Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].CCN(CC)CC>[Cl-].[Na+].O.[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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:15]([F:18])([F:17])[C:11]1[CH:10]=[C:9]([N:4]2[CH:5]=[CH:6][C:7](=[O:8])[C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[N:3]2)[CH:14]=[CH:13][CH:12]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 40 °C
Yield: 28 %

Procedure:
A mixture of 3-bromo-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (500 mg, 1.57 mmol), (trimethylsilyl)acetylene (0.222 mL, 1.57 mmol), Et3N (0.329 mL, 2.36 mmol), CuI (4.5 mg, 0.0236 mmol), Pd(PPh3)2Cl2 (55.1 mg, 0.0785 mmol) and PPh3 (10.3 mg, 0.0393 mmol) in TI-IF (7.5 mL) was heated to 40° C. for 8 h under Ar. To the suspension was added (trimethylsilyl)acetylene (0.111 mL, 0.785 mmol). The suspension was heated to 40° C. for 14 h under Ar. To the suspension was added (trimethylsilyl)acetylene (0.0888 mL, 0.628 mmol). The suspension was heated to 40° C. for 96 h under Ar. The mixture was diluted with brine, extracted with EtOAc, dried over MgSO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100) to yield the title compound (148 mg, 28% yield) as a brown solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 0.26 (9H, s), 6.64 (1H, d, J=7.9 Hz), 7.75-7.92 (2H, m), 8.00-8.15 (2H, m), 8.90 (1H, d, J=8.3 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[CH:21]=[CH2:22])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([CH:21]=[CH2:22])[CH:16]=1
Reactant: C=Cc1cc(C)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C=Cc1cc(C)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
A mixture of 4-bromo-3-chlorotoluene (2.1 g), Boc-piperazine (1.9 g), palladium acetate (112 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (312 mg), sodium tert-butoxide (1.4 g) and toluene (20 mL) was refluxed for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (3.1 g). To a mixture of 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (932 mg), 2,4,6-trivinylcyclotriboroxane pyridine complex (1 g), palladium acetate (74 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (271 mg) and potassium fluoride (697 mg) was added tetrahydrofuran (4 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(4-methyl-2-vinylphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.9 g). 4-(4-Methyl-2-vinylphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.9 g) was dissolve in chloroform (2 mL), 4N hydrogen chloride/ethyl acetate (1 mL) was added, and the mixture was stirred at room temperature for 3 hr. 1N aqueous sodium hydroxide solution (8 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give 1-(4-methyl-2-vinylphenyl)piperazine (606 mg). 1-(4-Methyl-2-vinylphenyl)piperazine (606 mg) was dissolved in tetrahydrofuran (8 mL), 4-iodobenzoyl chloride (1.1 g) and 1N aqueous sodium hydroxide solution (4 mL) were added, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give the title compound (1 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C(Cl)(Cl)Cl.CO>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1ccccn1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: c1ccc(NCCCOc2cccc(CN3CCCCC3)c2)nc1

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (20 g) and 2-bromopyridine (12.64 g) were stirred at 125° C. for 31/2 days. The cooled reaction mixture was subjected to column chromatography on silica ((chloroform:methanol 10:1) to afford the title compound as an oil. This was treated with maleic acid in ethanol to give, on addition of diethyl ether, as a white solid 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]pyridine dimaleate (11.40 g), m.p. 116°-7° C. (recrystallised from isopropanol).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26](C)(C)C)[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.C(Cl)(=O)OC>>[CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][CH3:26])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H](COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Agent: COC(=O)Cl
Product: COC(=O)N[C@@H](C)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1

Procedure:
By a method similar to Example 17, and using tert-butyl [(1S)-2-({1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)-1-methylethyl]carbamate and methyl chlorocarbonate, the title compound was obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([OH:18])[CH2:14][CH2:15][C:16]#[CH:17]>>[F:10][C:9]([F:12])([F:11])[O:8][C:4]1[CH:3]=[C:2]([C:17]#[C:16][CH2:15][CH2:14][CH2:13][OH:18])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCCO
Reactant: FC(F)(F)Oc1cccc(I)c1
Product: OCCCC#Cc1cccc(OC(F)(F)F)c1

Procedure:
In analogy to the procedures described in example 1F], 1-iodo-3-trifluoromethoxy-benzene and pent-4-yn-1-ol gave the title compound as a red liquid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[CH:19]=[N:20][CH:21]=[N:22][CH:23]=3)=[CH:7][CH:8]=2)[N:3]=1.[CH3:24][N:25]([CH3:53])[C:26](=[O:52])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)=[O:35])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>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>[CH3:24][N:25]([CH3:53])[C:26](=[O:52])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([C:2]3[N:11]=[C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:9]4[C:4](=[CH:5][C:6]([C:18]5[CH:19]=[N:20][CH:21]=[N:22][CH:23]=5)=[CH:7][CH:8]=4)[N:3]=3)=[CH:41][CH:42]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: Clc1nc(N2CCOCC2)c2ccc(-c3cncnc3)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ccc(-c5cncnc5)cc4n3)cc2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 12.7 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-4-morpholin-4-yl-7-pyrimidin-5-yl-quinazoline (150 mg, 0.00046 mol), N,N-Dimethyl-4-{3-[4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide (168 mg, 0.00041 mol), cesium carbonate (300 mg, 0.00092 mol), DMF (10 mL) and water (3 mL) were added. The reaction mixture was degassed with N2 for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (16 mg, 0.000023 mol) was added and again degassed with N2 for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 4% MeOH in chloroform) followed by preparative TLC (10% MeOH in chloroform) to yield the title compound [30 mg, 11%]. 1H NMR (400 MHz, DMSO-d6): δ 9.36 (s, 2H), 9.29 (s, 1H), 9.05 (s, 1H), 8.98 (s, 1H), 8.46 (d, J=8.8 Hz, 2H), 8.31 (d, J=2.0 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.93 (dd, J′=8.4 Hz, J″=1.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 3.87 (s, 8H), 2.96 (s, 6H); LC-MS (ESI): Calculated mass: 574.2; Observed mass: 575.1 [M+H]+ (RT: 0.26 min).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[C:26]([Cl:33])[CH:25]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[Cl:33][C:26]1[CH:25]=[C:24]([CH:32]=[CH:31][C:27]=1[C:28](=[O:29])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)[CH2:23][NH:22][C:20](=[O:21])[O:19][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)c(Cl)c1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((tert-butoxycarbonylamino)methyl)-2-chlorobenzoic acid via Procedure G to yield tert-butyl 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate. Tert-butyl 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate was subsequently treated with 4N HCl in Dioxane to remove the Boc protecting group and form the HCl salt of 4-(aminomethyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 54 mg of the crude HCl salt of 4-(aminomethyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to picolinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide. MS (Q1) 477.3 (M)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC[CH2:21][N:22]([CH2:30][C:31]1[N:32]([CH2:36]OCC[Si](C)(C)C)[CH:33]=[CH:34][N:35]=1)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[N:35]1[CH:34]=[CH:33][N:32]2[CH2:36][CH2:21][N:22]([C:23]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:29])[CH2:30][C:31]=12
Reactant: CC(C)(C)OC(=O)N(CCCl)Cc1nccn1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCn2ccnc2C1
Yield: 34.8 %

Procedure:
Tetrabutylammonium fluoride (1M in tetrahydrofuran, 7.1 mL, 7.1 mmol) was added to a solution of 1,1-dimethylethyl N-(2-chloroethyl)-N-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-ylmethyl)carbamate (Description 162, 2.52 g, 6.5 mmol) in tetrahydrofuran (50 mL) and the mixture was heated under reflux for 1.5 hours. Further tetrabutylammonium fluoride (1M in tetrahydrofuran, 7.1 mL, 7.1 mmol) was added and the mixture was heated under reflux for 20 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH (97:3), to give the title compound (505 mg, 35%). m/z (ES+) 224 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[Cl:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(OCC)(=O)C>C(O)C>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=3[Cl:15])[N:5]=[C:4]([NH2:16])[N:3]=2)=[CH:20][CH:19]=1
Reactant: Nc1nc(Cl)cc(-c2cc(Cl)ccc2Cl)n1
Reactant: Nc1ccc(Br)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nc(Nc2ccc(Br)cc2)cc(-c2cc(Cl)ccc2Cl)n1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A mixture of the hydrochloride salt of 4-chloro-6-(2,5-dichloro-phenyl)-pyrimidin-2-yl-amine (0.03 g, 0.096 mmol) and 4-bromoaniline (0.034 g, 0.020 mmol) in ethanol (7.5 ml) was heated under reflux for 1 hour. After evaporation of the solvent under reduced pressure, the residue was treated with 1.0 N hydrochloric acid (10 ml) and stirred for 30 minutes. Filtration provided the crude product, which was treated with ethyl acetate (10 ml) and stirred for 1 hour. After filtration the solid was dissolved in methanol (10 ml) and treated with aqueous sodium carbonate solution (1.0 M, 1 ml). After stirring for 1 hour, the solvent was evaporated under reduced pressure and the solid was treated with water (10 ml). After stirring for 15 minutes, filtration provided the title compound (59% yield) as a white powder. 1H NMR (DMSO-d6) δ 6.31 (s, 1H, Ar), 6.54 (s, 2H, NH2), 7.45 (d, 2H, J=8.9 Hz, Ar), 7.52 (dd, 1H, J=8.6 Hz, J-2.6 Hz, Ar), 7.60 (d, 1H, J=8.6 Hz, Ar), 7.64 (d, 1H, J=2.6 Hz, Ar), 7.77 (d, 2H, J=8.9 Hz, Ar), 9.46 (s, 1H, NH).
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:29]\[O:30][CH3:31])/[C@:18]5([OH:28])[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C([C@@H]1C2[C@](C)(CCC(=[O:52])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:28][C@:18]12[CH2:19][C:20](=[O:52])[CH2:21][CH2:22][C@:23]1([CH3:24])[C@@H:25]1[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]1)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]/[C:17]/2=[N:29]\[O:30][CH3:31]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CO/N=C1\C[C@H]2[C@@H]3CC45OCCOC4(OCCO5)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCCC[C@]12O
Product: CO/N=C1\C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C[C@]12O
Yield: 80 %

Procedure:
The title compound II-bn was prepared in 80% yield from 3,3:17,17-bis(ethylendioxy)-5α-hydroxy-6-(E)-methoxyiminoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone/CH2Cl2 60/20/20). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 5.47 (s, 1H), 3.75 (s, 3H), 3.02 (dd, 1H), 2.79 (d, 1H), 2.45-1.13 (m, 17H), 0.95 (s, 3H), 0.77 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:11][N:10]([CH2:20][CH2:21][C:22](O)=[O:23])[C:9]2=[S:25])=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30]O[CH2:28][CH2:27]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:11][N:10]([CH2:20][CH2:21][C:22]([N:26]3[CH2:31][CH2:30][CH2:28][CH2:27]3)=[O:23])[C:9]2=[S:25])=[CH:6][CH:7]=1
Reactant: O=C(O)CCn1cc(-c2ccc(F)cc2)n(-c2ccc(Cl)cc2)c1=S
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=C(CCn1cc(-c2ccc(F)cc2)n(-c2ccc(Cl)cc2)c1=S)N1CCCC1

Procedure:
To a solution of 3-(1-(4-chlorophenyl)-5-(4-fluorophenyl)-1,2-dihydro-2-thioxoimidazol-3-yl)propionic acid (1 eq), 1-3-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.7 eq) and morpholine (1.7 eq) in THF is stirred overnight at room temperature. The reaction is quenched with water and extracted with ethyl acetate. The organics are dried and concentrated under vacuum. The residue is purified by chromatography on silica to give 3-(1-(4-chlorophenyl)-5-(4-fluorophenyl)-1,2-dihydro-2-thioxoimidazol-3-yl)-1-(pyrrolidin-1-yl)propan-1-one.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][C:26]=4Cl)[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:32]=[C:33]([NH2:38])[CH:34]=[CH:35][C:36]=1[F:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCOCCOC>[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][C:26]=4[NH:38][C:33]4[CH:34]=[CH:35][C:36]([F:37])=[C:31]([Cl:30])[CH:32]=4)[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2nccc(Cl)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCOCCOC
Solvent: O
Product: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2nccc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 185 °C
Yield: 28 %

Procedure:
A mixture of 5-(4-chloro-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (10 mg, 0.024 mmol), 3-chloro-4-fluoro-phenylamine (50 mg, 0.34 mmol), p-toluene sulfonic acid monohydrate (5 mg, 0.026 mmol) and 1 mL of 2-methoxyethyl ether was heated to 180-190° C. in a sealed tube for 6 hours, cooled to room temperature and concentrated. The residue was then purified using preparative TLC plates eluting with 10% methanol in dichloromethane to give 5-[4-(3-chloro-4-fluoro-phenylamino)-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide as an orange solid (yield is about 28%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][C:5]1[C:6]([C:13]#[N:14])=[N:7][CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.O.C(=O)([O-])[O-:19].[Na+].[Na+].OO>CC(C)=O>[CH3:16][O:15][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[C:6]([C:13]([NH2:14])=[O:19])=[N:7][CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cnc(C#N)c(CC(OC)OC)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cnc(C(N)=O)c(CC(OC)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a 1 L round-bottomed flask was added 3-(2,2-dimethoxyethyl)-5-methoxypicolinonitrile (8.550 g, 38.5 mmol), water (480 ml), and acetone (120 ml). An aqueous solution of sodium carbonate (3M; 154 ml, 462 mmol) was added followed by hydrogen peroxide (35 wt. % solution in water; 138 ml, 1347 mmol). The tan mixture was stirred vigorously at rt for 2 h. The organic solvent was removed uncle reduced pressure and the aqueous residue was extracted with DCM (3×). The combined organic fractions were dried over sodium sulfate. The filtrate was concentrated under reduced pressure to afford 3-(2,2-dimethoxyethyl)-5-methoxypicolinamide (8.200 g, 34.1 mmol, 89% yield) as an off-white solid that was advanced without further purification. MS m/z=263.2 (M+Na)
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH2:55]([O:62][C:63]1[CH:90]=[CH:89][C:88](Br)=[CH:87][C:64]=1[C:65]([NH:67][C:68]1[CH:80]=[C:79]([C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)[CH:78]=[CH:77][C:69]=1[C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])=[O:66])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH2:55]([O:62][C:63]1[CH:90]=[CH:89][C:88]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:14][CH2:13]2)=[CH:87][C:64]=1[C:65]([NH:67][C:68]1[CH:80]=[C:79]([C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)[CH:78]=[CH:77][C:69]=1[C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])=[O:66])[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Br)ccc1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCNCC1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
4-(Tert-butyldimethylsilyloxy)piperidine (0.23 g), cesium carbonate (0.44 g), tris(dibenzylideneacetone)dipalladium(0) (9.8 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (26 mg), and palladium(II) acetate (4.8 mg) were added to a toluene (4.5 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate (0.30 g), followed by heating to reflux under a nitrogen atmosphere for 4 hours and 30 minutes. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The insoluble substance was removed by filtration. The organic layer was separated, washed with saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% hexane/ethyl acetate] to obtain 0.32 g of tert-butyl 2-(2-(benzyloxy)-5-(4-(tert-butyldimethylsilyloxy)piperidin-1-yl)benzamido)-4-phenylbenzoate.
Reaction SMILES: CC(C)N=C=NC(C)C.C([O:12][C:13](=[O:35])[C:14]1[CH:19]=[C:18]([NH:20][C:21]([NH:23][C:24]2[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:31])=S)[C:17]([NH:32][CH3:33])=[CH:16][C:15]=1[F:34])C>C(#N)C>[Cl:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:31])[C:24]=1[NH:23][C:21]1[N:32]([CH3:33])[C:17]2[CH:16]=[C:15]([F:34])[C:14]([C:13]([OH:12])=[O:35])=[CH:19][C:18]=2[N:20]=1
Reactant: CCOC(=O)c1cc(NC(=S)Nc2c(Cl)cccc2Cl)c(NC)cc1F
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)O)c(F)cc21
Reaction time: 1 h

Procedure:
DIC (1.50 mL, 9.6 mmol) was added to a stirred mixture of 5-[3-(2,6-dichloro-phenyl)-thioureido]-2-fluoro-4-methylamino-benzoic acid ethyl ester (2.70 g, 6.5 mmol) in acetonitrile. After stirring for 1 h the mixture was concentrated i.vac. The residue was taken up in ethanol and 1 M aq. NaOH and stirred for further 40 min at reflux. Ethanol was evaporated, the mixture was diluted with water and filtered. The filtrate was acidified with hydrochloric acid, stirred and filtered. Both residues were combined and dried.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]3[C:16](=[CH:17][C:7]=2[N:6]=1)[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:2][CH2:3][CH3:4].Br[CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[C:7]2[CH:17]=[C:16]3[C:11](=[CH:10][C:8]=2[N:9]=1)[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCCCc1nc2cc3ccccc3cc2[nH]1
Product: CCCCc1nc2cc3ccccc3cc2n1Cc1ccc(C#N)cc1
Yield: 67.8 %

Procedure:
Using the procedure of Step B of Example 1, 449 mg of the product of Step A and 392 mg of 4-bromomethyl benzonitrile were reacted to obtain 460 mg of the desired product melting at 138° C. after crystallization from ethyl ether.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][CH:10]1[CH2:14][CH2:13][CH:12]([CH3:15])[NH:11]1>O>[CH3:9][CH:10]1[CH2:14][CH2:13][CH:12]([CH3:15])[N:11]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(F)n1
Reactant: CC1CCC(C)N1
Solvent: O
Product: CC1CCC(C)N1c1cccc(N)n1
Temperature: 205 °C
Yield: 44.9 %

Procedure:
A mixture of 6-fluoropyridin-2-amine (0.5 g, 4.46 mmol) and 2,5-dimethylpyrrolidine (0.664 g, 6.7 mmol) in water (0.3 mL) was heated to 205° C. for 0.5 h in a microwave oven then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:30) to afford 6-(2,5-dimethylpyrrolidin-1-yl)pyridin-2-amine (0.383 g, 45%) as a yellow oil. LC-MS: [M+1]+=192, tR=1.048 min.