Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[C:3]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:19])=[C:12]([S:15](Cl)(=[O:17])=[O:16])[CH:13]=2)[C:8]([CH3:21])([CH3:20])[CH2:7]1)(=[O:5])[CH3:4]>C1COCC1>[CH3:1][NH:2][S:15]([C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH3:21])([CH3:20])[CH2:7][N:6]2[C:3](=[O:5])[CH3:4])=[CH:10][C:11]=1[Br:19])(=[O:17])=[O:16]
Reactant: CC(=O)N1CC(C)(C)c2cc(Br)c(S(=O)(=O)Cl)cc21
Reactant: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc2c(cc1Br)C(C)(C)CN2C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
Methylamine (2 M solution in THF, 2.4 mL, 4.9 mmol) was added to a solution of 1-acetyl-5-bromo-3,3-dimethyl-2,3-dihydro-1H-indole-6-sulfonyl chloride (300 mg, 0.82 mmol) in THF (10 mL). The solution was stirred at room temperature for 30 minutes then the solvent was removed in vacuo and the residue partitioned between water and EtOAc. The organic phase was dried (MgSO4), filtered and concentrated to give the title compound (271 mg) as a yellow solid. 1H NMR (CDCl3): 8.93 (1H, s), 7.44 (1H, s), 5.07 (1H, s), 3.88 (2H, s), 2.68 (3H, d), 2.25 (3H, s), 1.48-1.22 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: N=C(N)NN
Reactant: Cc1ccc(Cl)cc1C1CC(=O)c2c(C)ccnc2C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(Cl)cc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Yield: 211.5 %

Procedure:
To a solution of 7-(5-chloro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.0 g) and aminoguanidine hydrochloride (0.46 g) in ethanol (30 ml) were added concentrated hydrochloric acid (0.9 ml) and water (0.9 ml), and the mixture was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The mixture was washed with ethyl acetate, and to the aqueous layer was added sodium hydrogen carbonate solution to make it alkaline. The solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solution was concentrated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid (10 ml), and the mixture was concentrated. Precipitated crystals were recrystallized from ethanol to give 7-(5-chloro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 164) (1.4 g) as colorless crystals.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10](=[O:12])[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH:27][C@@H:28]([CH2:41][NH2:42])[CH2:29][O:30][C:31]1[C:39]2[NH:38][C:37](=[O:40])[NH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1>>[OH:27][C@@H:28]([CH2:41][NH:42][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:13]=[C:9]3[S:8][C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:11][C:10]3=[O:12])=[CH:15][CH:16]=2)[CH2:25][CH2:24]1)[CH2:29][O:30][C:31]1[C:39]2[NH:38][C:37](=[O:40])[NH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCOCC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=C1N=C(N2CCOCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 28) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a yellowish solid; mp>150° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ1.20-1-40 (m, 2 H), 1.80-1.95 (m, 2 H), 2.55-2.95 (m, 4 H), 3.60-4.10 (m, 14 H), 4.90 (br s, 1 H), 6.56 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.0 Hz, 1 H), 6.87 (dd, J=7.9, 7.9 Hz, 1 H), 7.02 (d, J=8.9 Hz, 2 H), 7.45 (d, J=8.9 Hz, 2 H), 7.54 (s, 1 H), 10.65(s, 1 H), 10.75 (brs, 1 H); MS (ES) m/z: 290.0 ((M+2H)2+, 100%); 579.1 (MH+, 80%); HRMS Calcd. for C29H36N6O5S (MH+): 579.2390. Found: 579.2392.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](Cl)[C:29]#[CH:30].[Cl-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:30][C:29]#[CH:28])[C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:24][CH:25]=1
Reactant: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Reactant: C#CCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)C(CC(NC(=O)c2ccc(Cl)cc2)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
479 Milligrams of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate prepared in Example 3 and 70 mg of 50% sodium hydride (in oil) were admixed in 5 ml of dimethylformamide, and the mixture was stirred at a room temperature for 2 hours. Then 0.17 g of propargyl chloride was added to the reaction mixture and the whole reaction mixture was stirred at a room temperature for 7 hours. The reaction mixture was poured into 13 ml of a saturated sodium chloride aqueous solution, and the organic material was extracted with chloroform. The chloroform layer was washed with water, dried, then chloroform was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography to yield 80 mg of 2-(4-chlorobenzoylamino)-3-[1-(2-propynyl)oxindol-3-yl]propionic acid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23].[C:27](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[C:19]([C:4]1[C:3]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:2]([NH:1][CH3:27])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CNc1c(C(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoroacetylpyrazole (1 g) in anhydrous N,N-dimethylformamide (5 ml) at room temperature was added potassium carbonate (0.69 g), then iodomethane (97 μl). The mixture was stirred at room temperature for one hour. Water (30 ml) was then added, and the mixture was extracted with ether (50 ml, ×2). The combined organic layers were washed with water (30 ml, ×2), and evaporated. The residue was purified by column chromatography on silica gel (50 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p 160-161° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][C:20]=1[CH3:26]>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:21][C:20]=1[CH3:26]
Reactant: Cc1cc(S)ccc1Br
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: Cc1cc(SCCCCOc2ccc3c(c2)CCC(=O)N3)ccc1Br

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 4-bromo-3-methyl-thiophenol.
Reaction SMILES: C([O:3][C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:10]=1)[CH3:7])=[O:5])C.[OH-].[K+]>C(O)C>[C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:10]=1)[CH3:7])([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)Oc1ncn(-c2ccc(OC)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-n2cnc(OC(C)C(=O)O)n2)cc1

Procedure:
Four g of the compound of Example 8 was refluxed for 4 hours with 1.5 g of potassium hydroxide in 50 ml of ethanol, and the product was collected as shown in Example 22 and recrystallized from ethanol to obtain 2.6 g of the desired product, m.p. 155°-157°.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:6]2)[CH2:3][CH2:2]1.C([O:22][C:23](=[O:36])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34]Cl)=[CH:27][CH:26]=1)C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:34][CH2:33][CH2:32][O:31][C:28]4[CH:29]=[CH:30][C:25]([CH2:24][C:23]([OH:36])=[O:22])=[CH:26][CH:27]=4)[CH2:16][CH2:15]3)=[CH:6]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cc1ccc(OCCCCl)cc1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O=C(O)Cc1ccc(OCCCN2CCC(c3cn(CC4CC4)c4ccccc34)CC2)cc1

Procedure:
This compound was prepared following the procedure described in Example 157 (part D) starting with 1.5 g (6 mmol) of 1-cyclopropylmethyl-3-piperidin-4-yl-1H-indole, 2 g (6.6 mmol) of [4-(3-chloro-propoxy)-phenyl]-acetic acid ethyl ester, 1.7 g (12 mmol) of potassium carbonate and 1 g (6.15 mmol) of potassium iodide in 32 mL of iso-butylmethylketone. The crude mixture was purified by flash chromatography over silica gel affording 1.6 g (58% of yield) of the desired product.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH2:32][C:33]([N:35]([CH3:43])[C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)=[O:34])[CH3:31]>>[CH3:31][N:30]([CH2:32][C:33]([N:35]([C:36]1[CH:37]=[CH:38][C:39]([NH:42]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:40][CH:41]=1)[CH3:43])=[O:34])[CH3:29]
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: CN(C)CC(=O)N(C)c1ccc(N)cc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and N-dimethylaminomethylcarbonyl-N-methyl-p-phenylenediamine Rf value: 0.1 (silica gel, methylene chloride/ethanol=10:1) C29H30N4O4
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C@@H:33]2[C@:35]3([C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[NH:37][C:36]3=[O:44])[CH2:34]2)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)CCN>C(#N)C.[Cu]I>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C@H:33]2[C@@:35]3([C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]([C:2]4[N:3]=[CH:4][N:5]([C:7]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:6]=4)[C:36]3=[O:44])[CH2:34]2)=[CH:31][CH:32]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: O=C1N(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Temperature: 40 °C

Procedure:
4-iodo-1-trityl-1H-imidazole (210 mg, 0.48 mmol) was added to a suspension of (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (107 mg, 0.4 mmol) in acetonitrile (2 mL) under a nitrogen atmosphere. A steady stream of nitrogen was bubbled through the suspension as it was heated to 40° C. over 15 minutes. Potassium carbonate (110 mg, 0.8 mmol), copper (I) iodide (12 mg, 15 mol %), and N,N-dimethylethylenediamine (0.12 mmol, 30 mol %) were added and the reaction mixture was heated to 80° C. for 21 hours under nitrogen atmosphere. The mixture was cooled to room temperature, filtrated, and concentrated to give the title product. The residue was purified by flash column chromatography (gradient elution, 5-10% ethyl acetate in petroleum ether) to give racemic trans-2-(4-chlorophenyl)-1′-(1H-imidazol-4-trityl) spiro[cyclopropane-1,3′-indolin]-2′-one (157 mg, 68%). LC/MS m/e calcd. for C38H28ClN3O: 577, observed (M+H)+: 578.3.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]=[C:12]1[NH:17][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:15][C:14]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[C:13]1[CH:31]([CH2:36][CH2:37][CH3:38])[C:32]([O:34][CH3:35])=[O:33].[CH3:39]I.[Cl-].[NH4+]>CN(C=O)C>[CH3:39][N:17]1[C:12](=[O:11])[C:13]([CH:31]([CH2:36][CH2:37][CH3:38])[C:32]([O:34][CH3:35])=[O:33])=[C:14]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[N:15]=[C:16]1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCCC(C(=O)OC)c1c(-c2ccc(C)cc2)nc(N2CCCCC2)[nH]c1=O
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(-c2ccc(C)cc2)nc(N2CCCCC2)n(C)c1=O
Reaction time: 0.08 h

Procedure:
LHMDS (1M in THF; 2 eq) is added to a cold (−10° C.) stirred solution of methyl 2-(6-oxo-2-(piperidin-1-yl)-4-p-tolyl-1,6-dihydropyrimidin-5-yl)pentanoate (1 eq) in dry DMF (2 mL/mmol of the limiting reagent). After stirring for 5 minutes, methyl iodide (2 eq) is added and the reaction mixture is stirred at room temperature for 18 hours. A saturated solution of ammonium chloride is then added and the aqueous layer is extracted with ethyl acetate. The organic layer is dried over magnesium sulphate, filtered and evaporated to dryness. The crude material is purified by flash chromatography on silica gel to provide the methyl 2-(1-methyl-6-oxo-2-(piperidin-1-yl)-4-p-tolyl-1,6-dihydropyrimidin-5-yl)pentanoate which is deprotected following general method D yielding to the title compound.
Reaction SMILES: C1COCC1.[CH2:6]([NH:13][C@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@H:15]1[O:27][CH3:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+].Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>O>[CH2:6]([N:13]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][C@H:15]1[O:27][CH3:28])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N(Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 46.8 %

Procedure:
THF (16 mL) and water (4 mL) were added to tert-butyl cis(±)-4-benzylamino-3-methoxypiperidine-1-carboxylate obtained in Example (259a) (1.00 g, 3.1 mmol). While the mixture was stirred, saturated aqueous sodium bicarbonate solution (4 mL) and benzyl chloroformate (0.96 g, 5.6 mmol) were added at room temperature, followed by stirring overnight. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/9, 1/1) to obtain 0.66 g of the title compound as a colorless oily substance (58%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[NH:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].C(N)CN.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.C1(C)C=CC=CC=1>[NH2:4][C:3]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:2]=1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]
Reactant: O=C1CCCN1
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: NCCN
Product: Nc1cc(C(F)(F)F)ccc1N1CCCC1=O
Temperature: 80 °C

Procedure:
A resealable tube was charged with 2-bromo-5-(trifluoromethyl)aniline (1.00 g, 4.16 mmol), 2-pyrrolidinone (0.425 g, 5.00 mmol), N,N′-ethylene diamine (0.037 g, 0.42 mmol), potassium carbonate (1.15 g, 8.32 mmol), copper iodide (0.80 mg, 0.42 mmol) and toluene (1.0 mL). The tube was sealed and the mixture was heated at 80° C. for 24 h. The resulting mixture was partitioned between ethyl acetate and water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (gradient elution with 0-100% ethyl acetate-hexane) to afford 1-(2-amino-4-(trifluoromethyl)phenyl)pyrrolidin-2-one as a gray solid. MS m/z=245 [M+H]+. Calc'd for C11H11F3N2O: 244.
Reaction SMILES: [F-].[K+].[NH2:3][CH2:4][C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:15][CH:14]=2)[CH:6]=1.Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>CS(C)=O>[Cl:32][C:29]1[CH:28]=[N:27][C:26]([NH:3][CH2:4][C:5]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:19][S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:6]=2)=[N:31][CH:30]=1
Reactant: CNS(=O)(=O)Cc1ccc(Oc2cc(CN)nc(C)n2)cc1
Reactant: Clc1cnc(Cl)nc1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNS(=O)(=O)Cc1ccc(Oc2cc(CNc3ncc(Cl)cn3)nc(C)n2)cc1
Temperature: 120 °C

Procedure:
Add potassium fluoride (1.82 g, 31.33 mmol) to a solution of 1-[4-[6-(aminomethyl)-2-methyl-pyrimidin-4-yl]oxyphenyl]-N-methyl-methanesulfonamide (11.1 g, 24.10 mmol) and 2,5-dichloropyrimidine (4.31 g, 28.92 mmol) in DMSO (111 mL). Heat the reaction mixture at 120° C. for two hours. Thereafter cool the mixture to room temperature; add water (200 mL), and extract with EtOAc (3×200 mL). Combine the organic extracts; sequentially wash the organic extracts with water (300 mL) then brine (300 mL); dry over sodium sulfate; filter; and concentrate the filtrate under reduced pressure to provide title compound as a crude material. Purify the title compound using silica gel chromatography eluting with a gradient of hexane/EtOAc (1:1) to EtOAc (100%). Collect the relevant fractions containing the title compound and concentrate the fractions. Dissolve the resulting material in THF (200 mL) and EtOAc (300 mL), then add SiliaMetS® Thiol (9.2 g) to remove traces of palladium. Stir the mixture for 2 hr at 55° C. Filter the mixture at 55° C.; collect the filtrate; and evaporate the solvent to provide a solid. Triturate the solid with cold EtOAc (20 mL); collect the solid by filtration; and dry the solid under reduced pressure to provide the title compound as a white solid (8 g, 75%). MS (m/z): 435 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][N:25]=1)[CH3:22].[Cl-].[Li+]>O1CCOCC1.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH2:21][CH3:22])=[N:25][CH:26]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: CCOc1ccc([Sn](C)(C)C)cn1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CCOc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)4-(4-bromophenyl)oxazoline (VP4) (5.00 g, 14.8 mmol) was mixed with 2-ethoxy-5-trimethylstannylpyridine (VP8) (5.06 g, 17.8 mmol), Pd(PPh3)4 (0.68 g, 0.59 mmol) and lithium chloride (0.12 g, 2.9 mmol) in dioxane (40 ml) and the mixture was refluxed under nitrogen (7 hours). After extraction and chromatography, 2-(2,6-difluorophenyl)4-[4-(2-ethoxypyridin-5-yl)phenyl]oxazoline was obtained, 3.86 g, m.p. 119° C.; 1H NMR (CDCl3, ppm): 1.42, 4.35, OCH2CH3; 4.40, 4.84, 5.51, oxazoline; 6.79, 7.77, 8.36, pyridine; 7.00, 7.41, 7.54, phenyl.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:29]#[N:30])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:31]=[C:32](Br)[CH:33]=[N:34][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].ClCCl>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:29]#[N:30])=[C:18]([O:19][CH:20]4[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][OH:28])[CH2:24][CH2:25]4)[C:13]=3[C:12]3[CH:31]=[CH:32][CH:33]=[N:34][C:11]2=3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ncc2c(c1OC1CCN(CCO)CC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: ClCCl
Product: N#Cc1ncc2c(c1OC1CCN(CCO)CC1)c1cccnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.3 %

Procedure:
A suspension of 9-benzenesulfonyl-3-bromo-5-[1-(2-hydroxyethyl)-piperidin-4-yloxy]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (283 mg, 0.51 mmol) and palladium on carbon (10 wt %, 50 mg) in industrial methylated spirits (3 mL) and dichloromethane (3 mL) was stirred at ambient temperature under an atmosphere of hydrogen for 48 hours. The reaction vessel was purged with nitrogen then the reaction mixture was filtered through a PTFE filter cup. The filtrate was evaporated in-vacuo and the resultant residue purified by flash chromatography (silica, 24 g column, ISCO, 0-30% methanol in dichloromethane) to afford the title compound as an off-white solid (125 mg, 51%). 1H NMR (300 MHz, CDCl3): 9.59 (s, 1H), 8.76 (dd, J=4.9, 1.7 Hz, 1H), 8.54 (dd, J=7.9, 1.7 Hz, 1H), 8.27-8.26 (m, 2H), 7.62-7.61 (m, 1H), 7.56-7.44 (m, 3H), 5.04-5.03 (m, 1H), 3.70 (t, J=5.2 Hz, 2H), 3.09-3.09 (m, 2H), 2.69 (t, J=5.2 Hz, 2H), 2.51 (t, J=11.0 Hz, 2H), 2.32-2.25 (m, 2H), 2.12-2.10 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[H-].[Na+].[CH2:34](I)[CH2:35][CH3:36]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:12]([N:13]([CH:35]([CH3:36])[CH3:34])[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCCI
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4ccccc4nc3OC)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2CCN(C(=O)N(c3nc4ccccc4nc3OC)C(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To 1-[(2-methoxyquinoxalin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine (216 mg, 0.51 mmol) dissolved in dimethylformamide (20 ml), 60% sodium hydride (20.4 mg, 0.51 mmol) was added and stirred at room temperature for 15 minutes, and thereto propyl iodide (86.7 mg, 0.51 mmol) was added. The resulting mixture was stirred at room temperature for 6 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.