Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][CH:14]=[C:13]([NH:20][C:21](=[O:23])[CH3:22])[CH:12]=3)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[C:21]([NH:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17](=[O:19])[CH:18]=[C:9]([C:8]3[CH:24]=[CH:25][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=3)[O:10]2)=[CH:15][CH:14]=1)(=[O:23])[CH3:22]
Reactant: COC(=O)c1ccc(-c2cc(=O)c3ccc(NC(C)=O)cc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1ccc2c(=O)cc(-c3ccc(C(=O)O)cc3)oc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
6 g of 7-acetamido-4'-flavonecarboxylic acid methyl ester are dissolved in 600 cc of dioxane. 12 g of sodium carbonate, dissolved in 250 cc of water, are added and the mixture is heated at 100° C. with stirring until the reaction is complete, for about 8 hours. The reaction is checked by plate chromatography (benzene (90)-dioxane (25)-acetic acid (4) elution solvent).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:12][C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1>C([O-])([O-])=O.[Na+].[Na+].CCO.C1(C)C=CC=CC=1.CCOC(C)=O.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:12][C:13]1[N:14]=[N:15][C:16]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Clc1ccc(Cl)nn1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(Cl)nn2)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-methoxyphenylboronic acid (3 g, 0.02 mol) and 3,6-dichloro-pyridazine (3.58 g, 0.024 mol) in 2 M Na2CO3/EtOH toluene (40 mL/20 mL/100 mL) was bubbled through N2 for 5 min. Pd(PPh3)4 (1.15 g, 0.001 mol) was added under N2 and the reaction was heated to 80° C. for 16 h. The mixture was diluted with 100 mL of EtOAc and 20 mL of water. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4 and concentrated in vacuo. The solid obtained was washed with 50% EtOAc/hexane to provide the title compound as off-white solid. MS (ESI pos. ion) m/z: 221.0 (M+H). Calc'd Exact Mass for C11H9ClN2O: 220.65.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:18])C=1.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([C:3]1[C:4]([CH3:9])=[N+:5]([O-:18])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 90 h
Yield: 89.6 %

Procedure:
First, 3-ethyl-2-methylpyridine (7.25 g, 59.8 mmol) was dissolved in dichloromethane (dehydrated)(100 ml) and 3-chloroperbenzoic acid (19.0 g, 71.6 mmol, as the content was regarded as 65%) was added in a nitrogen atmosphere at ice-cooling temperature. The mixture was stirred at room temperature for 90 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution was added. The aqueous layer was extracted twice with dichloromethane and three times with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtrated and concentrated. The residue was purified by silica gel column chromatography (silica gel: 100 g, elution solvent: heptane, ethyl acetate/methanol=10/1) to obtain the title compound (7.35 g, yield: 89.6%) as a reddish solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:11][C:10](=[O:20])[NH:9]2)[C:5]([F:21])=[CH:4][N:3]=1.[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1)#[CH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Cu]I.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>[F:21][C:5]1[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:11][C:10](=[O:20])[NH:9]2)=[CH:7][C:2]([C:23]#[C:22][C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)=[N:3][CH:4]=1
Reactant: O=C1N[C@H](c2cc(Br)ncc2F)[C@@H](c2ccc(F)cc2)O1
Reactant: C#Cc1cncc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1N[C@H](c2cc(C#Cc3cncc(F)c3)ncc2F)[C@@H](c2ccc(F)cc2)O1
Temperature: 90 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To a 15 ml sealable vial was added a 60:40 mixture of (4R,5R)-4-(2-bromo-5-fluoropyridin-4-yl)-5-(4-fluorophenyl)oxazolidin-2-one (50 mg, 0.141 mmol) and its regioisomer in triethylamine (3 mL). To this suspension was added 3-ethynyl-5-fluoropyridine (22.17 mg, 0.183 mmol), triphenylphosphine (11.08 mg, 0.042 mmol) and copper(I) iodide (0.536 mg, 2.82 mmol). The solution was degassed with nitrogen for 20 min, then bis(triphenylphosphine)palladium(II) chloride (1.976 mg, 2.82 mmol) was quickly added and the vial was sealed, heated to 90° C., and allowed to stir overnight. The next day the suspension had turned homogeneous and the reaction was cooled to room temperature and the solvent was evaporated in vacuo. The crude residue was purified by reverse phase chromatography to isolate a single peak (4R,5R)-5-(5-fluoro-2-((5-fluoropyridin-3-yl)ethynyl)pyridin-4-yl)-4-(4-fluorophenyl)oxazolidin-2-one (18.4 mg, 0.046 mmol, 49.8% yield). This single peak was still a mixture of the regioisomers. This single peak was a 65:35 mixture of regioisomers and was subsequently purified by chiral supercritical fluid chromatography Chiralpak AD-H column, 4.6×250 mm, 5 um particle size mobile phase: 35% MeOH in CO2 (w/0.1% diethylamine) column temp: 35 C flow rate: 2 mL/min., affording 1H-NMR (CDCl3, 400 MHz) δ 8.67 (s, 1H), 8.54 (s, 1H), 8.51 (d, J=4.0, 1H), 7.79 (d, J=4.0, 1H), 7.64-7.60 (m, 1H), 7.42-7.39 (m, 2H), 7.19-7.15 (m, 2H), 6.00 (brs, 1H), 5.36 (d, J=4.0, 1H), 5.12 (d, J=4.0, 1H), LC/Mass spec. (Analytical HPLC method 2): RT=1.95 min. Mass=395.99 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:11]([CH2:12][CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[OH:15])[C:10](=[O:23])[N:9]2[C:24]2[CH:33]=[CH:32][C:27]([C:28]([NH:30]O)=[NH:29])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.N.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:11]([CH2:12][CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[OH:15])[C:10](=[O:23])[N:9]2[C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH2:30])=[NH:29])=[CH:32][CH:33]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1ccc(N2C(=O)C(CCC(O)c3ccc(F)cc3)C2c2ccc(F)cc2)cc1
Agent: [Ni]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Product: N=C(N)c1ccc(N2C(=O)C(CCC(O)c3ccc(F)cc3)C2c2ccc(F)cc2)cc1

Procedure:
290 mg of 4-{2-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-1-yl}-N-hydroxybenzamidine (12) were dissolved in 15 ml of tetrahydrofuran and, with 1.5 ml of conc. ammonia, hydrogenated over Raney nickel at 25° C. for 6.5 h. After addition of magnesium sulfate, the reaction solution was filtered. The filtrate was concentrated. This gave the product of molecular weight 435.48 (C25H23F2N3O2); MS (ESI): 436.18 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[N+:19]([O-])=O)[CH:6]=1)[CH3:2].Cl[Sn]Cl>>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[NH2:19])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: CCOC(=O)c1cccc(Oc2ccc(Cl)cc2N)c1
Yield: 72.9 %

Procedure:
The product from Example 169a (1.5 g, 4.7 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (1.0 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Product: Cc1cccc(N)c1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 77 %

Procedure:
Starting from 2-amino-6-methylbenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (180 mg; 77% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1([CH2:15][CH2:16][NH2:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:16][CH2:15][C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=2)=[CH:3][CH:4]=1
Reactant: NCCC1=CCCCC1
Reactant: Cc1ccc(Br)cc1
Product: Cc1ccc(NCCC2=CCCCC2)cc1
Yield: 92 %

Procedure:
Using the general procedure, 4-bromotoluene (172 mg, 1.0 mmol) was coupled with 2-(1-cyclohexenyl)ethylamine (209 μL, 1.5 mmol) at 100° C. for 20 h. Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (20:1) as eluent afforded the desired product as a colorless oil (198 mg, 92% yield). Rf=0.6 (hexane/ethyl acetate=10:1).
Reaction SMILES: [NH2:1][OH:2].CO.[C:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2)=[N:11][CH:12]=1)#[N:6]>O1CCCC1>[NH2:6][C:5](=[N:1][OH:2])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2)=[N:11][CH:12]=1
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc(C#N)cn2)cc1
Reactant: NO
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(C)(C)COc1ccc(-c2ccc(C(N)=NO)cn2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
50% Aqueous hydroxylamine solution (40 g) was added to a methanol (100 mL) and tetrahydrofuran (100 mL) solution containing methyl 3-[4-(5-cyanopyridin-2-yl)-phenoxy]-2,2-dimethylpropanoate (6.0 g), and the mixture was stirred at 80° C. for 4 hours. After cooling the reaction mixture to room temperature, the mixture was concentrated under reduced pressure. To the obtained residue were added ethyl acetate and water, and the liquids were separated. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. Ether was added to the solid residue obtained by concentrating the mixture under reduced pressure to pulverize the same, and the solid was collected by filtration and dried to obtain methyl 3-(4-{5-[amino(hydroxyimino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate (5.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][N:4](C2C=NC=CC=2)[N:3]=1.BrC1C=NC=CC=1.Cl[C:21]1[CH:25]=[CH:24][NH:23][N:22]=1.N1C=CC=N1.[CH3:31][N:32]([CH3:37])[S:33](Cl)(=[O:35])=[O:34].[H-].[Na+]>>[Cl:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH3:31][N:32]([CH3:37])[S:33]([N:23]1[CH:24]=[CH:25][CH:21]=[N:22]1)(=[O:35])=[O:34]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Clc1ccn(-c2cccnc2)n1
Agent: Clc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: Brc1cccnc1
Product: CN(C)S(=O)(=O)n1cccn1

Procedure:
US 20130288893(A1) describes, inter alia, certain (3-halo-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amides and carbamates and their use as pesticides. The route to prepare such compounds involved the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine by the direct coupling of 3-bromopyridine with 3-chloropyrazole. The 3-chloropyrazole was prepared by a) treating 1H-pyrazole with 2 dimethylsulfamoyl chloride and sodium hydride to provide N,N-dimethyl-1H-pyrazole-1-sulfonamide, b) treating the N,N-dimethyl-1H-pyrazole-1-sulfonamide with perchloroethane and n-butyl lithium to provide 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide, and c) removing the N,N-dimethylsulfonamide from 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide with trifluoroacetic acid to give the 3-chloropyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.C(OCC)C.[CH:16]1([Mg]Br)[CH2:18][CH2:17]1.O>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([CH:16]2[CH2:18][CH2:17]2)[OH:7])=[C:4]([F:10])[CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1ccc(Cl)cc1F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc(Cl)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 g (6.31 mmol) of 4-chloro-2-fluorobenzaldehyde were introduced into 20 ml of diethyl ether at 0° C., 19 ml (9.46 mmol) of 0.5N cyclopropylmagnesium bromide solution in THF were added, and the mixture was stirred at RT overnight. The reaction mixture was added to water, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water) to result in 730 mg (58% of theory) of the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][C:34]([Cl:38])=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl.O1CCOCC1>O1CCOCC1>[ClH:38].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][C:34]([Cl:38])=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3cc(Cl)ccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc2cc(Cl)ccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To 0.35 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-chloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 6 mL of 1,4-dioxane and 2 mL of 4.0 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature overnight. The resulting solid was filtered to give 0.11 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-6-chloroquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C(OC(O)C)C>N1C=CC=CC=1>[F:18][C:19]([F:27])([F:28])[C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:24]=[CH:25][CH:26]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CCOC(C)O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(C(F)(F)F)c3)c2cc1OC
Yield: 72 %

Procedure:
A mixture of 1.24 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 1.61 g of 3-trifluoromethylaniline, 0.4 ml of pyridine, and 15 ml of ethoxyethanol was stirred, under nitrogen, at reflux temperature for 5 h. The mixture was cooled and partitioned with dichloromethane and aqueous sodium bicarbonate. The organic layer was washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate-hexanes to give 1.34 g of 4-[(3-trifluoromethylphenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile as a solid, mp 190-193° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][OH:23])[CH3:13]>N1C=CC=CC=1.Cl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([OH:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][OH:23])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCOCCOCCOCCO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
p-Toluenesulfonyl chloride (12.583 g, 66.0 mmol) was added to an ice-cooled solution of triethylene glycol monoethyl ether (10.484 ml, 10.694 g, 60.0 mmol) in pyridine (9.7 ml). After being stirred for 3.5 h the reaction was diluted with 10% hydrochloric acid and extracted with ethyl acetate. The organic phase was separated, washed with 10% hydrochloric acid, dried over MgSO4 and concentrated in vacuo to afford sufficiently pure p-toluenesulfonate of triethylene glycol monoethyl ether (19.92 g, 59.9 mmol, 100%) as a reddish liquid. The obtained tosylate (19.5 g, 58.7 mmol) was dissolved in 33% solution of methylamine in methanol (24 ml) and refluxed for 18 h, cooled and concentrated in vacuo. The residue was dissolved in 5% HCl and washed 3 times with dichloromethane. The combined organic solution was back extracted with 5% HCl. All aqueous extracts were combined and mixed with a solution of sodium hydroxide (6 g) in water (14 ml). The resultant solution was extracted with dichloromethane. The combined organic solution was washed with water, dried over MgSO4 and concentrated in vacuo to afford crude 2-(2-(2-ethoxyethoxy)ethoxy)-N-methylethanamine (6.50 g) as a yellowish liquid, which was then used further without additional purification. The crude 2-(2-(2-ethoxyethoxy)ethoxy)-N-methylethanamine (0.426 g, 1.86 mmol) was added to suspension of compound 1 (1.07 g, 0.928 mmol) in a mixture of triethylamine (1.293 ml, 0.939 g, 9.28 mmol) and DMF (5 ml). The reaction mixture was stirred overnight and diluted with ether. The obtained solid was collected by filtration, washed with ether, and dried in vacuo to afford the desired compound 2c (0.93 g, 0.80 mmol, 86%) as a pale solid. The crude material was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][CH2:14][CH2:15][OH:16])([O-])=O>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH:13][CH2:14][CH2:15][OH:16]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCCO
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc(N)c1NCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
Under hydrogen gas atmosphere, a mixture of 2-[(2,6-dinitrophenyl)amino]ethanol (5.54 g, 24.4 mmol) and 10% palladium on carbon (50% wet, 1.1 g) in tetrahydrofuran (240 mL) was stirred at room temperature for 2 h. The reaction mixture was filtered and concentrated in vacuo to give the title compound as a brown oil (3.63 g, 21.7 mmol, 89%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][N:2]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH:21][CH:22]=[O:23])=[CH:3][N:2]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cncc2ccccc12
Product: O=CC=Cc1cncc2ccccc12

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-isoquinolinecarboxaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]>>[CH3:8][C:6]1[CH:7]=[C:2]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: NCCCCO
Product: Cc1cc(C)cc(NCCCCO)c1
Yield: 90 %

Procedure:
Using the general procedure, 5-bromo-m-xylene (136 μL, 1.0 mmol) was coupled with 4-aminobutanol (138 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (2:1) as eluent afforded the desired product as a colorless oil (174 mg, 90% yield). Rf=0.4 (hexane/ethyl acetate=1:1).
Reaction SMILES: CC(C1CC1)C(Cl)=O.[C:9]([NH:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:30])[CH:25]([CH3:29])[CH:26]2[CH2:28][CH2:27]2)=[C:19]([O:31][C:32](=[O:38])[CH:33]([CH3:37])[CH:34]2[CH2:36][CH2:35]2)[CH:18]=1)=[O:16])([CH3:12])([CH3:11])[CH3:10]>>[CH3:37][CH:33]([CH:34]1[CH2:35][CH2:36]1)[C:32]([O:31][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[O:23][C:24](=[O:30])[CH:25]([CH3:29])[CH:26]1[CH2:27][CH2:28]1)[CH:15]([OH:16])[CH2:14][NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:38]
Reactant: CC(C(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1OC(=O)C(C)C1CC1)C1CC1
Agent: CC(C(=O)Cl)C1CC1
Product: CC(C(=O)Oc1ccc(C(O)CNC(C)(C)C)cc1OC(=O)C(C)C1CC1)C1CC1

Procedure:
Following the procedure described above in Example 15A using alpha-methylcyclopropaneacetyl chloride instead of cyclohexanecarbonyl chloride the acylation product obtained is 3,4-bis(alpha-methylcyclopropaneacetoxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated, using the procedure described above in Example 15B, there is obtained 3,4-bis(alpha-methylcyclopropaneacetoxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
Reaction SMILES: CS([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[C:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26]3)[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)=O.BrC1C=CC(C(=C2CC(C)(C)CC(C)(C)C2)C2C=CC(O)=CC=2)=CC=1.[N:60]1(C2C=CC(B(O)O)=CC=2)[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1.C([O-])([O-])=O.[Na+].[Na+]>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.O.C1COCC1>[N:60]1([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=[C:25]4[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26]4)[C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:7][CH:6]=2)[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC(C)(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccc(N4CCOCC4)cc3)cc2)CC(C)(C)C1
Yield: 59 %

Procedure:
The Suzuki protocol described for (163) was employed. A round bottom flash was charged with 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.200 g, 0.5 mmol), PdCl2(PPh3)2 (0.035 g, 0.05 mmol), [4-(4-morpholinyl)phenyl]boronic acid (0.270 g, 1.0 mmol), aqueous 2 M Na2CO3 (1.0 mL, 0.106 g, 1.0 mmol) solution, and 4:1 THF:H2O mixture (5 mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 3 h. Regular work-up and purification gave 0.142 g (59%) of the title compound (236) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.27 (s, 1H), 7.52 (d, J=5.2 Hz, 2H), 7.50 (d, J=4.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.66 (d, J=8.4 Hz, 2H), 3.72 (t, J=4.4 Hz, 4H), 3.12 (t, J=4.8 Hz, 4H), 1.93 (s, 2H), 1.92 (s, 2H), 1.25 (s, 2H), 0.89 (s, 12H). LCMS (APCI): m/z 482.08 (M+H)+.