerzon et al, J. Med. Chem., 6, 760, 1963) by stirring 0.944 grams (5.76 mmol) of 1-ethyladamantane with 10 ml of liquid bromine for 4 hours, over which time the temperature was increased to reflux. The heat was removed and after cooling, a 40 ml portion of carbon tetrachloride was added. The mixture was poured into 120 ml of ice water and enough solid sodium sulfite was added with stirring to destroy the excess bromine. The layers were separated and the aqueous phase was extracted with three portions of carbon tetrachloride. The combined extracts were washed with water, then 5% aqueous sodium bicarbonate solution, then dried over magnesium sulfate (anhydrous). Evaporation of solvent yielded a yellow liquid which was distilled to afford 1.263 grams (90.3%) of 1-bromo-3-ethyladamantane, bp 114°-115° C. (3.5 mm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([F:21])([F:20])[CH2:18]I.O>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:18][C:17]([F:21])([F:20])[F:16]
Reactant: COc1ccccc1O
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccccc1OCC(F)(F)F
Temperature: 120 °C
Reaction time: 10 h
Yield: 87.3 %

Procedure:
To a solution of 2-Methoxy phenol (IX) (5 g, 0.04 moles) in N-methylpyrrolidone (50 ml) were added, potassium carbonate (7.8 g, 0.06 mole) and 2,2,2-trifluoroethyl iodide (33.8 g, 0.16 mole) under stirring. The reaction mixture was stirred vigorously at 120° C. for 10 hours. Water (150 ml) was added to the reaction mixture and the mixture was extracted in Toluene (250 ml). Organic layer was washed with 1 N Sodium hydroxide solution (150 ml), followed by brine wash. The extract was dried over sodium sulphate. The solvent was evaporated under reduced pressure to give 7.2 g of (X) as oil. Purity (by GC)=94%
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)=[O:5])C.[Mg]>CO.ClCCl>[CH3:1][O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[CH:12]=2)[NH:7]1)=[O:5]
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Agent: [Mg]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1Cc2cc(OC)ccc2N1
Temperature: 7.5 °C
Reaction time: 3 h

Procedure:
5-Methoxyindole-2-carboxylic acid ethyl ester (2 g, 9.13 mmol) and magnesium turnings (0.432 g, 18 mmol) were suspended in dried methanol (30 ml). This mixture was stirred at 5 to 10° C. under nitrogen for 3 hours, then poured into dichloromethane (200 ml), and washed with saturated ammonium chloride solution. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (3×100 ml). The combined organic layers were dried over sodium sulphate and evaporated. A brown solid was obtained. After column chromatography on silica gel using dichloromethane as eluent, a brown solid was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([C:10]1[CH:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:13]([C:17]#[N:18])[NH:14][C:15]=1[CH3:16])([OH:9])=[O:8].[CH:32](O)([CH3:34])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:17]([C:13]1[NH:14][C:15]([CH3:16])=[C:10]([C:7]([O:9][CH:32]([CH3:34])[CH3:33])=[O:8])[CH:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:12]=1[C:19]([O:21][CH3:22])=[O:20])#[N:18]
Reactant: CC(C)O
Reactant: COC(=O)C1=C(C#N)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1=C(C#N)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Phosphorus pentachloride (2.46 g) was added to a suspension of (+)-methyl 5-carboxy-2-cyano-6-methyl-4-(3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate (3.12 g) in methylene chloride (30 ml) under ice-cooling, and the mixture was stirred for 30 minutes. Then, a solution of isopropyl alcohol (1.4 g) in methylene chloride (10 ml) was added dropwise thereto over a period of 10 minutes. After being stirred for 20 minutes, 5% aqueous sodium carbonate (30 ml ) was added to the reaction solution and then stirred at ambient temperature for an hour. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (75 g) using a mixture of benzene and ethyl acetate (10:1) as an eluent. The eluate was evaporated in vacuo and the residue was crystallized from diisopropyl ether to give (+)-5-isopropyl 3-methyl 2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (3.34 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:12](OC(OCC)OCC)C>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:12][NH:11][C:9](=[O:10])[C:3]=2[N:4]=1
Reactant: NC(=O)c1nc(Cl)ccc1N
Reactant: CCOC(OCC)OCC
Product: O=c1[nH]cnc2ccc(Cl)nc12
Temperature: 145 °C
Reaction time: 3 h

Procedure:
3-amino-6-chloro-pyridine-2-carboxylic acid amide (7.45 g, 43.41 mmol) is taken up in triethylorthoformate (150 mL) and stirred for 3 h at 145° C. After cooling the precipitate formed is filtered off, washed with Et2O, dried and 6-chloro-3H-pyrido[3,2-d]pyrimidin-4-one (HPLC-MS: tRet=0 min; MS (M+H)+=182) is obtained.