Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][C:10]=2[F:24])[C:6]2[S:25][C:26]([CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:5]=2[C:4](=[O:33])[NH:3]1.Br[CH2:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:37].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[F:24][C:10]1[CH:11]=[C:12]([C:16]2[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[C:14]([F:15])[C:9]=1[CH2:8][N:7]1[C:6]2[S:25][C:26]([CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:5]=2[C:4](=[O:33])[N:3]([CH2:35][C:36]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[O:37])[C:2]1=[O:1]
Reactant: N#Cc1ccccc1-c1cc(F)c(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)c(F)c1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Cn2c(=O)c3cc(CC(F)(F)F)sc3n(Cc3c(F)cc(-c4ccccc4C#N)cc3F)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′,5′-difluorobiphenyl-2-carbonitrile (0.65 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.34 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.082 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.5 g, 59%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].O1CCO[CH2:26][CH2:25]1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[C:2]([CH:25]=[CH2:26])=[N:3][CH:4]=[C:5]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(Cl)c(Cl)c1
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1ncc(CO[Si](C)(C)C(C)(C)C)cc1Cl
Yield: 49 %

Procedure:
In a sealed tube charged with a solution of 2,3-dichloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)pyridine (1500 mg, 5.13 mmol) in 1,4-dioxane (20 ml) was added K2CO3 (2128 mg, 15.40 mmol). The mixture was degassed with N2, then vinylboronic anhydride pyridine complex (1235 mg, 5.13 mmol) and tetrakis(triphenylphosphine)palladium (0) (178 mg, 0.154 mmol) were added. The reaction mixture was stirred at reflux temperature overnight. The crude was diluted with water and extracted twice with EtOAc. The combined organic phases were washed with water and with sat. NaCl, dried over anhydrous MgSO4 and concentrated under vacuum. Purification by flash chromatography using Flashmaster II, a 50 g Merck silica gel cartridge, and mixtures of hexane and EtOAc as eluent afforded 3-chloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-ethenylpyridine (754 mg, 49%).
Reaction SMILES: [C:1]([Cl:5])(Cl)([Cl:3])[Cl:2].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([Cl:18])[C:14]([F:17])=[CH:15][C:16]=1[C:1]([Cl:5])([Cl:3])[Cl:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Fc1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Fc1cc(C(Cl)(Cl)Cl)c(Cl)cc1Cl
Yield: 62.7 %

Procedure:
Into a 200 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, 97 ml (1 mol) of carbon tetrachloride and 26.7 g (0.2 mol) of aluminum chloride were charged, and 16.5 g (0.1 mol) of 1,3-dichloro-4-fluorobenzene was dropwised added thereto under reflux. Thereafter, the mixture was reacted for 20 minutes. Post treatment was conducted in the same manner as in Example 4 to obtain 17.7 g (yield: 62.6%) of 2.4-dichloro-5-fluorobenzotrichloride.
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C(O)C>[C:1]([C:3](=[CH:12][NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[CH3:16])[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: Cc1ccccc1N
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Solvent: CCO
Product: CCOC(=O)NC(=O)C(C#N)=CNc1ccccc1C
Yield: 88.2 %

Procedure:
Ten grams of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide is dissolved by heating in 50 ml of ethanol to 60°. Then 5.32 g of 2-methylaniline in 20 ml ethanol is added and the mixture heated at reflux for 4 hours with stirring. Crystals appear on cooling and the mixture is filtered and washed with ether to yield 11.36 g of α-cyano-β-(2-methylanilino)-N-ethoxycarbonylacrylamide, which is dissolved in tetralin and heated at reflux for 3 hours. After cooling, the mixture is filtered, washed with ether, to yield 5-cyano-1-(2-methylphenyl)uracil, m.p. 251.5°-252.5°.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:8]2[NH:7][C:6]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1CCCC1=O.O>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:26][CH:25]=3)[C:6]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CN1CCc2[nH]c3cc(F)c(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)c(F)cc3n2CCc2ccc(C(F)(F)F)nc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.5 %

Procedure:
To a solution of 8-Chloro-7-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.0041 mol) in N-methyl 2-pyrolidone (0.5 mL) was added powdered potassium hydroxide (0.08 g, 0.00143 mol) and allowed to stir for 10 min at RT. 2-trifluoromethyl-5-vinyl pyridine (0.079 g, 0.00046 mol) was added and stirred for further 15 h. at rt, After completion (TLC), reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through preparative HPLC to give the desired compound 10 as light yellow solid (0.02 g, 12% yield), 8-Chloro-7-fluoro-2-methyl-5-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.02 g, 0.0000485 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.006 g, 0.0000485 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as white solid (0.015 g, 62% yield).
Reaction SMILES: [NH2:1][CH:2]1[C:30](=[O:31])[N:4]2[C:5]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:6](OS(C)(=O)=O)[CH2:7][S:8][C@H:3]12.C[Si](N[C:37]([NH:39][Si](C)(C)C)=O)(C)C.[C:44](#N)[CH3:45]>>[NH2:1][CH:2]1[C:30](=[O:31])[N:4]2[C:5]([C:14]([O:16][CH:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:15])=[C:6]([S:8]/[CH:7]=[CH:6]\[C:5]3[CH:14]=[N:39][CH:37]=[CH:45][CH:44]=3)[CH2:7][S:8][C@H:3]12
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Reactant: CC#N
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12
Reaction time: 0.5 h

Procedure:
The mixture was stirred for 30 minutes. To the mixture was added a solution of benzhydryl 7-amino-3-mesyloxy-3-cephem-4-carboxylate (9.21 g) and bis-(trimethylsilyl)urea (12.26 g) in acetonitrile (276 ml) under ice-cooling. The reaction mixture was stirred for 10 minutes at the same temperature. The insoluble material was filtered off. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give benzhydryl 7-amino-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (6.17 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:7][Br:8])([O-:3])=[O:2].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br-:8].[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:6]([CH2:7][P+:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(CBr)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1[N+](=O)[O-]
Product: [Br-]
Temperature: 25 °C
Yield: 88.5 %

Procedure:
3-Nitro-4-methoxybenzyl bromide (3, 119 g) is charged into 1000 ml of stirred toluene in a 2 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a funnel for the addition of solids and a reflux condenser surmounted by a bubble counter, and the stirred mixture, warmed to 25° C., forms a solution. Triphenylphosphine (126.5 g) is then added and the resultant solution is gradually heated to 60° C.; a precipitate begins to form at about 30° C. The mixture is maintained at 60-65° C. for 4 hours, is then cooled to 30° C. and is filtered through a sintered glass filter. The filter cake is washed on the filter twice with 300 ml portions of toluene, sucked dry and dried in an oven (35° C./20 mmHg/ hours). (4-Methoxy-3-nitrobenzyl)triphenylphosphonium bromide (217 g) is obtained with a chemical yield of 88%. The synthesis is also described in the publication: (solvent used: dichloromethane) K. G. Piney et al., Bioorg. Med. Chem., 8(2000), 2417-2425.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:26][OH:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:29]>C(#N)C.[Ag-]=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:26][O:27][CH3:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: COc1ccc2c(c1)cc(CO)n2-c1ccc(OCc2ccccc2)cc1
Agent: O=[Ag-]
Solvent: CC#N
Product: COCc1cc2cc(OC)ccc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
[1-(4-Benzyloxyphenyl)-5-methoxy-1H-indol-2-yl]methanol (0.2 g, 0.56 mmol) was dissolved in acetonitrile (2 mL), and iodomethane (0.35 mL, 5.6 mmol) and silver(I) oxide (0.39 g, 1.68 mmol) were added. The mixture was stirred overnight at 40° C., then cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated. SiO2 chromatography with 3-50% ethyl acetate/hexanes gave 0.16 g (77% yield) of the desired product. LC-MS (C24H23NO3 calc'd 373) m/z 374 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:22]4[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=4)[CH:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:22]4[CH:23]=[CH:24][C:25]([S:28][CH3:29])=[CH:26][CH:27]=4)[CH:19]([NH:21][S:42]([CH:39]4[CH2:41][CH2:40]4)(=[O:44])=[O:43])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)C(C)N)cc1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc(C(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)C(C)NS(=O)(=O)C2CC2)cc1
Temperature: 25 °C

Procedure:
The racemic mixture of (1RS,2SR)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-amine (27a, 11 mg, 0.02 mmol) was dissolved in THF (1.5 mL). Excess N-ethyldiisopropylamine (0.185 mL, 1.1 mmol) and cyclopropanesulfonyl chloride (0.063 mL, 0.62 mmol) was added in portions over a period of 3 hours. The reaction mixture was stirred over night at room temperature, quenched by addition of water and purified by HPLC. Fractions with product was freeze dried to give the title compound as a colourless solid. Chiral HPLC was made using an Chiralpak IB™, 150×0.46 mm column, 15% EtOH in iso-Hexane, 0.5 mL/min, UV=254 nm. two peaks was seen in 1:1 ratio.
Reaction SMILES: C[Mg+].[Br-].CCOCC.[CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[C:19]#[N:20]>C1(C)C=CC=CC=1>[CH:9]([N:12]([CH:13]([CH3:15])[CH3:14])[C:19](=[NH:20])[C:18]1[C:17]([Cl:16])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:25])([CH3:11])[CH3:10]
Reactant: CC(C)NC(C)C
Reactant: N#Cc1c(Cl)cccc1Cl
Agent: C[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)N(C(=N)c1c(Cl)cccc1Cl)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
A solution of MeMgBr in ether (10 mL, 3.0 M, 30 mmol) was added to a solution of diisopropylamine (3.38 g, 33.5 mmol) in toluene (50 mL) at 50° C. The mixture was stirred for 1 h and a white precipitate formed. Next, the mixture was cooled to 0° C. and 2,6-dichlorobenzonitrile (5.0 g, 29 mmol) was added. The mixture was allowed to warm to room temperature and the mixture was stirred for 16 h subsequently. The conversion, determined by GC, appeared to be 100%. The mixture was quenched with an aqueous NH4Cl solution (1%, 150 mL). The organic phase was separated from the aqueous phase and the latter was extracted with CH2Cl2 (250 mL) twice. The combined organic phases were dried over Na2SO4, filtered and the solvents were removed under reduced pressure resulting in a sticky residue. Pure product 2.50 g (31%) was obtained by rinsing the residue with ligroin. A second portion of pure ligand (5.20 g (65%)) was obtained by evaporating the solvent slowly. Total yield: 7.70 g (97%). The ligand was characterized by 1H NMR (300 MHz) (CDCl3) δ (ppm): 7.3 (m, 2H), 7.1 (m, 1H), 3.6 (p, 1H), 3.2 (p, 1H), 1.6 (d, 6H), 1.1 (d, 6H) and by 13C-NMR (75.5 MHz) (CDCl3) δ (ppm) 160.7, 138.5, 132.7, 129.5, 128.6, 52.7, 46.2, 21.5, 20.2.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].CO.[CH:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>C(OC(=O)C)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:16][CH:17]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C=CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Acetophenone (0.5 g) and sodium hydroxide (0.17 g) were suspended in 15 Ml of methanol pre-chilled at −10° C. p-Anisaldehyde (0.57 g) was added thereto, and stirred for 10 hr at room temperature. After neutralization with 5% hydrochloric acid solution, the product was extracted with 100 Ml of ethylacetate. The extracted organic phase was dried with anhydrous magnesium sulfate, and concentrated under vacuum evaporator. Purified compound was obtained by elution with n-hexane:ethylacetate (v/v, 1:7) through silica gel column chromatography (5×3 cm, Merk), and identified as follows:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.II.[CH:12](=O)[CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1.O1CCCC1>[F:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:12][CH2:13][CH3:14])[CH:4]=1
Reactant: CCC=O
Reactant: Fc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: II
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cccc(F)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Magnesium chips (13.2 g) were placed into a 1 L flask equipped with mechanical stirrer, nitrogen inlet, 500 ml pressure-equilibrated dropping funnel, thermometer and reflux condenser connected to the inert gas outlet. The flask was flushed with nitrogen and minor flow was held during whole reaction time. 1-Bromo-3-fluorobenzene (95 g, 0.542 mol) and dry tetrahydrofurane (300 ml) was placed in dropping funnel. Magnesium was moistened with few milliliters of the solution from dropping funnel and an iodine crystal was added. When exothermic reaction starts 1-bromo-3-fluorobenzene solution was added dropwise to keep the boiling temperature of the mixture. After dropping all of the solution, the mixture was refluxed for 2 hours. Then the mixture was cooled down to −78° C. in a dry ice/acetone bath and propionaldehyde was added dropwise while mixture temperature was kept below −70° C. After adding all of the aldehyde, the mixture was left overnight at room temperature. Then the tetrahydrofurane was evaporated and the residue was acidified with hydrochloric acid. The organic phase was separated, washed twice with water and dried over magnesium sulfate. The raw 1-(3-fluorophenyl)propanol was distilled under reduced pressure of 20 mbar at 117° C. Alcohol 60 g, 66% of theor. yield was obtained. The alcohol and toluene (250 ml) and p-toluenesulfonic acid (0.2 g) were placed in (500 ml) round-bottom flask equipped with Dean-Stark trap. The mixture was refluxed. After the water stopped appearing, toluene was evaporated at reduced pressure. The obtained 1-(3-fluorophenyl)propene was placed in a three-necked flask and acetic acid (30 ml), ethyl acetate (50 ml) and catalyst—palladium on active carbon (2 g) were added. The flask was filled with hydrogen from gas burette at room temperature and the mixture was stirred. Reaction temperature increased spontaneously to 30° C. When the absorption of hydrogen was stopped, the catalyst was filtered off, the solution was washed off with water, dried over MgSO4 and the solvent was evaporated. The 1-fluoro-3-propylbenzene was distilled under atmospheric pressure, collecting the fraction boiling at 160° C. 32 g of 1-fluoro-3-propylbenzene were obtained, 42% of theor. yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.S(Cl)(Cl)=O.[C:15]([NH:18][NH2:19])([NH2:17])=[NH:16].Cl.[OH-].[Na+]>ClCCl.CN(C)C=O>[C:15]([NH:18][NH:19][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1)(=[NH:16])[NH2:17]
Reactant: N=C(N)NN
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N=C(N)NNC(=O)c1ccc(Cl)nc1
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of 6-chloronicotinic acid (10.0 g) in dichloromethane (100 ml) was added dropwise dimethylformamide (10 ml) and thionyl chloride (5.1 ml), and the mixture was stirred for 1 hour with refluxing. The resulting reaction mixture was dropwise added to aminoguanidine hydrochloride (24.6 g) in a 2.2N aqueous sodium hydroxide solution (100 ml) under ice-cooling. After the dropwise addition, the mixture was stirred at said temperature for 10 minutes to give 6.87 g of a pale-brown solid by filtration (yield 51%).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[O:14]([CH2:13][CH2:12][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1NCc2ccccc21
Reactant: BrCCOc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1c2ccccc2CN1CCOc1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
A mixture of 2,3-dihydroisoindol-1-one (0.066 g, 0.5 mmol,), 2-(bromoethoxy)benzene (0.121 g, 0.6 mmol), Cs2CO3 (0.408 g, 1.25 mmol), and 18-crown-6 (0.013 g, 0.05 mmol) in acetone (3 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(2-phenoxy-ethyl)-2,3-dihydro-isoindol-1-one (0.099 g, 78%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.05 (t, 2H), 4.26 (t, 2H), 4.64 (s, 2H), 6.92 (m, 3H), 7.22-7.60 (m, 5H), 7.88 (d, 1H), GC-MS: m/z 253 (M)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[C:22]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[C:21]([F:29])[CH:20]=[CH:19][C:18]=1B(O)O>>[F:29][C:21]1[C:22]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[C:17]([F:16])[CH:18]=[CH:19][C:20]=1[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)c(F)c1-c1cccnc1
Yield: 31.7 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2,4-difluoro-3-(pyridin-3-yl)benzeneboronic acid (66 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(2,4-difluoro-3-pyridin-3-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (27 mg, 34%). δH (360 MHz, CDCl3) 7.28 (1H, m), 7.42-7.49 (2H, m), 7.63 (1H, d, J 4.6), 7.84-7.88 (2H, m), 8.35 (1H, dd, J 2.3 and 8.6), 8.69 (1H, dd, J 1.8 and 4.9), 8.80 (1H, s), 9.33 (1H, d, J 4.2). m/z (ES+) 388 [MH]+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]1([C:31]2[C:39]3[C:38]([N:40]4[CH2:45][CH2:44][CH2:43][CH:42]([C:46]([OH:48])=O)[CH2:41]4)=[N:37][CH:36]=[N:35][C:34]=3[S:33][CH:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.[O:56]1[CH2:61][CH2:60][N:59]([CH2:62][CH2:63][NH2:64])[CH2:58][CH2:57]1>C(#N)C>[O:56]1[CH2:61][CH2:60][N:59]([CH2:62][CH2:63][NH:64][C:46]([CH:42]2[CH2:43][CH2:44][CH2:45][N:40]([C:38]3[C:39]4[C:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:32][S:33][C:34]=4[N:35]=[CH:36][N:37]=3)[CH2:41]2)=[O:48])[CH2:58][CH2:57]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)C1CCCN(c2ncnc3scc(-c4ccccc4)c23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCOCC1)C1CCCN(c2ncnc3scc(-c4ccccc4)c23)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.23099 g, 0.58928 mmol) was added to a suspension of 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidine-3-carboxylic acid (0.1 g, 0.29464 mmol) in acetonitrile (2 mL). Triethylamine (0.123 mL, 0.089443 g, 0.88391 mmol) and 2-morpholinoethanamine (0.0773 mL, 0.076718 g, 0.58928 mmol) were added and the mixture was stirred for 4 hr at room temperature. The solvent was evaporated and the residue was diluted with ethyl acetate (2 mL) and water (2 mL). The layers were separated and the aqueous was extracted with ethyl acetate (2×2 mL). The combined organic layers were washed with saturated aqueous sodium hydrogencarbonate (1×10 mL), dried (magnesium sulfate), filtered and evaporated to give a brown oil. Mass: 0.275 g. This was purified by prep HPLC (basic method 1). Fractions corresponding to the main peak were combined and evaporated to give a yellow oil. Yield=92 mg. LCMS [M+H]+=452; RT=2.89 min Other compounds prepared by Method K using the appropriate starting materials are listed in TABLE 1.