Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][C:7]([C:19]3[CH:24]=[CH:23][C:22](OS(C(F)(F)F)(=O)=O)=[CH:21][CH:20]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[CH2:6]2)[CH2:3][CH2:2]1.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.[Pd].P>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)([C:19]3[CH:24]=[CH:23][C:22]([C:34]4[S:33][CH:37]=[CH:36][CH:35]=4)=[CH:21][CH:20]=3)[CH2:6]2)[CH2:3][CH2:2]1
Reactant: OB(O)c1cccs1
Reactant: COc1cccc(C2(c3ccc(OS(=O)(=O)C(F)(F)F)cc3)CCCN(CC3CC3)C2)c1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: COc1cccc(C2(c3ccc(-c4cccs4)cc3)CCCN(CC3CC3)C2)c1

Procedure:
To a solution of trifluoro-methanesulfonic acid 4-[1-cyclopropylmethyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenyl ester (0.1 9, 0.2 mmol) in ethanol (4.5 mL) and water (0.5 mL) was added 2-thiophene boronic acid (0.052 g, 0.5 mmol) and sodium carbonate (0.037 g, 0.29 mmol) and tetrakis tripheny;phosphine palladium (0.02 g, 0.18 mmol). The reaction mixture was heated to reflux for 2 hours. The mixture was then filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography with hexanes/EtOAc (3:1) to afford 0.08 9 of 1-cyclopropylmethyl-3-(3-methoxy-phenyl)-3-(4-thiophen-2-yl-phenyl)-piperidine. 1HNMR (400 MHz, CDCl3) δ 749 (d, 2H), 7.35 (d, 2H), 7.22-7.06 (comp, 3H), 7.05-7.00 (m, 1H), 6.96 (s, 1H), 6.89 (d, 1H), 6.70-6.67 (m, 1H), 3.76 (s, 3H), 3.17-2.82 (comp, 2H), 2.61-2.39 (comp, 2H), 2.27-2.18 (comp, 4H), 1.62-1.39 (comp, 3H), 0.60-0.45 (comp, 2H), 0.18-0.11 (comp, 2H); MS (M+1) 404.2.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:48])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=5[F:47])[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:49])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[CH3:51][N:52]1[CH2:57][CH2:56][CH:55]([NH:58][CH3:59])[CH2:54][CH2:53]1>CN(C)C=O>[F:47][C:41]1[CH:42]=[C:43]([F:46])[CH:44]=[CH:45][C:40]=1[NH:39][C:38]([C:35]1([C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][C:23]3[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:58]([CH3:59])[CH:55]4[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]4)=[O:7])[CH:24]=3)=[CH:27][C:28]=2[F:49])=[O:34])[CH2:37][CH2:36]1)=[O:48]
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4F)CC3)c(F)c2)ccn1
Reactant: CNC1CCN(C)CC1
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5F)CC4)c(F)c3)ccn2)CC1
Reaction time: 8 h
Yield: 14 %

Procedure:
To a solution of [4-(4-{[1-(2,4-difluorophenylcarbamoyl)cyclopropanecarbonyl]amino}-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (116 mg) in N,N-dimethylformamide (2.0 ml) was added 1-methyl-4-(methylamino)piperidine (0.150 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:1 to the resultant residue. The solid was collected by filtration. The solid was dried under aeration to provide the titled compound as white powder (14.0 mg, 14%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Br[C:16]1[CH:17]=[CH:18][C:19]([F:22])=[N:20][CH:21]=1.CN(C)[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[F:22][C:19]1[N:20]=[CH:21][C:16]([N:4]2[CH2:5][CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:2]([CH3:1])[C:3]2=[O:14])=[CH:17][CH:18]=1
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Reactant: Fc1ccc(Br)cn1
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CN1C(=O)N(c2ccc(F)nc2)CC1C(=O)OC(C)(C)C
Yield: 71.5 %

Procedure:
To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 1.998 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 5-bromo-2-fluoropyridine (352 mg, 1.998 mmol) in 1,4-dioxane (20 ml) was added trans-N,N-dimethylcyclohexane-1,2-diamine (0.062 ml, 0.400 mmol), potassium phosphate (1272 mg, 5.99 mmol) and copper(I) iodide (38.0 mg, 0.200 mmol) and the reaction mixture was heated at reflux under argon overnight. The reaction mixture was allowed to cool and the solvent was evaporated. The residue was partitioned between dichloromethane and water. The organic layer was separated and washed with water (˜50 ml) containing 0.880 ammonia solution (˜5 ml), then brine and passed through a hydrophobic frit and the organic layer was reduced under vacuum. The residue was purified by SP4 automated silica gel chromatography eluting with 10-80% ethyl acetate in isohexane to give 1,1-dimethylethyl 1-(6-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (422 mg, 68.7% yield). LC/MS [M+H]+=296. (ii) Trifluoroacetic acid (2 ml) was added to a solution of 1,1-dimethylethyl 1-(6-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (420 mg, 1.422 mmol) in dichloromethane (5 ml) and the mixture was stirred at room temperature for 36 hours. The reaction mixture was reduced under vacuum and the residue was azeotroped with toluene and dried under heated vacuum to give 1-(6-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜1.4 mmol) which was used in the next step. LC/MS [M+H]+=240.
Reaction SMILES: C(OC(=O)C)(=O)C.C(O)(=O)C.[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[CH3:23][N:24]([CH3:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>CO>[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[C:31]3[C:27](=[CH:26][C:25]([N:24]([CH3:34])[CH3:23])=[CH:33][CH:32]=3)[C:28](=[O:29])[O:19]2)=[CH:16][CH:15]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CN(C)c1cccc(C(=O)O)c1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN(C)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1
Temperature: 55 °C
Yield: 76.6 %

Procedure:
A stirred mixture of 306.0 g of acetic anhydride, 200.0 ml of glacial acetic acid, 298.0 g p-dimethylaminobenzaldehyde and 386.0 g of m-dimethylaminobenzoic acid was heated at reflux for a period of approximately four hours. The resulting mixture was cooled to 55° C., diluted with 700 ml of methanol and heated at reflux for approximately thirty minutes. The mixture was then cooled to approximately 15° C. and the solid which separated was collected by filtration and washed with 700.0 ml of fresh methanol chilled to 10°-15° C. The methanolwet solid was reslurried in 400 ml of fresh methanol at 10°-15° C. for approximately twenty minutes, separated by filtration and washed with 150 ml of chilled methanol. The solid was dried at 70° C. in vacuo to yield 453.2 g of 3-(4-dimethylaminophenyl)-6-dimethylaminophthalide (Formula II: R=CH3 ; X=H; Y=4-(CH3)2N-C6H4 which after recrystallization from toluene was obtained as an ivory-colored solid melting at 184.5°-185.5° C.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:47]1[C:51]2[CH:52]=[CH:53][C:54]([C:56]([OH:58])=O)=[CH:55][C:50]=2[N:49]=[CH:48]1.C(N(C(C)C)C(C)C)C.[CH2:68]1[C@H:77]2[C@H:72]([CH2:73][CH2:74][C:75]3[CH:81]=[CH:80][CH:79]=[CH:78][C:76]=32)[NH:71][CH2:70][CH2:69]1.N>CN(C)C=O.CO.C(OCC)(=O)C>[NH:47]1[C:51]2[CH:52]=[CH:53][C:54]([C:56]([N:71]3[C@@H:72]4[C@@H:77]([C:76]5[CH:78]=[CH:79][CH:80]=[CH:81][C:75]=5[CH2:74][CH2:73]4)[CH2:68][CH2:69][CH2:70]3)=[O:58])=[CH:55][C:50]=2[N:49]=[CH:48]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Reaction time: 0.33 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.50 g; alternatively, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate may be used) is added to a solution of 1H-benzoimidazole-5-carboxylic acid (0.23 g) and ethyl-diisopropyl-amine (0.50 mL) in N,N-dimethylformamide (2 mL) at room temperature. The solution is stirred for 20 min prior to the addition of cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline (0.30 g) dissolved in N,N-dimethylformamide (2 mL). The resulting solution is stirred at room temperature for 3 h. 32% aqueous ammonia (1 mL) in methanol (2 mL) is then added and the mixture is stirred for another 30 min. The mixture is diluted with ethyl acetate and washed with water and brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol containing 1% NH3 95:5→80:20) to afford the title compound as a foam-like solid that is triturated with ether and dried to give a colorless solid [alternatively, the product may be purified by HPLC on reversed phase (MeOH/H2O)]. Yield: 0.38 g (80% of theory); LC (method 1): tR=2.53 min; Mass spectrum (ESI+): m/z=332 [M+H]+; 1H NMR (400 MHz, DMSO-d6, mixture of 2 rotamers) δ 1.52-1.82 (m, 4H), 1.82-1.94 (m, 1H), 2.24-ca. 2.48 (m, 1.5H), 2.71-3.02 (m, 3H), 3.03-3.18 (m, 0.5H), 3.50-3.65 (m, 0.5H), 3.88-4.05 (m, 0.5H), 4.39-4.56 (m, 0.5H), 4.83-4.99 (m, 0.5H), 6.89-7.20 (m, 4H), 7.21-7.27 (m, 1H), 7.56-7.70 (m, 2H), 8.23-8.35 (m, 1H), 12.58 (broad s, 1H).
Reaction SMILES: [CH:1]1([C:7]2[C:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=3)=[CH:10][N:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.O.[NH2:44][C:45]1[NH:49][N:48]=[N:47][N:46]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(Cl)CCl>[CH:1]1([C:7]2[C:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH:44][C:45]4[NH:49][N:48]=[N:47][N:46]=4)=[O:18])=[CH:15][CH:14]=3)=[CH:10][N:9]([C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:26][CH:27]=3)[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(Cc2cn(-c3ccc(OC(F)(F)F)cc3)nc2C2CCCCC2)cc1
Reactant: Nc1nnn[nH]1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1nnn[nH]1)c1ccc(Cc2cn(-c3ccc(OC(F)(F)F)cc3)nc2C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 66.7 mg product from Step B above, 71.9 mg EDC, 30.4 mg HOBt and 23.2 mg aminotetrazole monohydrate was dissolved in 1 mL DMF. DIEA (92 μL) was added immediately and the resulting solution was stirred at room temperature for 17 hours. The reaction mixture was diluted with about 2:1 mixture of DMF and water and purified on preparative HPLC using 70˜80% MeCN gradient over 10 minutes at 8.0 mL per minute with 0.1% TFA. The title compound was obtained as a white solid following lyophilization. 1H NMR (DMSO-d6, 500 MHz) δ 8.26 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.84˜7.87 (m, 2), 7.40˜7.45 (m, 4H), 3.92 (s, 2H), 2.58 (tt, J=3.4 & 11.9 Hz, 1H), 1.62˜1.74 (m, 5H), 1.41˜1.50 (m, 2H), 1.17˜1.31 (m, 3H). LC-MS: 2.41 min. (M+H=512.3).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]#[N:22])[CH2:16][C@H:15]2[O:23][CH3:24])=[O:12])=[CH:4][C:3]=1[Cl:25].O1CCCC1.[H][H]>[Ni].CO>[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH2:22])[CH2:16][C@H:15]2[O:23][CH3:24])=[O:12])=[CH:4][C:3]=1[Cl:25]
Reactant: CO[C@@H]1CN(CC#N)CC[C@@H]1NC(=O)c1cc(Cl)c(N)c2c1OCC2
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CO[C@@H]1CN(CCN)CC[C@@H]1NC(=O)c1cc(Cl)c(N)c2c1OCC2
Yield: 53.6 %

Procedure:
A solution of 15.7 parts of cis-4-amino-5-chloro-N-[1-(cyanomethyl)-3-methoxy-4-piperidinyl]-2,3-dihydro-7-benzofurancarboxamide in 178 parts of tetrahydrofuran and 158 parts of methanol was hydrogenated at normal pressure and at room temperature with 6 parts of Raney nickel. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH(NH3) 93:7). The eluent of the desired fraction was evaporated and the residue was crystallized from acetonitrile (to which a few drops of water were added). The product was filtered off at 0° C. and dried in vacuo at 40° C., yielding 8.5 parts (53.6%) of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2,3-dihydro-7-benzofurancarboxamide (comp. 35).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.[OH-].[Na+].CN(C)[CH:20]=[O:21]>>[CH:20]([C:10]1[S:6][C:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)=[O:21]
Reactant: CN(C)C=O
Reactant: c1csc(-c2cccs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2cccs2)s1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To dimethyl formamide (250 ml) was added phosphoryl chloride (50.2 ml) with quick stirring. 2,2'-Bithiophene (83 g) in dimethyl formamide (200 ml) was then added and stirred at -10° C. for 30 minutes. Then the temperature was raised to 40° C. and was further stirred for 20 hours. The reaction mixture was then poured into crushed ice and stirred for 30 minutes. Sodium hydroxide aqueous solution (10%, 600 ml) was added and the solution was extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated and separated by silica gel chromatography. Product 90 g was obtained, melting point 56°-57° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC.[OH-].[Na+]>[CH3:22][C:19]1[CH:18]=[CH:17][C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:8]([C:3]3([CH:2]=[O:1])[CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:9])[CH2:15][CH2:14]2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(N2CCN(C(=O)C3(CO)CCCC3)CC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(N2CCN(C(=O)C3(C=O)CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 105 %

Procedure:
(1-Hydroxymethyl-cyclopentyl)-(4-(4-methylphenyl)piperazin-1-yl)-methanone from the previous step (1.57 g, 5.22 mmol) was dissolved in DCM (40 mL). Dess-Martin periodinane (3.06 g, 7.22 mmol) was added and the reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture diluted with Et2O (100 mL) and 1M aq NaOH solution (50 mL) was added. The reaction mixture was stirred for 20 minutes and then the organic layer was separated and washed with 1M aq NaOH solution (50 mL), water (50 mL), dried (MgSO4) and concentrated in vacuo to give 1-(4-(4-methylphenyl)-piperazine-1-carbonyl)-cyclopentanecarbaldehyde (1.64 g, 105%) as a brown oil which was used without further purification.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][C:14]([CH3:16])=[O:15].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C1COCC1.CCCCCC>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](=[O:21])[CH2:13][C:14](=[O:15])[CH3:16]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)CC(=O)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 2.5 M hexane solution of BuLi (16.46 mL, 41.1 mmol) was added dropwise to a solution of diisopropylamine (6.11 mL, 42.9 mmol) in THF (150 mL) at −78° C. The mixture was stirred at 0° C. for 15 min and cooled to −78° C. Acetone (3.02 mL, 41.1 mmol) was added dropwise. After 2 h at −78° C., 2-chlorobenzoyl chloride (3.00 g, 17.14 mmol) in THF (10 mL) was added dropwise. The flask was rinsed with THF (2 mL) and added. After 1 h at −78° C., the mixture was quenched with brine (200 mL) and acidified to pH ˜1 with 1 N HCl. The organic solvents were evaporated in vacuo. The aqueous residue was extracted with EtOAc (3×100 mL). The combined extracts were dried (MgSO4) and concentrated to give crude 1-(2-chlorophenyl)butane-1,3-dione as a yellow liquid. The crude material was taken to next step without purification. MS (ES+) m/z: 197 (M+H).
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
1.8 g (60 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced under a stream of nitrogen into a round-bottomed flask. 7.5 g (50 mmol) of 4-formylbenzoic acid, dissolved in 100 ml of DMF, are added dropwise and the mixture is stirred at room temperature until gaseous evolution has ceased. A solution of 7.1 ml (60 mmol) of benzyl bromide in 50 ml of DMF is then introduced dropwise and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and hexane (50:50). After evaporation of the solvents, 10.9 g (91%) of the expected benzyl ester are collected in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:16][CH3:17])[CH2:12][N+:13]([O-])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:16][CH3:17])[CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C[N+](=O)[O-])SC)cc1OC
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(CN)SC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
Under argon, a solution of 2-(3,4-dimethoxyphenyl)-2-(methylthio)nitroethane (1.22 g, 4.8 mmol) in tetrahydrofuran (20 ml) was dropwise added to an ice-cooled and stirred solution of lithium aluminum hydride (0.47 g) in tetrahydrofuran (10 ml). After stirring at room temperature for 30 minutes, water (0.47 ml), 15% aqueous sodium hydroxide solution (0.47 g) and water (1.14 ml) were sequentially added dropwise to the reaction mixture under ice-cooling and stirring. A small amount of potassium carbonate was added and stirred for a few minutes. Inorganic salts were filtered out and washed with tetrahydrofuran and the filtrate was concentrated under reduced pressure and dried to yield a crude oily 2-(3,4-dimethoxyphenyl)-2-(methylthio)ethylamine (0.98 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=4[F:36])=[O:27])=[CH:21][CH:20]=3)[CH:15]=[CH:14][N:13]=2)[NH:9][CH:8]=1)=[O:6].C(N(CC)C(C)C)(C)C.Br[CH2:47][C:48]([O:50][CH3:51])=[O:49].O>CN(C=O)C>[F:36][C:30]1[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:29]=1[NH:28][C:26]([NH:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:16]2[CH:15]=[CH:14][N:13]=[C:12]([C:10]3[NH:9][CH:8]=[C:7]([C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:47][C:48]([O:50][CH3:51])=[O:49])=[O:6])[CH:11]=3)[CH:17]=2)=[CH:20][CH:21]=1)=[O:27]
Reactant: COC(=O)CBr
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCN)c[nH]4)c3)cc2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CNCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(2-aminoethyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (200 mg, 0.41 mmol) in 10 ml of anhydrous DMF, were added N,N-diisopropylethylamine (137 mg, 1.06 mmol) and methyl bromoacetate (82 mg, 0.54 mmol). The mixture was stirred at room temperature for 1 hour and poured into 100 ml of water. The precipitates were filtered, washed with water, and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with a gradient of 3˜8% of methanol in chloroform to give methyl [(2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)amino]acetate as white solid. Yield: 100 mg, 43%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][OH:13].B.[K].O>C(O)(=O)C>[O:13]=[C:12]1[C:6]2[C:5](=[CH:4][CH:3]=[CH:2][CH:7]=2)[CH2:8][N:1]1[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: B
Agent: [K]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(N2Cc3ccccc3C2=O)cc1

Procedure:
1.64 g of o-phthalaldehydic acid methyl ester and 1.5 g of p-aminophenylacetic acid were added to 30 ml of methanol to form a mixture which was agitated at room temperature for one hour and incorporated with 0.54 g of potassium boron hydride in several portions. The whole was reacted at room temperature for 15 hours and freed from the solvent by distillation at a reduced pressure to obtain a residue. The thus obtained residue was incorporated with 50 ml of water and then with a small amount of acetic acid to form an acidic solution, after which crystals precipitated from said solution were filtered off, dried and recrystallized from ethanol thereby to obtain 2.4 g of 1-oxo-2-{p-(carboxymethyl)-phenyl}-isoindoline having the following properties:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[N:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Pd]>[N:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)=[C:3]([NH2:8])[CH:4]=1
Reactant: OB(O)c1ccncc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Nc1cnccc1-c1ccncc1

Procedure:
4-chloro-3-nitro-pyridine (100 mg, 0.6307 mmol), 4-pyridylboronic acid (77.52 mg, 0.6307 mmol), palladium; triphenylphosphane (36.45 mg, 0.03154 mmol), K3PO4 (946.0 μL, of 2 M, 1.892 mmol) in dioxane (3 mL) was heated at 130° C. for 30 min in a microwave. The mixture was loaded on a SCX column, washed with MeOH. The product was eluted with a 2M NH3 in MeOH. The filtrate was concentrated in vacuo. The residue was dissolved in MeOH (20 mL), Pd/C 10% (42.04 mg, 0.3950 mmol) was added and the mixture was hydrogenated (H2 balloon) overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo yielding [4,4′-bipyridin]-3-amine that was used in next step without further purification. MS (ES+) 172.1.