Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH3:13][C:14]([OH:20])([CH3:19])[C:15]#[C:16][CH2:17]O>>[OH:20][C:14]([CH3:19])([CH3:13])[C:15]#[C:16][CH2:17][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: CC(C)(O)C#CCO
Reactant: COC(=O)c1ncc(O)cc1C
Product: COC(=O)c1ncc(OCC#CC(C)(C)O)cc1C

Procedure:
The title compound was synthesized analogously according to Method S starting from methyl 5-hydroxy-3-methylpicolinate and 4-methylpent-2-yne-1,4-diol. MS m/z=264 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[CH3:19]I>>[CH3:1][N:2]([CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([N:5]([CH3:19])[C:6]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[O:8][N:7]=1)=[O:4]
Reactant: CI
Reactant: CCCCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Product: CCCCN(C)C(=O)N(C)c1cc(C(C)(C)C)on1

Procedure:
The reaction is effected as in Example 171 by using 1-methyl-1-butyl-3-(5-t-butyl-3-isoxazolyl)urea and methyl iodide to give 1,3-dimethyl-1-butyl-3-(5-t-butyl-3-isoxazolyl)urea as an oil boiling at 130° to 135° C (bath temperature)/0.25 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=[O:30])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(NCC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-isobutylamino-phenyl)-carbamic acid tert-butyl ester (Example J34) (314 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white foam (340 mg, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH2:23][CH3:24])=[CH:17][CH:16]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[CH2:23]([O:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:16][CH:17]=1)[CH3:24]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCOCc1ccc(Br)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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOCc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Temperature: 80 °C
Yield: 73.6 %

Procedure:
To a mixture of 4-methoxycarbonylphenylboronic acid (2.01 g) and 1-bromo-4-ethoxymethylbenzene (2.00 g) in a mixed solvent of ethylene glycol dimethyl ether (20 ml) and 2M aqueous sodium carbonate solution (6 ml) was added tetrakis(triphenylphosphine)palladium (0) (0.54 g). The mixture was heated at 80° C. for 5 hours. After cooling to room temperature, water (150 ml) was added to the reaction mixture and the resulting precipitate was collected by filtration, washed thoroughly with water and dried to give a crude solid. This solid was purified by column chromatography on silica gel (60 g) eluting successively with the following solvents: (1) n-hexane:ethyl acetate=50:1, (2) n-hexane:ethyl acetate=10:1. The fractions containing the object compound were concentrated and dried to give methyl 4-(4′-ethoxymethylphenyl)benzoate as a white solid (1.85 g).
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(OC(=O)C)(=O)C.[NH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)(=O)C>[C:1]([N:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: C1CCCNCC1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCCCCCCCCCC(=O)N1CCCCCC1
Yield: 83.4 %

Procedure:
A mixture of dodecanoic acid (20.03 g, 0.1M), acetic anhydride (13.27 g, 0.13M), hexahydro-1H-azepine (12.9 g, 0.13M) was heated with distillation of formed acetic acid. The residue on distillation gave 23.46 g (83.5%) of colorless product, b.p. 204-205/7 mm.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[CH2:5][CH2:6][OH:7].I[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1>O1CCCC1.[Cu]I>[F:3][C:4]([F:9])([F:8])[CH2:5][CH2:6][O:7][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCCC(F)(F)F
Reactant: Ic1cccs1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)CCOc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a suspension of hexanes-washed sodium hydride (918 mg, 22.95 mmol) in 10 mL anhydrous tetrahydrofuran at 0° C. was added 3,3,3-trifluoropropanol (3.5 g, 30.60 mmol) dropwise. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. 2-Iodothiophene (3.21 g, 15.30 mmol) and copper(I) iodide (728 mg, 3.82 mmol) were added, the reaction vessel was flushed with argon, sealed and stirred at 100° C. for 48 h. The reaction mixture was allowed to cool to room temperature and poured into 150 mL of 5% aqueous potassium cyanide solution. Organics were extracted with 1:1 ether/hexanes (3×100 mL), dried with magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel (100% hexanes) to give 2-(3,3,3-trifluoropropoxyl)thiophene (1.70 g, 57%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)[C:5]([CH3:18])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH:24]=[C:23]([NH2:25])[CH:22]=[N:21]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:18][C:5]1[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)=[N:7][C:2]([NH:25][C:23]2[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: Cc1cnc(Cl)nc1NC1COC2C(O)COC12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1COC2C(O)COC12
Temperature: 150 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a suspension of 6-((2-chloro-5-methylpyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-ol (54 mg, 0.20 mmol) in n-BuOH (1 mL) was added 1-methyl-1H-pyrazol-4-amine (32 mg, 0.24 mmol) and DIPEA (78 mg, 0.60 mmol). Then the mixture was stirred under nitrogen atmosphere at 150° C. overnight and concentrated in vacuo. To the residue was added water (20 mL), and extracted with DCM (20 mL×3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude oil. Then it was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to give the title compound as an off-white solid (46 mg, 70%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][N:5]([CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:7]=1.I[C:24]1C=CC(N2CC[C@H](N(C)C)C2)=CC=1>>[CH3:1][N:2]([CH3:22])[C@H:3]1[CH2:24][CH2:21][N:5]([C:6]2[CH:7]=[CH:8][C:9]([B:12]3[O:16][C:15]([CH3:17])([CH3:18])[C:14]([CH3:20])([CH3:19])[O:13]3)=[CH:10][CH:11]=2)[CH2:4]1
Reactant: CN(C)[C@H]1CCN(c2ccc(I)cc2)C1
Reactant: CN(C)CCN(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CN(C)[C@H]1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1

Procedure:
The title compound was synthesized according to the synthesis of N,N,N′-trimethyl-N′-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1,2-diamine, except substituting (S)-1-(4-iodophenyl)-N,N-dimethylpyrrolidin-3-amine (500 mg, 1.58 mmol). The title compound was purified by silica gel chromatography (MeOH/CH2Cl2, 5:95 to 15:85) followed by passing a solution of the desired product (20 mL MeOH) through a PoraPak Rxn CX ionic exchange column as a yellow solid (125 mg, 25%). 1H NMR and LCMS were identical to the enantiomer, (R)—N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-amine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:9]2=[C:10](Cl)[N:11]=1)=[O:5])[CH3:2].[CH3:30][Sn](C)(C)C>CN(C=O)C.CCOC(C)=O.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>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:9]2=[C:10]([CH3:30])[N:11]=1)=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Cl)c2c(c(-c3ccccc3)cn2-c2ccc(F)cc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C)c2c(c(-c3ccccc3)cn2-c2ccc(F)cc2)c1O
Temperature: 135 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A mixture of 7-chloro-1-(4-fluoro-phenyl)-4-hydroxy-3-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (60 mg, 0.146 mmol), tetramethyltin (104 mg, 0.584 mmol) and Pd(PPh3)2Cl2 in DMF (1 mL) was stirred at 135° C. for 2 h; then the reaction was cooled, diluted with EtOAc, washed with water and saturated sodium chloride aqueous solution respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, the residue was purified on column to give the desired title product (30 mg); ESI MS (m/z): 391 (M+H+).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([NH:12]C(=O)C(F)(F)F)=[CH:6][C:5]=1[O:19][CH3:20])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:12][C:7]1[CH:6]=[C:5]([O:19][CH3:20])[C:4]([C:1](=[O:3])[CH3:2])=[C:9]([O:10][CH3:11])[CH:8]=1
Reactant: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(N)cc(OC)c1C(C)=O
Yield: 86.5 %

Procedure:
To N-(4-Acetyl-3,5-dimethoxy-phenyl)-2,2,2-trifluoro-acetamide (4.3 g, 14.8 mmol) dissolved in methanol (90 mL) was added anhydrous potassium carbonate (4.67 g, 33.8 mmol). After refluxing for 18 hours, the reaction mixture was cooled and concentrated under reduced pressure. The concentrate was extracted with ethyl acetate and the organic layer was washed with brine, dried using anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 1-(4-Amino-2,6-dimethoxy-phenyl)-ethanone (2.5 g, 87%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][CH2:19]O)=[C:7]([Si:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][CH3:13])[NH:8]2)=[CH:4][C:3]=1[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:41]C(Br)(Br)Br>C1COCC1>[Br:41][CH2:19][CH2:18][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[C:3]([CH3:21])[CH:4]=2)[NH:8][C:7]=1[Si:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][CH3:13]
Reactant: BrC(Br)(Br)Br
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCBr
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
A solution 2-(6-chloro-5-methyl-2-(triethylsilyl)-1H-indol-3-yl)ethanol (1.44 g; 4.45 mmol) in THF (6 mL) was added to a solution of triphenyl phosphine (1.75 g; 6.67 mmol) and perbromomethane (2.21 g; 6.67 mmol) in THF (40 mL) pre-stirred for 30 minutes. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to afford 0.725 g (42%) of the title compound as a brown oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]2[O:14][CH2:15][O:16][C:11]2=[C:10]([O:17][CH3:18])[CH:9]=1)(=O)=O.[I-:19].[Na+]>CC(C)=O>[CH3:18][O:17][C:10]1[CH:9]=[C:8]([CH2:7][CH2:6][I:19])[CH:13]=[C:12]2[O:14][CH2:15][O:16][C:11]=12
Reactant: COc1cc(CCOS(C)(=O)=O)cc2c1OCO2
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(CCI)cc2c1OCO2
Yield: 95.2 %

Procedure:
5.45 g (19.9 mmol) of 2-(3-methoxy-4,5-methylenedioxyphenyl)ethyl methanesulfonate (4) and 3.58 g (23.9 mmol) of sodium iodide were added to 100 ml of acetone and refluxed under heating for 2 hours. To this reaction mixture was added again 0.89 g (5.9 mmol) of sodium iodide, and the reaction mixture was refluxed under heating for 3 hours and 20 minutes. After the refluxed mixture was cooled, the deposited salt was filtered out and washed with acetone. The filtrate and the acetone used for washing were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluate: ethyl acetate n-hexane=1/2) to obtain 5.80 g of 2-(3-methoxy-4,5-methylenedioxyphenyl) ethyl iodide (7) as a crystal with a yield of 95%, which was recrystallized from n-hexane/ethyl acetate. Melting point: 78°-80° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cc(F)ccc3F)c2)CC1
Yield: 108.5 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2,5-difluorobenzoyl chloride (28 μL, 0.229 mmol), 44.7 mg (>100%) of the title compound were recovered.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)(=O)[CH3:5].[NH4+].[Cl-]>CCOCC>[Cl:12][C:9]1[S:8][C:7]([C:4]([CH3:1])=[CH2:5])=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccc(Cl)s1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=C(C)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 80 mL of 3M methyl magnesium bromide in ether was added to a solution of 32 g of 2-acetyl-5-chlorothiophene in 400 mL of ether at 0° to 10° C. After being stirred for 1 hour at 25° C., the reaction mixture was poured onto saturated aq NH4Cl, washed with brine, dried (MgSO4), and concentrated. The crude carbinol was dissolved in 400 mL of 1-chlorobutane, 0.5 g of potassium hydrogen sulfate was added, and the mixture was heated at reflux with a water separator until the distillate was clear. The reaction mixture was washed with aq. NaHCO3, dried (MgSO4), and concentrated after first adding 0.1 g of 4-t-butyl catechol. Distillation at 90° at aspirator pressure afforded the title compound as a yellow oil. 1H NMR (CDCl3): δ2.08 (s, 3H), 4.95 (s, 1H), 5.25 (s, 1H), 6.77 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.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:13][C:6]1[CH:5]=[C:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([C:21]([F:32])([F:31])[F:20])=[CH:23][CH:24]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)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: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (4 g, 0.011 mol), 4-Trifluoromethyl phenylboronic acid (2.6 g, 0.012 mol), Palladium Tetrakis (triphenylphosphine) (1.3 g, 0.001 mol), Cesium carbonate (13.1 g, 0.04 mol) in DMF/water mixture (100 ml/5 ml) was stirred overnight at 100° C. Upon completion of reaction, the precipitate were removed by filtration. The filtrate was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by Flash Column Chromatography to give ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate in 57% yield. (2.7 g). 1HNMR (CDCl3): 7.69 (bs, 4H); 7.36 (s, 1H); 7.17 (s, 1H); 4.18 (q, 2H); 3.59 (s, 2H); 3.39 (d, 2H); 1.28 (t, 3H); 0.96 (m, 1H); 0.41 (m, 2H); 0.01 (m, 2H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:6]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([N+]([O-])=O)[CH:16]=2)=[N:7][N:8]([CH3:14])[C:9]=1[O:10][CH:11]([F:13])[F:12]>CO>[Cl:4][C:5]1[C:6]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([O:2][CH3:1])[CH:16]=2)=[N:7][N:8]([CH3:14])[C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: C[O-]
Reactant: Cn1nc(-c2ccc(C#N)c([N+](=O)[O-])c2)c(Cl)c1OC(F)F
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.9 ml of a 30% strength by weight solution of sodium methylate in methanol was added to a solution of 1.4 g (4.3 mmol) of 4-chloro-3-(4-cyano-3-nitrophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 30 ml of methanol. The mixture was stirred at room temperature for 6 hours and then cooled to 0° C. for about 16 h. The solid reaction product was then isolated. Yield: 0.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[C:37]([NH:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:36]=2)[CH2:28][CH2:27]1)(OC(C)(C)C)=O>>[CH2:43]([N:42]1[C:37]2[CH:36]=[C:35]([O:34][CH2:33][CH2:32][N:29]3[CH2:28][CH2:27][NH:26][CH2:31][CH2:30]3)[CH:40]=[CH:39][C:38]=2[N:41]=[C:15]1[C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1)[CH2:44][CH2:45][CH3:46]
Reactant: O=Cc1ccc(OCCc2ccc(Cl)cc2)cc1
Reactant: CCCCNc1cc(OCCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Product: CCCCn1c(-c2ccc(OCCc3ccc(Cl)cc3)cc2)nc2ccc(OCCN3CCNCC3)cc21
Yield: 59.6 %

Procedure:
A mixture of 4-[2-(4-chloro-phenyl)-ethoxy]-benzaldehyde (0.08 g)and 1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine (0.10 g) was subjected to General Procedure K. Ethanol was removed in vacuo and the residue purified on silica gel with 1-2% MeOH/DCM. The BOC-group was removed employing General Procedure T1 to give 1-butyl-2-{4-[2-(4-chlorophenyl)ethoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole (0.081 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C@@H:13]1[CH2:17][C@H:16]([N:18]=[N+]=[N-])[CH2:15][NH:14]1)=[O:12])[CH3:9].COC([C@@H]1C[C@H](N)CN1[CH2:31][CH:32]1[CH2:37]CCC[CH2:33]1)=O>>[CH2:8]([O:10][C:11]([C@@H:13]1[CH2:17][C@H:16]([NH2:18])[CH2:15][N:14]1[CH2:31][CH:32]([CH3:37])[CH3:33])=[O:12])[CH3:9]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Reactant: CCOC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1C[C@H](N)CN1CC(C)C

Procedure:
(2S,4S)-4-Amino-1-isobutyl-pyrrolidine-2-carboxylic acid ethyl ester was prepared from (2S,4S)-4-azido-pyrrolidine-2-carboxylic acid ethyl ester trifluoroacetate salt in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C11H23N2O2 [(M+H)+] 215, obsd. 215.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([Cl:36])[CH:23]=1)(C)(C)C.Cl.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O1CCCC1>[NH2:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([Cl:36])[CH:23]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(/C=C/CNC(=O)OC(C)(C)C)cc34)cc2Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(/C=C/CN)cc34)cc2Cl)cn1
Temperature: 60 °C
Yield: 83.6 %

Procedure:
To a solution of 4.42 g of E-(3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-carbamic acid tert-butyl ester in 21 mL of tetrahydrofuran was added 21 mL of 2 N hydrochloric acid. The mixture was heated at 60° C. for 3 hours, cooled to room temperature and basified with 10% aqueous potassium carbonate. Methylene chloride was added to the aqueous mixture and a solid precipitated. The solid was filtered and dried to yield 2.98 g of E-[6-(3-amino-propenyl)-quinazolin-4-yl]-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine. 1H NMR (d6 DMSO): δ 8.62 (s, 1), 8.53 (m, 1), 8.26 (m, 2), 7.99 (m, 1), 7.89 (m, 1), 7.77 (m, 1), 7.30 (m, 3), 6.67 (m, 2), 3.44 (m, 2), 2.47 (s, 3).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:29][C:9]2=[N:10][CH:11]=[C:12]([C:27]#[N:28])[C:13]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[C:8]2[CH:7]=1.C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:31][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:29][C:9]2=[N:10][CH:11]=[C:12]([C:27]#[N:28])[C:13]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[C:8]2[CH:7]=1
Reactant: COc1cc(Nc2c(C#N)cnc3sc(CCCCO)cc23)cc(OC)c1OC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(Nc2c(C#N)cnc3sc(CCCCBr)cc23)cc(OC)c1OC

Procedure:
To a solution of 2-(4-hydroxybutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile (413 mg, 1.0 mmol) and carbon tetrabromide (464 mg, 1.4 mmol) in 10 mL of dichloromethane is added a solution of triphenylphosphine (314 mg, 1.2 mmol) in 5 mL of dichloromethane with stirring. The mixture is stirred at room temperature for 2 hours and concentrated. The residue is purified by flash column chromatography eluting with a gradient of 9:1 hexane:ethyl acetate to 1:2 hexane:ethyl acetate to provide crude 2-(4-bromobutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile. The crude 2-(4-bromobutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile is heated 70° C. in 2 mL of morpholine in the presence of sodium iodide (100 mg, 0.67 mmol) for 1 hour. The mixture is concentrated, and the residue is purified by flash column chromatography eluting with a gradient of ethyl acetate to 10% methanol in ethyl acetate to provide 2-[4-(4-morpholinyl)butyl]-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile as a yellow oil; 1H NMR (DMSO-d6) δ 1.49 (quintet, J=7 Hz, 2H), 1.68 (quintet, J=7 Hz, 2H), 2.31 (m, 6H), 2.87 (t, J=7 Hz, 2H), 3.55 (m, 4H), 3.67 (s, 3H), 3.74 (s, 6H), 6.59 (s, 2H), 7.23 (s, 1H), 8.37 (s, 1H), 9.46 (s, 1H); MS 483.5 (M+H)+.