Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10]1([CH3:21])[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([CH:19]=O)[C:12]=2[O:11]1>C(O)(=O)C>[CH3:9][C:10]1([CH3:21])[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([CH2:19][NH:1][C:2]3[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=3)[C:12]=2[O:11]1
Reactant: CC1(C)Cc2cccc(C=O)c2O1
Reactant: Nc1cccnc1Cl
Solvent: CC(=O)O
Product: CC1(C)Cc2cccc(CNc3cccnc3Cl)c2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.6 %

Procedure:
5 g of 3-amino-2-chloropyridine was dissolved in 80 ml of acetic acid, and 7.1 g of 2,2-dimethyl-7-formyl-2,3-dihydrobenzofuran was added. Then, the mixture was stirred at room temperature for about 30 minutes, and 16.5 g of triacetoxy sodium borohydride was added gradually under ice-cooling. After stirring the obtained reaction mixture at room temperature for about four hours, the solvent was concentrated. After adding ice-water to the residue and alkalizing it with an aqueous sodium hydroxide solution, it was extracted twice with ethyl acetate. After washing the organic layer with water and drying, it was concentrated and purified with a short column (dichloromethane/methanol=10:1) using silica gel to obtain 12.2 g of oily 3-[(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methyl]amino-2-chloropyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])=[C:18]([O:28][CH3:29])[CH:17]=3)=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:31][CH2:32]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:13](=[O:14])[N:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([OH:27])([CH3:25])[CH3:26])=[C:18]([O:28][CH3:29])[CH:17]=4)[CH2:32][CH2:31][N:11]3[CH:12]=2)=[CH:6][CH:7]=1
Reactant: BrCCBr
Reactant: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCC(C)(C)O
Product: COc1cc(N2CCn3cc(-c4ccc(Cl)cc4)cc3C2=O)ccc1OCC(C)(C)O

Procedure:
Following the procedure described in Example 1 step D, the product of step B (11 mg) was alkylated with 1,2-dibromoethane to yield 1.8 mg of the title compound. MS (ESI) 441 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:3].C[Si](C)(C)[N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20]>C1(C)C=CC=CC=1>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])=[O:3])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: COc1ccc(OC(=O)Cl)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(OC(=O)N2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a solution of 4-methoxyphenyl chloroformate (3.73 g, 20.2 mmol) in anhydrous toluene (10 ml) was added a solution of 1-trimethylsilyl-2-pyrrolidinone (3.46 g, 22.0 mmol) in anhydrous toluene (10 ml). The mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated under reduced pressure to dryness to give a solid material. Recrystallization from ethanol afforded 3.45 g of colorless prisms. Yield 73.4%
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[F:30][C:31]([F:36])([F:35])[CH:32]1[O:34][CH2:33]1>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[C:9]([N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:16]=3)[CH2:33][CH:32]([OH:34])[C:31]([F:36])([F:35])[F:30])[CH:10]=[CH:11][CH:12]=2)=[CH:28][CH:29]=1
Reactant: FC(F)(F)C1CO1
Reactant: Fc1ccc(Oc2cccc(NCc3cccc(OC(F)(F)C(F)F)c3)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Oc2ccc(F)cc2)c1)C(F)(F)F
Temperature: 40 °C
Yield: 80.9 %

Procedure:
The N-[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine (612 mg, 1.5 mmol) product from EX-634C and 1,1,1-trifluoro-2,3-epoxypropane (268 mg, 2.4 mmol) were dissolved in 1.0 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (43 mg, 0.07 mmol) was added, and the stirred solution was warmed to 40° C. for 2.5 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine and water, then dried over anhydrous MgSO4. The ether was removed in vacuo, and the crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:11) to give 633 mg (81%) of the desired 3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, 99% pure by HPLC analysis. 1H NMR(CDCl3) δ7.35 (t, 1H), 7.15 (m, 3H), 6.98 (m, 5H), 6.49 (dd, 1H), 6.38 (dd, 1H), 6.33 (m, 1H), 5.92 (tt, 1H), 4.67 (ABq, 2H), 4.37 (m, 1H), 3.91 (dd, 1H), 3.59 (dd, 1H), 2.48 (d, 1H). 19F NMR (CDCl3) δ−79.2 (d, 3F), −88.5 (m, 2F), −120.33 (m, 1F), −[137.2 (dt, 2F). HRMS calcd: for C24H19F8NO3: 522.1315 [M+H]+, found: 522.1297.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15](C=O)=[C:11]2[O:12][C:13]=1[CH3:14].C1C=C(Cl)C=C(C(OO)=[O:29])C=1.C([O-])([O-])=O.[K+].[K+].CO>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([OH:29])=[C:11]2[O:12][C:13]=1[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1O
Temperature: 0 °C

Procedure:
3-(2,4-Dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole-7-carbaldehyde (750 mg, 2.426 mmol) and m-CPBA (897 mg, 3.64 mmol) are stirred in DCM (10.5 ml) at RT for 3 hours, whereupon the reaction mixture is diluted with DCM (120 ml). The organic phase is washed with sat. NaHCO3 (70 ml) and the phases separated via a phase separator. Back extraction of the aqueous phase with DCM (50 ml) is carried out and the combined organic phases are concentrated in vacuo. The resultant yellow gum is dissolved in MeOH (16.80 ml) and K2CO3 (1676 mg, 12.13 mmol) is added. The reaction is stirred at RT for 30 mins before the MeOH is removed in vacuo. The resulting solid is diluted with water (˜100 ml) and the product is extracted into EtOAc (2×100 ml). The combined organic extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is isolated as a light orange solid which is dissolved DCM (15 ml), cooled to 0° C. and the resultant solid collected by filtration to afford the title compound as a pale yellow solid. MS: m/z 297.15 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(CSc1ccc(Cl)cc1)OC
Reaction time: 24 h
Yield: 98 %

Procedure:
To a solution of 4-chlorobenzenethiol (5.78 g; 40 mmol) in anhydrous acetone (50 mL) was added potassium carbonate (5.52 g, 40 mmol) and dropwise at room temperature 2-bromo-1,1-dimethoxy-ethane (4.7 mL, 40 mmol). After 24 h of stirring, the precipitate was filtered, the filtrate concentrated, the residue diluted with water and diethyl ether (150 mL), the organic layer washed successively with water (60 mL), NaOH 4N (30 mL) and water (60 mL), dried over Na2SO4 and concentrated to give 1-chloro-4-(2,2-dimethoxy-ethylsulfanyl)-benzene (compound PRE9) (9.12 g; orange oil) (Yield=98%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[C:4]([N:6]([CH:15]([CH3:19])[C:16](O)=[O:17])[C:7]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[CH:9][CH:8]=1)=[O:5].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[C:4]([N:6]([CH:15]([CH3:19])[C:16]([N:33]([CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:30]1[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=1)=[O:17])[C:7]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[CH:13][CH:14]=1)=[O:5]
Reactant: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)C(C)C(=O)O)cc1
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Product: COC(=O)CCCN(C(=O)C(C)N(C(=O)c1ccc(Cl)cc1Cl)c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(2,4-dichlorobenzoyl)-2-(p-anisidino)propionic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(2,4-dichlorobenzoyl)-2-(p-anisidino)propionyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-(2,4-dichlorobenzoyl)-2-(p-anisidino)propionyl]-4-(p-anisidino)butyric acid (M.P. 159° to 160°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Cl[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Reactant: ClCc1cccc2ccccc12
Solvent: CN(C)C=O
Product: O=C(NCC1CN(Cc2cccc3ccccc23)CCO1)Nc1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of Intermediate 9 (0.01 g) in N,N-dimethylformamide (1 ml) was added 1-(chloromethyl)naphthalene (6.1 μl). The mixture was stirred at 22° C. for 24 h before tris-(2-aminoethyl)amine polystyrene (Argonaut Technologies, 0.01 g @ 4.46 mmol/g) and polystyrene methyl isocyanate (Argonaut Technologies, 0.033 g @ 1.39 mmol/g) was added. Stirring was continued for a further 2 h before the mixture was purified by solid phase extraction (Isolute SCX sulphonic acid column), eluting with methanol followed by 10% 0.880 ammonia solution in methanol. The basic fraction was evaporated in vacuo to give the title compound (0.003 g). LC/MS (System A) Rt 2.82 min, Mass Spectrum m/z 4140 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].O[CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:24][CH2:25][NH:26][C:27]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:33]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CCOC(=O)C(Cc1ccc(O)c(Br)c1)Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)c(Br)c1)Oc1ccccc1
Yield: 89.5 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using ethyl 3-(3-bromo-4-hydroxyphenyl)-2-phenoxypropionate (374 mg), which is the product of Reference example 52(a), t-butyl 2-hydroxyethylcarbamate (403 mg), triphenylphosphine (672 mg) and a solution of diethylazodicarboxylate in toluene (40%, 1.16 ml) and the reaction mixture was treated to afford the desired compound (466 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1([Cl:8])[CH2:7][O:6][CH2:5][CH2:4][O:3]1.[N+:9]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[Cl:8][CH2:2][CH2:7][O:6][CH2:5][C:4]([NH:16][C:15]1[CH:17]=[CH:18][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=1)=[O:3]
Reactant: ClC1(Cl)COCCO1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Product: O=C(COCCCl)Nc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1.53 g of a mixture of 2-chlorodioxene and 2,2-dichlorodioxane (molar ratio 1:1) are added to 1.00 g (7.24 mmol) of 4-nitroaniline, and the mixture is heated to 80° C. with stirring. A solid brown mass forms within one hour and becomes liquid again and crystallises within the following 12 hours. The crude product is recrystallised from ethanol with addition of water, giving 1.80 g of 2-(2-chloroethoxy)-N-(4-nitrophenyl)acetamide (“A1”) as yellowish crystals, m.p. 101-102° C. 1H-NMR (d6-DMSO): δ=3.82 (m; 4H), 4.23 (s; 2H), 7.91 (d, J=9 Hz, 2H), 8.23 (d, J=9 Hz, 2H), 10.34 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][C:16]2[C:24]3[C:23]([C:25]([O:27]C)=[O:26])=[CH:22][CH:21]=[N:20][C:19]=3[N:18](C(OC(C)(C)C)=O)[CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][C:16]2[C:24]3[C:23]([C:25]([OH:27])=[O:26])=[CH:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccnc2c1c(CNCC1CCN(C(=O)OC(C)(C)C)C1)cn2C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(CNCc2c[nH]c3nccc(C(=O)O)c23)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-tert-butyl 4-methyl 3-(((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (70 mg, 0.143 mmol) in dioxane (2 mL) was added 1N LiOH (0.358 mL, 0.358 mmol) at 0° C. and stirred for 4 h at rt. The reaction mixture was extracted with ether and the aqueous layer was neutralized with 1N HCl, and concentrated in vacuo to afford 3-(((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid as an off-white solid. [M+H] found 375.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[N:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13]Br)[O:5][CH3:6].C[N+]1([O-])CC[O:20]CC1>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[N:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[O:20])[O:5][CH3:6]
Reactant: C[N+]1([O-])CCOCC1
Reactant: COC(=O)N(OC)c1ccccc1CBr
Solvent: CC#N
Product: COC(=O)N(OC)c1ccccc1C=O
Reaction time: 16 h

Procedure:
A solution of 27.4 g of (2-bromomethyl-phenyl)-N-methoxycarbamic acid methyl ester in 50 ml of acetonitrile is added dropwise at room temperature to 40 g of N-methyl-morpholine-N-oxide in 150 ml of acetonitrile. After stirring for 16 hours, the mixture is concentrated and the residue partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate and, after drying over sodium sulphate, the solvent is distilled from the combined organic phases. The residue is purified on silica gel using ethyl acetate/hexane (1:5% by volume). The title compound is obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][CH:56]([OH:59])[CH2:55][CH2:54]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:59][CH:56]1[CH2:57][CH2:58][N:53]([CH2:52][CH2:51][NH:50][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:54][CH2:55]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: NCCN1CCC(O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.19 mmol), DIPEA (115 mg, 5 eq.) and 1-(2-amino-ethyl)-piperidin-4-ol TFA salt (88 mg, 1.2 eq.) in 2 mL) was stirred at rt for 45 mins. To the mixture was added HATU (83 mg, 1.1 eq.). After stirring for 18 hours, the reaction was concentrated and purified on a silica gel column to give the titled compound as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.CS(C)=O.[OH-].[K+].[CH2:24](OS(OCC)(=O)=O)[CH3:25]>C1(C)C=CC=CC=1>[CH2:24]([N:9]([CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH3:25]
Reactant: COc1ccc(NCCc2ccccn2)cc1
Reactant: CCOS(=O)(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCN(CCc1ccccn1)c1ccc(OC)cc1
Temperature: 40 °C
Yield: 48.8 %

Procedure:
With stirring 10.6 g (0.044 mole) of N-[2-(2-pyridyl)ethyl]-4-methoxy-aniline, prepared in a manner similar to that described in Example 1, part A, was added to 25.0 ml of dimethylsulfoxide. After the solution was complete, 4.9 g of ground potassium hydroxide was added slowly to the solution maintaining a temperature under 40° C. After approximately one hour 13.6 g (0.088 mole) of diethylsulfate was added dropwise to the reaction mixture while maintaining a temperature in the range of 25°-40° C., and the resultant mixture was stirred for approximately eighteen hours at ambient temperature. To the reaction mixture there was added 50.0 ml of toluene with stirring. The insoluble potassium sulfate was collected by filtration and discarded. The toluene solution was washed several times with saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate. The toluene was removed under reduced pressure to obtain 5.5 g of N-ethyl-N-[2-(2-pyridyl)ethyl]-4-methoxyaniline (Formula VI: R1 =C2H5 ; R2 =R9 =H; R11 =CH3O) a brown-colored oil. A significant infrared maximum appeared at 1592 cm-1 (C=C;s). The nuclear magnetic resonance spectrum was consistent with the assigned structure.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][OH:20])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1>>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][O:20][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:17])[F:15])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(N(CCO)CC2CC2)cc1C(F)(F)F
Reactant: Oc1ccc(F)cc1
Product: N#Cc1ccc(N(CCOc2ccc(F)cc2)CC2CC2)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(cyclopropylmethyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-fluorophenol: MS (APCI) m/z 379 (M+1).
Reaction SMILES: [C-]#N.[Na+].C1(C)C=CC=CC=1.C[NH:12][CH2:13][CH2:14]NC.BrC1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=1>N>[CH3:25][C:20]1[CH:19]=[C:14]([CH:23]=[C:22]([CH3:24])[CH:21]=1)[C:13]#[N:12]
Reactant: CNCCNC
Reactant: Cc1cc(C)cc(Br)c1
Agent: N
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(C#N)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
An oven dried 100 mL three necked round bottom flask was charged, under positive pressure of argon, with NaCN (2.04 g, 41.6 mmol) CuI (660 mg, 3.47 mmol, 10 mol %), KI (1.14 g, 6.87 mmol, 20 mol %), and anhydrous toluene (25 mL). N,N′-Dimethylethylenediamine (3.7 mL, 35 mmol) and 5-bromo-m-xylene (4.7 mL, 35 mmol) were added dropwise under mechanical stiring. The reaction mixture was stirred at 110° C. for 24 h. The resulting suspension was allowed to reach room temperature, diluted with 30% aq ammonia (20 mL) and extracted with toluene (2×10 mL). The combined organic phases were dried over MgSO4, concentrated, and the residue was purified by distillation under reduced pressure (bp 100° C. @10 Torr) to provide the desired product as a white crystalline solid (4.08 g, 90% yield). Mp 42-43° C. (lit. 42.9° C., See Birch, S. F.; Dean, R. A.; Fidler, F. A.; Lowry, R. A. J. Am. Chem. Soc. 1949, 71, 1362). 1H NMR (400 MHz, CDCl3; lit. See Nomura, Y.; Takeuchi, Y. Tetrahedron 1969, 25, 3825): δ 7.27 (s, 2H), 7.23 (s, 1H), 2.36 (s, 6H); 13C NMR (100 MHz, CDCl3): 139.4, 135.0, 130.1, 119.7, 112.4, 21.5; IR (neat, cm−1): 2230, 1605, 1378, 907, 854, 682. Anal. Calcd. for C9H9N: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.11; H, 6.88, N, 10.52.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[I:34]I>C(OCC)C.C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][C:13]=1[I:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(-c2ccccc2)cc1I
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
A solution of (6-phenylpyridin-3-yl)carbamic acid tert-butyl ester (5.54 g, 20.5 mmol) and TMEDA (6.49 mL, 43.0 mmol) in 100 mL of anhydrous diethyl ether was treated with n-BuLi at −78° C. After 15 minutes at −78° C., the mixture was warmed to −10° C. and stirred for an additional 3 hours. The reaction mixture was then cooled to −78° C. and a solution of iodine in a mixture of 10 mL of THF and 100 mL of diethyl ether was added dropwise. After 2 hours at −78° C., the mixture was allowed to warm to 0° C. and was quenched with 400 mL of saturated aqueous ammonium chloride solution. The organic layer was washed with five 100 mL portions of saturated aqueous sodium thiosulfate. The combined aqueous layers extracted with three 200 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO2 (0% to 70% ethyl acetate in hexanes, gradient) afforded 900 mg of the title product as yellow oil that solidified over time (11% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[CH:12]=[C:13](/[C:16](=O)[CH3:17])\[C:14]#[N:15])[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[CH3:19][C:20]1[CH:24]=[C:23]([NH2:25])[O:22][N:21]=1>>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]3[C:13]([C:14]#[N:15])=[C:16]([CH3:17])[NH:25][C:23]4[O:22][N:21]=[C:20]([CH3:19])[C:24]3=4)[CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: Cc1cc(N)on1
Reactant: CCc1n[nH]c2ccc(/C=C(\C#N)C(C)=O)cc12
Product: CCc1n[nH]c2ccc(C3C(C#N)=C(C)Nc4onc(C)c43)cc12

Procedure:
100 mg (0.42 mmol) (2E)-2-[(3-ethyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 18A) were treated with 3-methyl-1,2-oxazol-5-amine following the procedure described in Example 2. The crude material was purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient) to yield 51 mg (38% of th.) of the racemic title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1B(O)O>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:32]4[CH:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:31]=4[CH3:30])[CH:29]=[CH:28][CH:27]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(C)c(B(O)O)c1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Product: Cc1ccc(C)c(-c2cccc(C(=O)Nc3ccc(OCCN4CCOCC4)c4ccccc34)c2)c1

Procedure:
Compound is prepared from 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide and 2,5-dimethylphenyl boronic acid according to conditions described in general procedure K. 1H NMR 300 MHz (CDCl3) δ 8.3(d, 1H), 7.4-8.05(m, 9H), 7.2(d, 1H), 7.1(d, 2H), 6.8(d, 1H), 4.3(t, 2H), 3.75(m, 4H), 3.0(t, 2H), 2.7(m, 4H), 2.4(s, 3H), 2.3(s, 3H).