Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[C:11]([Cl:17])[CH:10]=2)=[O:5])C.[NH2:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[C:28]([C@@H:20]([NH:19][C:7]1[C:6]([C:4]([OH:3])=[O:5])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([Cl:17])=[C:12]([Cl:16])[CH:13]=2)[N:8]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:30])=[O:29]
Reactant: CCOC(=O)c1cc2cc(Cl)c(Cl)cc2nc1Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc2cc(Cl)c(Cl)cc2nc1N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 130 °C
Reaction time: 22 h
Yield: 38 %

Procedure:
A mixture of 2,6,7-trichloroquinoline-3-carboxylic acid ethyl ester (80 mg, 0.26 mmol), L-phenylalanine (80 mg, 0.52 mmol) and potassium carbonate (180 mg, 1.31 mmol) in DMF (1 mL) is stirred for 22 h at 130° C. in closed reaction vial. After cooling the reaction mixture is diluted with water, acidified by addition of 2N HCl, and the precipitated solid is collected on filter, washed with water and air dried to give the title compound (40 mg, 38%) as yellow powder.
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][C:25]=1[CH3:31].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)=[CH:26][C:25]=1[CH3:31]
Reactant: Cc1cc(Br)ccc1Br
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
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: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)ccc1Br
Temperature: 80 °C
Yield: 67 %

Procedure:
A mixture of 4-diphenylaminophenyl boronic acid (1.25 g, 4.33 mmol), 2,5-dibromotoluene (2.16 g, 8.65 mmol), Pd(PPh3)4 (0.25 g, 0.22 mmol) and K2CO3 (1.38 g, 10 mmol) in dioxane/water (50 mL/9 mL) was degassed and heated at 80° C. for 15 hours. The resulting mixture was mixed with ethyl acetate/brine. The organic phase was dried over Na2SO4, loaded on silica gel, and purified by flash column (hexanes to hexanes/dichloromethane 9:1 to 4:1). The desired fraction was collected and concentrated. After removal of solvent, a white solid (Compound 18) was obtained (1.2 g, in 67% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:9]#[N:10].Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24].C(N(C(C)C)CCC(C1C=CC=CC=1)C#N)(C)C.ClCCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:9]#[N:10]
Reactant: CC(C)N(CCC(C#N)c1ccccc1Cl)C(C)C
Reactant: CN(C)CCCl
Agent: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Agent: CC(C)N(CCCl)C(C)C
Product: CC(C)N(CCC(C#N)(CCN(C)C)c1ccccc1Cl)C(C)C

Procedure:
Substitution of equivalent quantities of α-(o-chlorophenyl)-α-[2-(diisopropylamino)ethyl]acetonitrile and 2-chloro-N,N-dimethylethylamine for α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile and 2-chloro-N,N-diisopropylethylamine called for respectively in the procedure of Example 2, Method B, there is obtained α-(o-chlorophenyl)-α-[2-(diisopropylamino)ethyl]-α-[2-(dimethylamino)ethyl]acetonitrile, as an oil boiling at about 160°-165° C. at 0.5 mm. pressure.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[N:21]1([C:27]2[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([N:24]1[CH2:25][CH2:26][N:21]([C:27]2[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=2)[CH2:22][CH2:23]1)=[O:12])(=[O:3])=[O:4]
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: N#Cc1cnc(N2CCNCC2)s1
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C#N)s2)CC1)C(F)(F)F
Yield: 59 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 59%). MS (m/e): 489.1 (M+H+, 100%), 506.1 (M+NH4+, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)C=O.ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([OH:22])[CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCOc1ccc(Br)cc1C=O
Solvent: ClCCl
Product: COCOc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.2 %

Procedure:
To 660 ml of dichloromethane solution containing 27.9 g (0.11 mol) of 5-bromo-2-methoxymethoxybenzaldehyde obtained in Reference example 5-(a) was added 42.9 g (0.132 mol) of m-chloroperbenzoic acid (purity: 53%), and the mixture was stirred at room temperature for 3 days. After completion of the reaction, the precipitated solid was removed from the reaction suspension by filtration, 97 ml of 2M aqueous sodium thiosulfate solution was added to the filtrate, and the mixture was stirred at room temperature for 2 hours. The organic layer after separation was concentrated under reduced pressure and the obtained solid was dissolved in diethyl ether. The solution was washed successively with 1M aqueous sodium thiosulfate solution, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 20.3 g of the title compound as a colorless oil. (Yield: 79%)
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH:33]=[CH:34][NH:35]2)=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:31]3[CH:39]=[CH:38][CH:37]=[C:36]4[C:32]=3[CH:33]=[CH:34][NH:35]4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cccc5[nH]ccc45)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-formylindole to the procedure of step 1, Example 66. MS (ES) m/z 506.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=1[I:21].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[C:15]=1[I:21])=[CH:7]2
Reactant: Fc1cccc(F)c1I
Reactant: Oc1cnc2c(F)cccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Fc1cccc(Oc2cnc3c(F)cccc3c2)c1I
Temperature: 130 °C
Reaction time: 24 h
Yield: 22.1 %

Procedure:
16 ml of N-methylpyrrolidone was added to 1.06 g of 8-fluoro-3-hydroxyquinoline, 1.94 g of 2,6-difluoroiodobenzene, and 1.7 g of potassium carbonate, and the mixture was stirred for 24 hours at 130° C. The reaction solution was purified by silica gel column chromatography, and 0.55 g of 8-fluoro-3-(3-fluoro-2-iodophenoxy)-quinoline was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].[CH3:10][C:11]1[CH:15]=[CH:14][O:13][C:12]=1[C:16](O)=[O:17].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][C:16]([C:12]2[O:13][CH:14]=[CH:15][C:11]=2[CH3:10])=[O:17])[CH:7]=[CH:8][CH:9]=1)#[CH:2]
Reactant: Cc1ccoc1C(=O)O
Reactant: C#Cc1cccc(N)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#Cc1cccc(NC(=O)c2occc2C)c1
Temperature: 60 °C

Procedure:
To the solution of 3-ethynylaniline (1.2 mL, 11.2 mmol, 1.0 eq) in anhydrous DMF (25 mL) was added 3-methyl-furan-2-carboxylic acid (1.84 g, 1.3 eq), diisopropylethyl amine (7.85 mL, 4.0 eq), and BOP (6.72 g, 1.35 eq). After the reaction solution was heated at 60° C. for two hours, it was cooled to room temperature, diluted with EtOAc, washed sequentially with aqueous NH4Cl, water, brine, and lastly dried with anhydrous sodium sulfate. The clear solution was decanted, concentrated, and the yellow oily residue was subject to column chromatography (EtOAc-Hex from 1:100 to 1:10). The product eluting fractions were concentrated to give the title compound as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3([C:15]([O:17]C)=[O:16])[CH2:14][CH2:13]3)[CH:10]=2)[O:5][CH2:4][CH2:3]1.O[Li].[OH2:21].[CH3:22]O>O>[OH:1][C:2]1([O:21][CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]3)[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: COC(=O)C1(c2ccc3c(c2)C(=O)CCO3)CC1
Reactant: O
Reactant: CO
Agent: [Li]O
Product: COC1(O)CCOc2ccc(C3(C(=O)O)CC3)cc21
Yield: 44 %

Procedure:
To a solution of methyl 1-(4-oxochroman-6-yl)cyclopropanecarboxylate (1.0 g, 4.1 mmol) in MeOH (20 mL) and water (20 mL) was added LiOH.H2O (0.70 g, 16 mmol) in portions at room temperature. The mixture was stirred overnight at room temperature before the MeOH was removed by evaporation under vacuum. Water and Et2O were added to the residue and the aqueous layer was separated, acidified with HCl and extracted with EtOAc (50 mL×3). The combined organic extracts dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(4-hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid (480 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 12.16 (s, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.47 (dd, J=2.0, 8.4 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 3.83-3.80 (m, 2H), 3.39 (s, 3H), 3.28-3.25 (m, 2H), 1.71-1.68 (m, 2H), 1.25-1.22 (m, 2H). MS (ESI) m/z (M+H+) 263.1.
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=2)[NH2:15])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:27][O:28][CH2:29][C:30](Cl)=[O:31].O>C(Cl)Cl>[F:1][CH:2]([F:19])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([NH:15][C:30](=[O:31])[CH2:29][O:28][CH3:27])[CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: COCC(=O)Cl
Reactant: Nc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCC(=O)Nc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A cold (0° C.) solution of 3-{[4-(difluoromethoxy)phenyl]ethynyl}aniline (1 g, 3.86 mmol), triethylamine (0.65 mL, 4.63 mmol) in CH2Cl2 was treated dropwise with methoxyacetyl chloride (0.5 g, 4.63 mmol), allowed to come to room temperature, stirred for 2 hours, poured into water and extracted with EtOAc/ethyl ether 1/1. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue on silica gel (Biotage) using hexanes/EtOAc (1/1) as the eluting solvent gave N-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)-2-methoxyacetamide as a yellow solid (1.25 g, 94% yield), MS m/e (M+H)+ 332; 1H NMR (400 MHz, DMSO-d6) 3.30 (s, 3H), 3.97 (s, 2H), 7.2 (m, 3H), 7.3 (m, 2H), 7.6 (m, 3H), 7.9(t, J=1.7 Hz, 1H), 9.84 (s, 1H).
Reaction SMILES: [C:1]([O:11][C:12]1(C(O)=O)[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH2:13]1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:29])=O.CN(C)[CH:33]=[O:34]>>[C:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:33]([Cl:29])=[O:34])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCC(=O)OC1(C(=O)O)C=CC(c2ccccc2)=CC1
Product: CCCCCCCCC(=O)Oc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
4-n-Nonanoyloxybiphenyl-4-carboxylic acid (5.0 g) was added to thionyl chloride (10 g), and N,N-dimethylformamide in a very small amount was added to the mixture. The resulting mixture was refluxed for 4 hours. The unaltered thionyl chloride was removed by evaporation to give the desired compound (5.2 g).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH2:10][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[CH3:17][OH:18]>>[OH:1][C:2]1[C:9]([CH2:10][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[NH:5])[O:18][CH3:17]
Reactant: N#Cc1cccc(Cc2c[nH]cn2)c1O
Reactant: CO
Agent: Cl
Product: COC(=N)c1cccc(Cc2c[nH]cn2)c1O
Temperature: 5 °C
Reaction time: 20 h

Procedure:
A suspension of 14.1 g (0.071 mole) of 2-hydroxy-3-(1H-imidazol-4-ylmethyl)-benzonitrile (prepared in example 1.1 above) in 400 ml of methanol is cooled to -45° C. and saturated with gaseous hydrochloric acid. The suspension is allowed to return to 10° C. and gaseous hydrochloric acid is bubbled through the suspension for 4 hours more at that temperature. The suspension is cooled to 5° C. and kept at that temperature for 20 hours. The precipitate which has formed is filtered off and 11.4 g of methyl 2-hydroxy-3-(1H-imidazol-4-ylmethyl)-benzenecarboximidate are obtained in the form of a white solid which is used as such in the following step.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[CH2:14]([O:13][C:11](=[O:12])[CH:10]([CH2:1][CH:2]([CH3:7])[CH3:3])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 163.1 %

Procedure:
128 grams of malonic acid dibenzyl ester were dissolved in 500 ml of dimethylformamide and treated carefully in portions with 21.6 g of 50% sodium hydride which has been decanted once with absolute benzene. After stirring at 20° for 1.5 hours, 92 g of isobutyl iodide were added dropwise to the mixture. After stirring at 20° for a further 65 hours, the mixture was evaporated under reduced pressure. The residue was stirred with ether, filtered off from undissolved material and the ethereal solution washed three times with water, dried over magnesium sulfate and evaporated under reduced pressure. After distillation of the residue under a high vacuum, there were obtained 125 g (79% of theory) of isobutyl malonic acid dibenzyl ester as a practically colorless oil of boiling point 175°/0.4 Torr.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1(C)C=CC=CC=1.[N+:18]([C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][NH:27]2)=[CH:23][CH:22]=1)([O-:20])=[O:19].IC>O1CCCC1.CO>[CH3:11][N:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([N+:18]([O-:20])=[O:19])[CH:29]=2)[CH2:25][CH2:26]1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CO
Product: CN1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium bis(trimethylsilyl)amide (67 ml of a 0.5M toluene solution) was added slowly to a stirred solution of 6-nitroindoline (5.0 g) in anhydrous tetrahydrofuran (200 ml) at -78° C. under a nitrogen atmosphere. Iodomethane (2.09 ml) was added then the reaction mixture was allowed to warm to room temperature then stirred overnight. Methanol (5 ml) was added then the solution was evaporated to dryness. The residue was dissolved in diethyl ether (300 ml), washed with water, saturated brine then dried (magnesium sulphate) and evaporated to dryness. The crude product was purified by column chromatography on silica using 10% ethyl acetate/petroleum ether (60-80)→30% ethyl acetate/petroleum ether (60-80) and the product crystallised from diethyl ether/petroleum ether (60-80) to afford 0.9 g.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[F:10]F.[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15]>>[F:1][C:2]1([F:10])[CH:7]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])[NH:6][C:5](=[O:8])[NH:4][C:3]1=[O:9]
Reactant: FF
Reactant: OCC(F)(F)F
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Product: O=C1NC(=O)C(F)(F)C(OCC(F)(F)F)N1
Yield: 79.5 %

Procedure:
5-fluorouracil (1.00 g, 0.0077 moles) was suspended in anhydrous 2,2,2-trifluoroethanol (20 ml) and treated with an equal volume mixture of gaseous fluorine and nitrogen at 68°-70° C. for 103 minutes at which time gaseous fluorine was detected leaving the reaction vessel, representing a consumption of 0.0182 moles of fluorine. The mole ratio of fluorine to 5-fluorouracil was 2.36. The solvent was removed under reduced pressure at room temperature (25° C.) to give a white solid which was dried at 50° C. at reduced pressure. The product was identified as 5,5-difluoro-5,6-dihydro-6-(2,2,2-trifluoroethoxy) uracil (1.67 g) representing a yield of 79.5% with a melting point of 142°-146° C.; NMR confirmed the structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[NH2:11][C:12]1[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=1.[S:18]1(=O)(=O)[CH2:24][CH2:23][CH2:22][CH2:21][C:20](=O)[CH2:19]1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:19]3[S:18][CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[NH:11][C:12]3[CH2:16][CH2:15][C:14](=[O:17])[C:13]2=3)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=C1CCCCS(=O)(=O)C1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: NC1=CC(=O)CC1
Solvent: CCO
Product: O=C1CCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCCCS1)N2
Yield: 56.5 %

Procedure:
A solution of 3-bromo-4-fluorobenzaldehyde (639 mg, 3.14 mmol), 3-amino-2-cyclopenten-1-one (305 mg, 3.14 mmol) and thiacycloheptan-3-one 1,1-dioxide (510 mg, 3.14 mmol) in ethyl alcohol (10 mL) was heated to 80° C. in a sealed tube for 3 days, cooled, the solid precipitate collected, washed with ethyl alcohol and dried to provide 700 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:22]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[Cl:31])=[C:21]([F:32])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[C:7]=2[CH:6]=1)=[O:4].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[OH:39][C:33]([C:35]([F:38])([F:37])[F:36])=[O:34].[CH3:1][O:2][C:3]([C:5]1[C:22]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[Cl:31])=[C:21]([F:32])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(ncn2CCC(=O)OC(C)(C)C)c(F)c1Nc1ccc(Br)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc2c(ncn2CCC(=O)O)c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 0.75 h
Yield: 88 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-3-(2-tert-butoxycarbonyl-ethyl)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester (0.050 g, 0.095 mmol) is dissolved in methylene chloride (0.5 mL) and TFA (0.5 mL) is added. After 45 minutes, the reaction mixture is concentrated to dryness to give 0.49 g (88%) desired product: LC/MS ESI (+) m/z 472, 470 (M+ Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.64 (d, 1H), 7.29 (dd, 1H), 6.45 (dd, 1H), 4.55 (t, 2H), 2.89 (t, 2H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([CH3:26])[CH:16]=2)=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1.[O:32]=[S:33]1(=[O:38])[CH2:37][CH2:36][CH2:35][NH:34]1>>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([CH3:26])[CH:16]=2)=[N:7][C:8]([N:34]2[CH2:35][CH2:36][CH2:37][S:33]2(=[O:38])=[O:32])=[N:9][CH:10]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccccc2c1=O
Product: Cn1cc(-c2nc(N3CCCS3(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccccc2c1=O

Procedure:
The title compound of Example 151 was treated with 1,1-dioxidoisothiazolidine instead of MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.65 (t, J=7.2 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.31-7.26 (m, 1H), 7.13-7.07 (m, 1H), 6.89-6.87 (m, 1H), 3.97 (t, J=6.4 Hz, 2H), 3.57 (t, J=7.2 Hz, 2H), 3.54 (s, 3H), 2.40-2.33 (m, 2H). LCMS: 485.2 (M+H)+
Reaction SMILES: O[C:2]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(O[CH2:12][CH:13]=[C:14]([C:17]#[N:18])[C:15]#[N:16])C.C([OH:21])C>>[OH:21][CH:3]1[CH2:4][CH2:5][CH2:6][CH:2]1[N:7]1[C:17]([NH2:18])=[C:14]([C:15]#[N:16])[C:13]([CH3:12])=[N:8]1
Reactant: NNC1(O)CCCC1
Reactant: CCOCC=C(C#N)C#N
Reactant: CCO
Product: Cc1nn(C2CCCC2O)c(N)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a stirred solution of 2-(hydroxycyclopentyl)hydrazine (11.6 g, 0.1 mol) in ethanol (75 ml) was added ethoxyethylidene malononitrile (13.6 g, 0.1 mol). The reaction mixture was heated to reflux for 32 hours, cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in boiling isopropanol (100 ml), treated with charcoal and the filtrate was concentrated to approximately 40 ml. The solution was diluted with ether (20 ml), allowed to stand for 1 hour at room temperature and the resulting precipitate was collected by filtration to afford 8.7 g (42%) of 1-(2-hydroxycyclopentyl)-3-methyl-5-amino-1H-pyrazole-4-carbonitrile as light orange crystals, m.p. 157°-159° C. when dried at 75° C. in high vacuum.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:9]([O:14]C)([O:12][CH3:13])(=[O:11])=[O:10]>>[CH3:13][O:12][S:9]([O-:14])(=[O:11])=[O:10].[C:1]1([S+:7]([CH3:13])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: COS(=O)(=O)OC
Product: COS(=O)(=O)[O-]
Product: C[S+](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
24.8 g (0.2 mole) of thioanisole was heated to 90° C. with stirring and 27.8 g (0.22 mole) of dimethyl sulfate was added dropwise thereto over a period of 30 minutes keeping the temperature between 90 ° and 95° C. After the stirring was continued for an additional 30 minutes at the same temperature, the reaction mixture was cooled to room temperature to give phenyldimethylsulfonium methylsulfate quantitatively as solid mass.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[C:7]([OH:13])[CH:6]=[CH:5]2.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:13]
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc2cc(Br)ccc2c1Cl
Product: Oc1ccc2cc(-c3ccccc3)ccc2c1Cl

Procedure:
The title compound was prepared by reacting 6-bromo-1-chloro-naphthalen-2-ol (300 mg, 1.17 mmol) with phenylboronic acid (170.7 mg, 1.40 mmol) according to method A to yield 240 mg (81%) of white solid: mp 135-137° C.; 1H NMR (DMDO-d6): δ 7.33 (1H, d, J=8.85 Hz), 7.39 (1H, td, J=7.25 Hz, J=0.75 Hz), 7.51 (2H, t, J=7.59 Hz), 7.80 (2H, d, J=7.63 Hz), 7.88 (1H, d, J=8.96 Hz), 7.93 (1H, dd, J=8.85 Hz, J=1.19 Hz), 8.10(1H, d, J=8.84 Hz), 8.20 (1H, s), 10.53 (1H, s); MS (ESI) m/z253/255 (M−H)−.