Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:17]4[S:18][C:19]([C:28]([NH2:30])=O)=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:21]=4)=[C:14]([CH3:16])[N:15]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:32]N.COC(OC)[N:37]([CH3:39])C>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:17]4[S:18][C:19]([C:28]5[N:30]=[CH:39][NH:37][N:32]=5)=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:21]=4)=[C:14]([CH3:16])[N:15]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc2ccc(C3CCCCC3)cn2c1-c1nc(-c2ccccc2)c(C(N)=O)s1
Reactant: COC(OC)N(C)C
Reactant: NN
Solvent: O
Product: Cc1nc2ccc(C3CCCCC3)cn2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A suspension of 2-(6-cyclohexyl-2-methylimidazo[1,2-a]pyridin-3-yl)-4-phenyl-1,3-thiazole-5-carboxamide (104 mg, 0.25 mmol) obtained above in N,N-dimethylformamide dimethylacetal (20 mL) was stirred at 100° C. for 12 h. The reaction mixture was allowed to cool to rt and then concentrated under reduced pressure. The residue was suspended in AcOH (5 mL), and then was added hydrazine monohydrate (70 μL, 1.4 mmol) at 0° C., and the mixture was stirred at 90° C. for 1 h, allowed to cool to rt, and then concentrated under reduced pressure. The residue was diluted with EtOAc (20 mL), water (10 mL) and saturated aqueous solution of sodium bicarbonate (10 mL), and the aqueous layer was extracted with a 2:1 mixture of EtOAc and THF (30 mL). The combined organic layers were dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]([NH:7]C1C=CC=CC=1)=[O:6].[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1.O>C1(C)C(C)=CC=CC=1>[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[C:4]([C:3](=[O:14])[CH:2]([CH3:15])[CH3:1])[C:5]([NH2:7])=[O:6])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)C(=O)CC(=O)Nc1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: CC(C)C(=O)C(=Cc1ccc(OCc2ccccc2)cc1)C(N)=O

Procedure:
Step A—A solution of 4-methyl-N-phenyl-3-oxopentanamide, 12, (5 mmol), 4-benzyloxybenzaldehyde (5 mmol) and pyridine (1 mL) in xylene (100 mL) is heated at reflux, with azeotropic removal of water. The progress of the reaction is monitored by tlc. When the reaction is complete, the solvent is removed under reduced pressure, and the residue is chromatographed to afford 2-(4-benzyloxyphenylmethylene)-4-methyl-3-oxopentanamide, 13, (R=4-benzyloxy).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[N:16]([O-])=O.[Na+]>CC(O)=O>[N+:13]([C:10]1[C:11]2[N:12]=[N:16][NH:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1)([O-:15])=[O:14]
Reactant: COC(=O)c1cc(N)c(N)c([N+](=O)[O-])c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc([N+](=O)[O-])c2nn[nH]c2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of methyl 3,4-diamino-5-nitrobenzoate (D245) (2.5 g, 12 mmol, 1 equiv) in AcOH (10 ml) at room temperature was added NaNO2 (900 mg, 13 mmol, 1.1 equiv) and the resulting mixture was stirred at 60° C. for 1 h, cooled to room temperature and concentrated in vacuo. the residue was partitioned between AcOEt and a 5% aqueous citric acid solution and the layers were separated. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. Trituration of the residue in Et2O/iso-hexane gave methyl 4-nitro-1H-1,2,3-benzotriazole-6-carboxylate (D246) (2.08 g, 78%) as an orange solid which was used in the next step without further purification. [M+H]+=223.3, RT=2.31 min.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH3:35])[CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH3:35])[CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: CCCOc1ccc2cc(C3(O)CCNCC3)ccc2c1
Product: CCCOc1ccc2cc(C3(O)CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)ccc2c1
Yield: 55.4 %

Procedure:
Beginning with 0.199 gm (1.1 mMol) (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 0.300 gm (1.1 mMol) 4-hydroxy-4-(6-propoxynaphth-2-yl)piperidine, 0.289 gm (60%) of the title compound were recovered as an off-white solid by the procedure described in Example 9.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)=[C:27]([Cl:40])[CH:26]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>O1CCCC1>[Cl:40][C:27]1[CH:26]=[C:25]([NH:24][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: O=C(OCCOCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCOCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.6 %

Procedure:
To a solution of 2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl benzoate (760 mg) in tetrahydrofuran (7.0 mL) was added 1N aqueous sodium hydroxide solution (7.0 mL), and the mixture was stirred at room temperature for 14 hrs. 1N Hydrochloric acid (7.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 min. and extracted with a mixed solvent (100 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer washed successively with 5% aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel column chromatography (eluent:ethyl acetate/methanol=100/0→90/10). The object fraction was concentrated under reduced pressure. A mixed solvent of ethanol/isopropyl ether (1/4) was added to the residue, and the mixture was heated to 80° C. and then allowed to cool to room temperature. The resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (431 mg) as white powder crystals.
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].Cl.[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH:18]3[N:19]4[CH2:29][CH2:28][N:27]=[C:20]4[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[N:17]3[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C(Cl)Cl.N1C=CC=CC=1>[ClH:5].[CH3:1][S:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH:18]3[N:19]4[CH2:29][CH2:28][N:27]=[C:20]4[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[N:17]3[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc(C2CCN3c4ccccc4C4=NCCN4C23)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(C2CCN3c4ccccc4C4=NCCN4C23)cc1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
6 ml of methylsulfonyl chloride were added dropwise at 0°-5° C. to a vigorously stirred suspension of 8.55 g of 2,3,5,6,7,8-hexahydro-5-(4-hydroxyphenyl)imidazo[1,2-c]pyrrolo[1,2-a]quinazoline hydrochloride in 100 ml of methylene chloride and 25 ml of pyridine, and the reaction mixture was stirred at room temperature for 70 h. The solvent was removed by distillation and then 1N HCl was added, and the resulting precipitate was recrystallized from ethanol/methyl t-butyl ether. Yield: 8.0 g (76%); melting point 241°-242° C. (decomposition).
Reaction SMILES: [CH2:1]([SiH:9]([CH3:11])[Cl:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:12]([Si:30]([CH:33]=[CH2:34])([CH3:32])[Cl:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[CH2:12]([Si:30]([CH3:32])([Cl:31])[CH2:33][CH2:34][Si:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH3:11])[Cl:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C=C[Si](C)(Cl)CCCCCCCCCCCCCCCCCC
Reactant: CCCCCCCC[SiH](C)Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC[Si](C)(Cl)CC[Si](C)(Cl)CCCCCCCC

Procedure:
Compound B (61.3 g) and 0.05M H2PtCl6, 0.04 mole percent of a chloroplantinic acid/ethyl acetate solution was stirred and heated at 50° to 60° while the 134 g of compound A was added over 45 minutes. The mixture was kept at 60° C. for an additional hour to yield 1-(octadecyl methylchlorosilyl)-2-(octyl methylchlorosilyl) ethane (compound C), as a pale-yellow oil. The analysis calculated for this product (C30H64Cl2Si2): C, 65.28; H, 11.69%. Elemental analysis showed: C, 65.80; H, 11.56%.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[O:21]1CCOCC1.[OH-].[Na+]>O>[NH2:3][C:4]1[C:5]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:21])=[O:1]
Reactant: C1COCCO1
Reactant: O=C1Cc2cccc(S(=O)(=O)c3ccc(Cl)cc3)c2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 6 h

Procedure:
A mixture of 2-oxo-7-(4-chlorophenylsulfonyl)indoline (3.3 g) and dioxane (20 ml) was added to a solution of sodium hydroxide (2.0 g) in water (20 ml), and the mixture was refluxed with stirring for 6 hrs. The reaction mixture was concentrated in vacuo, and the residue was dissolved in water. The aqueous solution was washed with diethyl ether, adjusted to pH 4 with 5% sulfuric acid and extracted with diethyl ether. The extract was washed with saline, dried over magnesium sulfate, treated with charcoal and then evaporated in vacuo to give 2-[2-amino-3-(4-chlorophenylsulfonyl)phenyl]acetic acid (2.8 g). mp 139°-141° C.
Reaction SMILES: [C:1]([CH:3]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[C:5]=1[O:14][CH3:15])#[N:2].N1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(OCC)C>[C:1]([CH:3]([N:16]1[CH2:21][CH2:20][N:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:18][CH2:17]1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[C:5]=1[O:14][CH3:15])#[N:2]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(C(C#N)N2CCNCC2)c(OC)c1OC
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)N1CCN(C(C#N)c2ccc(OC)c(OC)c2OC)CC1
Temperature: 25 °C

Procedure:
14.5 g. of N-(α-cyano-2,3,4-trimethoxybenzyl)piperazine was dissolved in 50 ml. of anhydrous diethyl ether and to the resultant solution was added 4 g. of pyridine. To the mixture was added dropwise 6 g. of ethyl chloroformate dissolved in 10 ml. of anhydrous diethyl ether over a period of about 30 minutes with ice cooling while the internal temperature was kept at 10° - 15°C. The mixture was further stirred at room temperature and filtered off to separate an insoluble matter. The filtrate was evaporated to give crude N-(α-cyano-2,3,4-trimethoxybenzyl)-N'-ethoxycarbonylpiperazine as an oily substance. This product was dissolved in toluene and the resultant solution was saturated with dry hydrochloric gas to separate crystal which was collected by filtration. Recrystallization from tetrahydrofuran-methanol afforded 14 g. of crystal having a melting point of 137.5° - 139.0°C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]([Br:24])(Br)Br.OC[C:27]1[O:28][C:29](=[O:44])[C:30]2[C:35]([C:36]=1[C:37]1[CH:38]=[C:39]([CH3:43])[CH:40]=[CH:41][CH:42]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2>CN(C=O)C>[Br:24][CH2:21][C:27]1[O:28][C:29](=[O:44])[C:30]2[C:35]([C:36]=1[C:37]1[CH:38]=[C:39]([CH3:43])[CH:40]=[CH:41][CH:42]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2
Reactant: Cc1cccc(-c2c(CO)oc(=O)c3ccccc23)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cccc(-c2c(CBr)oc(=O)c3ccccc23)c1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
Triphenylphosphine (270 mg, 1.030 mmol) and perbromomethane (342 mg, 1.030 mmol) were added to a solution of 3-(hydroxymethyl)-4-m-tolyl-1H-isochromen-1-one (intermediate B5, 211 mg, 0.792 mmol) in DMF (2 ml), and the resulting mixture was stirred at RT. The reaction was then purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 4.5%, formic acid 0.5%; Phase B ACN 99.5%, formic acid 0.5%) to give the title compound (192 mg, 73.6%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:18]1[C:23]([I:24])=[C:22]([CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1>[C:28]([O:27][CH:25]([C:22]1[N:21]=[CH:20][N:19]=[C:18]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:23]=1[I:24])[CH3:26])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)c1ncnc(Cl)c1I
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)c1ncnc(NCCc2ccccc2)c1I
Temperature: 60 °C

Procedure:
In 20 ml of toluene were dissolved 2-phenylethylamine (0.6 g) and triethylamine (0.6 g), then, 4-chloro-6-(1-acetoxy-ethyl)-5-iodopyrimidine (1.7 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: [ClH:1].[CH:2]1([C:8]2[CH:16]=[CH:15][C:11]([CH:12]([NH2:14])[CH3:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.C[CH:19]([NH2:34])[C:20]1C=[CH:24][C:23](CCC2C=CC=CC=2)=[CH:22][CH:21]=1>>[ClH:1].[CH:2]1([C:8]2[CH:9]=[CH:10][C:11]([CH:12]([N:14]=[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:34]3)[CH3:13])=[CH:15][CH:16]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Reactant: CC(N)c1ccc(C2CCCCC2)cc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccc(C2CCCCC2)cc1

Procedure:
Following essentially the same procedure described in Example IV above and substituting ρ-cyclohexyl-α-methylbenzylamine hydrochloride for the α-methyl-ρ-phenyethylbenzylamine hydrochloride above, results in the formation of 2-(ρ-cyclohexyl-α-methylbenzylimino)hexahydroazepine hydrochloride having a M.P. of 245°-7° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](Br)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].CO>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1cc(Br)c2ncccc2c1
Solvent: c1ccccc1
Solvent: CO
Product: Cc1cc(-c2cccc([N+](=O)[O-])c2)c2ncccc2c1
Yield: 98.6 %

Procedure:
To a mixture of 6-methyl-8-bromoquinoline (1.0 g), 3-nitrobenzene boronic acid (0.63 g), purchased from Lancaster Chemicals, 2M NaCO3 (1.9 mL), methanol (6.5 mL) and benzene 32 mL) was added palladium tetrakis triphenylphosphine (0.47 g) and heated to reflux for 6 hours. The progress of the reaction was monitored by thin-layer chromatography. Upon completion, the reaction mixture was cooled and the solvents removed. Ethyl acetate was added to the residue and the solution was filtered through a pad of Na2SO4. The solution was concentrated and the desired product was purified and isolated by preparative thin-layer chromatography yielding 6-methyl-8-(3-nitrophenyl)quinoline (983 mg) as a yellow oil. Characteristic analytical data are: elemental analysis [calculate (found)] C: 72.72 (72.63), H: 4.58 (4.32), and N: 10.60 (10.72).
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH2:46]([O:53][C:54](=[O:88])[NH:55][CH2:56][C:57]([N:59]1[CH2:63][CH:62]([C:64](=[O:76])[NH:65][C:66]2[C:75]3[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=3)[CH:69]=[CH:68][CH:67]=2)[CH:61]2[N:77]([C:80](=[O:87])[CH:81]([NH2:86])[C:82]([CH3:85])([CH3:84])[CH3:83])[CH2:78][CH2:79][CH:60]12)=[O:58])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN1C(=O)CCC1.CCOC(C)=O>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:9]([C:11](=[O:13])[NH:86][CH:81]([C:80]([N:77]1[CH2:78][CH2:79][CH:60]2[N:59]([C:57](=[O:58])[CH2:56][NH:55][C:54]([O:53][CH2:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[O:88])[CH2:63][CH:62]([C:64](=[O:76])[NH:65][C:66]3[C:75]4[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=4)[CH:69]=[CH:68][CH:67]=3)[CH:61]12)=[O:87])[C:82]([CH3:83])([CH3:84])[CH3:85])[CH3:10])[CH3:14])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)C(N)C(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)CNC(=O)OCc1ccccc1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)CNC(=O)OCc1ccccc1)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
A solution of Boc-N(Me)Ala-OH (152 mg, 0.74 mmol) in NMP (3 mL) was cooled to 0° C. and treated with HATU (313 mg, 0.83 mmol) followed by NMM (0.15 mL). After 10 min, 58 (450 mg) in NMP (2 mL) was added. The reaction mixture was allowed to warm to ambient temperature overnight. The solution was diluted with EtOAc, washed successively with 1M HCl, saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated. Purification by reverse phase HPLC (2″ Dynamax® C18, 10-70% ACN in H2O with 0.1% HOAc over 30 min) afforded 59 as a white solid (430 mg). Mass spectrum, m/z [771.3] (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:26]([C@@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[CH:26]([C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2CCCN2)cc1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCC[C@H]2C(c2ccccc2)c2ccccc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, (2S)-2-benzhydrylpyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 5.18 minutes; C34H30Cl2N4O2 (597.54); mass spectrum: (M−H)−=597/599/601 (chlorine isotope).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.O.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:20])=O>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:20])=[N:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Temperature: 130 °C

Procedure:
A suspension of 5-bromo-2-hydroxy-3-nitro-pyridine (10 g; ex. Maybridge) in phosphorus oxychloride (10 ml) was heated at 130° C. to give a red solution. The solution was heated at 130° C. for 2.5. The reaction mixture was poured onto iced water and then neutralised by the portionwise addition of solid sodium bicarbonate. The aqueous was extracted twice with ethyl acetate and the combined organics were dried (MgSO4), filtered and evaporated to give the title compound as a yellow solid (10.28 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][C:7](Br)=[O:8].[CH3:10][C:11]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:12]=1[NH:13][C:14](=[O:16])[CH3:15]>C(=S)=S>[Br:5][CH2:6][C:7]([C:19]1[C:18]([CH3:21])=[CH:17][C:12]([NH:13][C:14](=[O:16])[CH3:15])=[C:11]([CH3:10])[CH:20]=1)=[O:8]
Reactant: CC(=O)Nc1cc(C)ccc1C
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1cc(C)c(C(=O)CBr)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of aluminum chloride (13.4 g) in carbon disulfide (68 ml) was added bromoacetyl bromide (8.8 ml) under ice-cooling, and the mixture was stirred for 30 minutes. 2′,5′-Dimethylacetanilide (5.57 g) was added to the stirred mixture, and the mixture was heated under reflux for 12 hours. After cooling, the reaction mixture was poured into ice-water, and the resulting precipitate were collected by filtration and washed with water. The cake was dissolved in ethyl acetate, and the solution was dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was washed with diethyl ether to give 4′-(2-bromo-acetyl)-2′,5′-dimethylacetanilide (5.65 g).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH2:18])=[NH:17])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[OH-].[Na+].[CH:21](O)([CH3:23])[CH3:22]>>[Cl:1][C:22]1[N:6]=[CH:9][C:10]([C:11]2[CH:12]=[CH:13][N:18]=[C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([N:6]4[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]4)=[CH:14][CH:13]=3)[N:17]=2)=[CH:23][CH:21]=1
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2)CC1
Reactant: Cl
Reactant: CC(C)O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(c2ccc(Nc3nccc(-c4ccc(Cl)nc4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33 %

Procedure:
4.22 g 1-(6-Chloro-pyridin-3-yl)-3-dimethylamino-propenone (20 mmol) was dissolved in 100 mL isopropanol, 5.92 g N-[4-(4-Methyl-piperazin-1-yl)-phenyl]-guanidine hydrochloride (20 mmol) and 0.96 g sodium hydroxide (24 mmol) were added and heated at reflux for 18 h. The mixture was allowed to cool to room temperature and stirred at room temperature for three days. The yellow-green precipitate was filtered to give [4-(6-Chloro-pyridin-3-yl)-pyrimidin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (2.50 g, Y=33%). Purity: 94% (LCMS); 1H NMR (400 MHz, DMSO-d6) δ ppm 9.49 (s, 1H), 9.14 (d, J=2.5 Hz, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.52 (dd, J=8.5, 2.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.41 (d, J=5.3 Hz, 1H), 6.91 (d, J=9.0 Hz, 2H), 3.03-3.10 (m, 4H), 2.42-2.47 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[C:23]3[CH:33]=[CH:32][C:31]([CH3:34])=[N:30][C:24]=3[N:25]([CH2:28][CH3:29])[CH2:26][N:27]=2)[CH:19]=[CH:20][CH:21]=1.C(=O)(O)[O-].[Na+]>ClCCCl>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[C:23]3[CH:33]=[CH:32][C:31]([CH3:34])=[N:30][C:24]=3[N:25]([CH2:28][CH3:29])[C:26](=[S:2])[N:27]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CCN1CN=C(c2cccc(Cl)c2)c2ccc(C)nc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCn1c(=S)nc(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 25 °C
Yield: 54 %

Procedure:
Diphosphorus pentasulfide (3.00 g, 13.5 mmol) was added to a solution of 2.00 g (6.69 mmol) of 4-(3-chlorophenyl)-1-ethyl-7-methylpyrido[2,3-d]pyrimidine in 100 ml of 1,2-dichloroethane, followed by heating under reflux for 6 hours. The reaction solution was cooled to room temperature, mixed with saturated sodium bicarbonate and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-chloroform) and further recrystallized from ethyl acetate-diisopropyl ether to give 1.14 g of 4-(3-chlorophenyl)-1-ethyl-7-methylpyrido[2,3-d]pyrimidin-2(1H)-thione. The yield was 54%.