Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[C:11]([F:17])[CH:10]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[F:17][C:11]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]([OH:18])=[O:5])[CH:14]=[CH:13][C:12]=1[CH:15]=[O:16]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=O)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccc(C=CC(=O)O)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 104.3 %

Procedure:
3-(3-fluoro-4-formyl-phenyl)-acrylic acid tert-butyl ester (2 g, 8 mmol) was dissolved in DCM (23 ml) and trifluoroacetic acid (6 ml). The mixture was stirred at room temperature for 6 h then the solvent was evaporated under vacuo giving 1.62 g of 3-(3-fluoro-4-formyl-phenyl)-acrylic acid
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[C:33]2[C:28](=[C:29]([F:35])[CH:30]=[CH:31][C:32]=2[F:34])[C:27](Cl)=[N:26][N:25]=1.CC(O)(C)C>C(OCC)C>[Cl:23][C:24]1[C:33]2[C:28](=[C:29]([F:35])[CH:30]=[CH:31][C:32]=2[F:34])[C:27]([NH:1][C:2]2[CH:22]=[CH:21][C:5]([O:6][C:7]3[C:12]([C:13]4[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=4)=[CH:11][CH:10]=[CH:9][N:8]=3)=[CH:4][CH:3]=2)=[N:26][N:25]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Reactant: Fc1ccc(F)c2c(Cl)nnc(Cl)c12
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(Cl)c4c(F)ccc(F)c34)cc2)n1
Temperature: 100 °C

Procedure:
To 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.100 g, 0.34 mmol) and 1,4-dichloro-5,8-difluorophthalazine (0.096 g, 0.41 mmol) was added tBuOH (1.0 mL). The resulting mixture was heated to 100° C. in a sealed tube for 45 min. The reaction was diluted with diethyl ether and the resulting solids were filtered and triturated with EtOAc. The solids were dried to yield 4-chloro-5,8-difluoro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine as a dark gray solid. MS m/z=492 [M+H]+. Calc'd for C24H16ClF2N7O: 491.89.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:23])[NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)([CH3:6])([CH3:5])[CH3:4].I[CH2:25][CH3:26]>O1CCCC1>[C:3]([O:7][C:8](=[O:23])[N:9]([CH2:25][CH3:26])[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc([N+](=O)[O-])cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CCCOc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a suspension of sodium hydride (477 mg, 18.88 mmol) (Aldrich, 95%) in tetrahydrofuran (25 mL) was added a solution of [3-(4-nitrophenoxy)propyl]-carbamic acid tert-butyl ester (3.0 g, 10.13 mmol) (from Example 64, Step A) in tetrahydrofuran (15 mL) at 0° C. Upon addition, the mixture was allowed to stir at room temperature for 30 minute, treated with iodoethane (3.76 g, 24.25 mmol) (Aldrich), and heated at 55° C. for one hour before it was quenched with aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL) and the combined organic extracts were washed with brine and dried (Na2SO4) and evaporated in vacuo. The residue was purified on silica gel with 75:25 hexane/ethyl acetate to give ethyl-[3-(4-nitrophenoxy) propyl]carbamic acid tert-butyl ester (3.15 g, 96%). MS (ES) MH+=325.
Reaction SMILES: Br[CH2:2][C:3](=[O:24])[CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32].[OH-].[K+].O>C(O)C>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:2][C:3](=[O:24])[CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1ccccc1Cl
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)COc1ccccc1Cl
Yield: 50.2 %

Procedure:
3-Bromo-2-oxopropylidenetriphenylphosphorane (8.0 g) was added to a solution of o-chlorophenol (3.8 g) and potassium hydroxide (1.56 g) in anhydrous ethanol (60 ml), and the resulting mixture was heated at reflux for 2 hours and was then poured into water (200 ml). The mixture was extracted with methylene chloride and the extract was washed with dilute aqueous sodium hydroxide solution (2 N) and with water, dried over magnesium sulphate, and evaporated. The residual solid was recrystallised from a mixture of petroleum ether (b.p. 60°-80° C.) and ethyl acetate, to give 3-(2-chlorophenoxy)-2-oxopropylidenetriphenylphosphorane (4.5 g), m.p. 102°-104° C. A further recrystallisation from a similar solvent gave a purer sample, m.p. 107°-109° C. [elemental analysis: C, 73.1; H, 5.3; P, 7.0%. C27H22ClO2P requires C, 72.9; H, 5.0; P, 6.95%. νmax 715, 750, 1110, 1405, 1440, 1485 and 1550 cm-1 ].
Reaction SMILES: [NH:1]([C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[N:6]=1)=[O:4])[NH2:2].Cl.[N:21]([O-])=O.[Na+]>C(O)(=O)C.O>[N:1]([C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[N:6]=1)=[O:4])=[N+:2]=[N-:21]
Reactant: NNC(=O)c1nc(-c2cccc3ccccc23)no1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: [N-]=[N+]=NC(=O)c1nc(-c2cccc3ccccc23)no1
Yield: 86.2 %

Procedure:
5-Hydrazinocarbonyl-3-α-naphthyl-1,2,4-oxadiazole (6.47g.) was dissolved in acetic acid (125 ml.) and 2N-hydrochloric acid (75 ml.). A solution of sodium nitrite (2.0g) in water (6 ml.) as added at 0° with stirring. After 15 minutes the precipitate was filtered off and dissolved in chloroform. The chloroform solution was washed with water and dried (MgSO4). Evaporation to dryness gave title compound (5.82 g.), m.p. 114° (decomp.), λmax. (EtOH) 300 nm. (ε 8,250), νmax. (CHBr3) 1710 (C=O), 2150 and 2190 cm.-1 (N3).
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[S:7][C:6]1=[NH:12])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:20]12([C:30](Cl)=[O:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>C1COCC1>[CH2:1]([N:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[S:7]/[C:6]/1=[N:12]\[C:30]([C:20]12[CH2:29][CH:24]3[CH2:23][CH:22]([CH2:28][CH:26]([CH2:25]3)[CH2:27]1)[CH2:21]2)=[O:31])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CCCCN1CC(C)(C)SC1=N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCN1CC(C)(C)S/C1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Yield: 9 %

Procedure:
To a solution of Example 2A (149 mg, 0.8 mmol) in THF (10 mL) was added triethylamine (0.4 mL) and adamantane-1-carbonyl chloride (0.2 g, 1 mmol). The mixture was heated to reflux overnight and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with 1 M NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-100% ethyl acetate:hexanes) to provide 25 mg of the title compound. MS (ESI+) m/z 349 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.3 Hz, 3H), 1.19-1.36 (m, 2H), 1.39 (s, 6H), 1.51-1.61 (m, 2H), 1.61-1.73 (m, 6H), 1.74-1.81 (m, 6H), 1.89-2.02 (m, 3H), 3.40-3.44 (m, 2H), 3.55-3.64 (m, 2H); Anal. Calculated for C20H32N2OS: C, 68.92; H, 9.25; N, 8.04. Found: C, 68.94; H, 8.73; N, 8.02.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.[OH-].[Na+]>>[O:14]1[CH2:15][CH2:16][N:1]([C:2]2[CH:10]=[CH:9][C:5]3[S:6][CH:7]=[CH:8][C:4]=3[CH:3]=2)[CH2:12][CH2:13]1
Reactant: ClCCOCCCl
Reactant: Nc1ccc2sccc2c1
Agent: [Na+]
Agent: [OH-]
Product: c1cc2cc(N3CCOCC3)ccc2s1
Yield: 69.3 %

Procedure:
5-Aminobenzo[b]thiophene (5.4 g, 0.0362 mole), bis-(2-chloroethyl)ether (5.2 g, 0.0364 mole) and 40% aqueous NaOH (0.073 mole) were stirred vigorously and heated to refluxing for 22 hours. The cooled mixture was extracted with CHCl3. Evaporation of the washed and dried CHCl3 extract under reduced pressure left 7.0 g (88%) of the crude product as a slightly oily, dark yellow solid. This material was combined with 1.75 g of comparable crude product from a previous run. Recrystallization from CH3CN afforded 5.50 g of 5-morpholinobenzo[b]thiophene, m.p. 127°-132° C., that was characterized by nmr.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:29]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:31])[CH3:30].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[C:13]([O:12][C:10]([NH:1][C@H:2]([C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:7](=[O:9])[CH2:30][C:29]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=O)OCc1ccccc1
Reactant: CC[C@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of Boc-D-alloIle-OH (15.26 g, 65.9 mmol) in dry THF (200 ml) at 0° C. under argon, was added CDI (16.04 g, 98.96 mmol). After 15 min, the mixture was allowed to warm to room temperature, and stirred over a period of 16 h. The resulting solution was cooled to −78° C., and added via cannula to a well stirred solution of benzyl lithium enolate cooled at −78° C. (625 ml, 0.37 M), [prepared by adding dropwise a solution of benzyl acetate (33.34 ml), in THF (165 ml) to a solution of lithium diisopropylamide (0.36M) in THF/hex 3:1 (642 ml) at −78° C.]. The temperature should be kept <−75° C. The reaction mixture was stirred at −78° C. for 60 min. Then, it was allowed to come to −10° C. (30 min), recooled to −78° C. and quenched with saturated aq. ammonium chloride (200 ml), then extracted with DCM (3×500 ml) at room temperature. The combined extracts were washed successively with aq sat. NaHCO3 (500 ml) and brine (200 ml). Drying (Na2SO4) followed by removal of solvent gave an oil, which was coated on silica C18 and loaded to the top of a LC-RPC18 [Lichroprep RPC-18 (40-60 microns) column. Elution using a gradient ACN-H2O (60 to 100% ACN)] yielded the product C4 as a colourless oil (16.7 g, 70%). [α]20D −20.0 (c 1, CHCl3), TLC: Rf=0.32 (Merck, RP-C18, ACN-H2O 7:3).
Reaction SMILES: C[N:2](C)/[C:3](=[N:5]/[C:6]([C:8]1[N:17]=[C:16]2[N:10]([CH2:11][CH2:12][O:13][C:14]3[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:15]=32)[CH:9]=1)=O)/[CH3:4].Cl.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[NH:33]N>C(O)(=O)C>[Br:22][C:20]1[CH:19]=[CH:18][C:15]2[C:16]3[N:10]([CH2:11][CH2:12][O:13][C:14]=2[CH:21]=1)[CH:9]=[C:8]([C:6]1[N:33]([C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[F:25])[N:2]=[C:3]([CH3:4])[N:5]=1)[N:17]=3
Reactant: NNc1ccc(F)cc1F
Reactant: C/C(=N\C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)N(C)C
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(-c2ccc(F)cc2F)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid [1-dimethylamino-eth-(E)-ylidene]-amide (0.0162 mol) was dissolved in Acetic acid (50 mL). 2,4-Difluorophenylhydrazine hydrochloride (3.52 g, 0.0195 mol) was added and the reaction was stirred at 95° C. overnight. The acetic acid was removed in vacuo. The crude was loaded as a solid onto silica gel and purified by flash chromatography (4-10% methanol in methylene chloride) to afford 3.662 g 8-Bromo-2-[2-(2,4-difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as an orange solid. MS(ESI+) 458.0/460.0
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:30])[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[C:17]([OH:24])=[C:16]([C:25](OC)=[O:26])[C:15]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl-].[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][NH3+:49])=[C:44]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:43]=1>CO>[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][NH:49][C:25]([C:16]2[C:15](=[O:29])[N:14]([CH2:13][CH2:12][N:11]([CH3:30])[C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:23]3[C:18]([C:17]=2[OH:24])=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:26])=[C:44]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:43]=1
Reactant: CS(=O)(=O)c1cc(F)ccc1C[NH3+]
Reactant: COC(=O)c1c(O)c2ncccc2n(CCN(C)C(=O)OCc2ccccc2)c1=O
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN(CCn1c(=O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)c(O)c2ncccc21)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of methyl 1-{2-[[(benzyloxy)carbonyl](methyl)amino]ethyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.5 g, 1.21 mmol) in MeOH (6 mL) was treated with Hunig's base (0.33 mL, 1.82 mmol) and 1-[4-fluoro-2-(methylsulfonyl)phenyl]methanaminium chloride (0.35 g, 1.46 mmol) and heated in a sealed reaction vessel at 80 degrees C. After overnight, an additional 0.5 equivalents of the amine and 1.5 equivalents of Hunig's base was added and the reaction heated until HPLC showed the starting material gone. The reaction was cooled and the solids that percipitated were collected by filtration to give pure product.
Reaction SMILES: C[C:2]([CH3:5])([O-])[CH3:3].[K+].[C:7]([O:11][C:12]([N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[Cl-].[Li+]>O1CCCC1>[C:7]([O:11][C:12]([N:14]1[C@H:15]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[CH2:16]/[C:17](=[CH:12]\[N:14]([CH:15]([CH3:20])[CH3:16])[CH:2]([CH3:5])[CH3:3])/[C:18]1=[O:19])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of potassium tert-butoxide (2.8 eq, 2.8 mmol, 1 M solution in THF) and N,N,N′N′-tetramethylformamidinium chloride (18, R6=Me, R7=Me) (3 eq, 3 mmol) are stirred at 60° C. for 1 h. The mixture is then cooled to room temperature. The mixture is then diluted with tetrahydrofuran to a total volume of 5 ml. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (8-a, R1=Boc) (1 eq, 1 mmol) and lithium chloride (1 eq, 1 mmol) is then added to the mixture. The mixture is then stirred at room temperature for 3 h. The volatiles are removed under reduced pressure. Ethyl acetate (20 ml) is added to the mixture. The phases are separated and the organic phase washed with saturated sodium carbonate solution (2×20 ml) and brine (20 ml). The organic phase is dried (Na2SO4) and concentrated under reduced pressure to afford (R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) or a salt thereof. The solutions are analysed by TLC (50% ethyl acetate in hexane). RF 0.21 (salt of 7-a, R1=Boc, R6=Me, R7=Me); RF 0.27 (7-a, R1=Boc, R6=Me, R7=Me); RF 0.68 (8-a, R1=Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11].[H-].[Na+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>CN(C=O)C.CCOC(C)=O>[Cl:15][C:13]1[CH:12]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:11][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH3:18])[CH:21]=1
Reactant: Nc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: COc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(CNc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5 %

Procedure:
1-(3,5-Dichloro-benzyl)-1H-imidazol-2-ylamine (see Example 12) was dissolved in anhydrous DMF and NaH was added to the solution under H2. The reaction mixture was stirred at room temperature for 10 min and 3-methoxybenzylbromide was added. The reaction mixture was stirred at 65° C. for 5 h. The reaction mixture was then diluted with EtOAc and washed with water (×5). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using CH2Cl2:MeOH 95:5 to afford the title compound (7 mg, 5%); LCMS m/z 362 [C18H17Cl2N3O+H]+.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)[C:23](O)=[O:24]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([N:29]3[CH:33]=[N:32][CH:31]=[N:30]3)=[C:20]([F:19])[CH:21]=2)[CH2:2][CH2:3]1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: O=C(O)c1ccc(-n2cncn2)c(F)c1
Product: CC(C)c1noc(N2CCC(N(C(=O)c3ccc(-n4cncn4)c(F)c3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 3-fluoro-4-[1,2,4]triazol-1-yl-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.84 min; Mass spectrum (ESI+): m/z=440 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[OH:7])=[O:5].[OH-].[K+]>CO>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][N:6]1[C:4](=[O:5])[C:3]([CH3:17])([CH3:16])[CH2:2][O:7]1
Reactant: CC(C)(CCl)C(=O)N(O)Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CON(Cc2ccccc2Cl)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
One method for production of COMMAND® is disclosed in U.S. Pat. No. 4,405,357. Such preparation includes adding to a stirred solution of 6.3 grams (0.023 mole) of 3-chloro-N-(2-chlorophenyl)methyl-N-hydroxy-2,2-dimethylpropanamide in 45 ml of methanol dropwise a solution of 1.5 grams (0.023 mole) KOH (85% pure) in 25 ml methanol. The addition required 15 minutes and the temperature rose from 24° to 32° C. Upon completion of addition the reaction mixture was stirred for 18 hours at ambient temperature. By-product KCl was removed by filtering the mixture. The filtrate was poured into 500 ml of ice-water. The mixture was extracted with two portions of 250 ml each of methylene chloride. The combined extracts were dried with MgSO4 and filtered. Under reduced pressure the filtrate was concentrated to give 5.2 grams of 2-(2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone as an oil.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH:34]4[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35]4)[C:31]([CH2:41][O:42][CH2:43][CH3:44])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+:46].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH:34]4[CH2:38][O:37][C:36]([CH3:39])([CH3:40])[O:35]4)[C:31]([CH2:41][O:42][CH2:43][CH3:44])=[N:30][C:25]=3[C:26]([NH2:46])=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1COC(C)(C)O1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC1COC(C)(C)O1
Reaction time: 2 h

Procedure:
3-Chloroperoxybenozic acid (mCPBA) (75% pure, 11.57 g, 50.27 mmol, 1.5 eq) was added to a solution of 7-benzyloxy-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (15.00 g, 33.52 mmol. 1 eq) in dichloromethane (200 mL), and the reaction mixture was stirred for two hours. Analysis by thin layer chromatography indicated the reaction was incomplete and additional mCPBA (1.2 g) was added and the reaction was stirred overnight. The reaction mixture was diluted with dichloromethane (300 mL), washed sequentially with 4% aqueous sodium carbonate solution (2×300 mL) and brine (300 mL), and concentrated under reduced pressure to afford a residue. Concentrated ammonium hydroxide (75 mL) was then added to a mixture of the residue in dichloromethane (200 mL) and cooled to 4° C. p-Toluenesulfonyl chloride (2.75 g, 14.44 mmol, 1.1 eq) was added in portions to the reaction mixture and stirred at ambient temperature for 16 hours. The reaction mixture was then diluted with dichloromethane (200 mL), washed with 4M aqueous sodium carbonate solution and separated. The aqueous layer was re-extracted with dichloromethane (200 mL) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a brown solid. The crude material was purified by crystallization from diethyl ether to provide 9.8 g of 7-benzyloxy-1-[(2,2-dimethyl[1,3]dioxolan-4yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-ylamine as white plates of solid, mp 186-187° C. 1H-NMR (300 MHz, CDCl3) δ 7.89 (d, J=9.1 Hz, 1H), 7.53-7.29 (m, 6H), 7.05 (dd, J=9.0, 2.6 Hz, 1H), 5.42 (br s, 2H), 5.18 (s, 2H), 4.94 (d, J=12.6 Hz, 1H), 4.83-4.69 (m, 3H), 4.68-4.58 (m, 1H), 4.15 (dd, J=8.6, 6.2 Hz, 1H), 3.86 (dd, J=8.6, 6.1 Hz, 1H), 3.62 (q, J=7.0 Hz, 2H), 1.45 (s, 3H), 1.29 (s, 3H), 1.25 (t, J=7.0 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 158.3, 151.7, 149.0, 147.1, 136.8, 134.7, 128.6, 128.0, 127.6, 125.4, 120.9, 113.8, 110.2, 109.7, 108.9, 74.6, 70.0, 66.7, 66.3, 65.3, 48.2, 26.7, 25.1, 15.0; MS (APCI) m/z 463.1 (M+H)+; Anal, calcd for C26H30N4O4: C, 67.51; H, 6.54; N, 12.11. Found: C, 67.29; H, 6.33; N, 12.03.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:14]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][CH:7]=3)[C:13]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=3[Cl:11])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: Clc1ccc2cc[nH]c2c1
Product: Fc1ccc(C(c2c[nH]c3cc(Cl)ccc23)c2c[nH]c3cc(Cl)ccc23)c(Cl)c1

Procedure:
The compound Bis(6-chloroindol-3-yl)-(4-fluoro-2-chlorophenyl)methane was prepared following procedure A, starting from 6-chloro indole and 2-chloro 4-fluoro benzaldehyde. LC: Tr 2.79 min, MS: 443 (M+H)+