Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.[CH2:20]([O:27][CH:28]1[CH2:31][CH:30]([NH2:32])[CH2:29]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(N(C)C)=O.CCOC(C)=O>[S:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[NH:32][C@H:30]1[CH2:31][C@@H:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:29]1
Reactant: Clc1nc2ccccc2s1
Reactant: NC1CC(OCc2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: c1ccc(CO[C@H]2C[C@@H](Nc3nc4ccccc4s3)C2)cc1
Temperature: 130 °C

Procedure:
A mixture of N-ethyl-N-isopropylpropan-2-amine (3 g, 24 mmol), 2-chlorobenzo[d]thiazole (2.0 g, 12 mmol), and 3-benzyloxy-cyclobutylamine (2.08 g, 12 mmol) in DMA (20 mL) was heated to 130° C. for 20 h. Then it was cooled to RT and diluted with EtOAc (50 mL). The mixture was washed with water (2×25 mL), brine (25 mL), dried over MgSO4, filtered, and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography (0 to 30% EtOAc/hexane gradient) to give two products as a white solid.
Reaction SMILES: CCN(CC)CC.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]2[O:29][C:26]([CH3:28])([CH3:27])[C:23]([CH3:25])([CH3:24])[O:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[CH3:27][C:26]1([CH3:28])[C:23]([CH3:24])([CH3:25])[O:22][B:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:11]([CH:8]3[CH2:10][CH2:9]3)=[O:12])=[CH:16][CH:17]=2)[O:29]1
Reactant: O=C(Cl)C1CC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NC(=O)C3CC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
Et3N (239 μL, 1.71 mmol) and cyclopropanecarbonyl chloride (114 μL, 1.26 mmol) were added to a solution of 4-aminophenylboronic acid pinacol ester (250 mg, 1.14 mmol) in DCM (5 mL) at 0° C. After stirring the mixture for 4 hours at room temperature, the mixture was concentrated. The residue was diluted with EtOAc and washed with 10% aqueous citric acid, sat. NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=9:1→4:1) to afford desired product (291 mg, 88.9%) as white solid. 1HNMR (CDCl3) 400 MHz δ: 7.82-7.70 (m, 2H), 7.59-7.47 (m, 2H), 7.43 (br s, 1H), 1.54-1.44 (m, 1H), 1.33 (s, 12H), 1.09 (dt, J=7.4, 4.2 Hz, 2H), 0.85 (td, J=7.4, 4.2 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:11].[H-].[Na+].I[CH3:15]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:15])=[CH:4][C:3]=1[F:11]
Reactant: Fc1cc2cc[nH]c2cc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(F)c(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To the solution of 6-bromo-5-fluoro-1H-indole (0.92 g, 4.28 mmol) in dry DMF (10 mL) was added sodium hydride as 60% in oil (0.26 g, 6.41 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, and then iodomethane (0.32 mL, 5.14 mmol) was added. The mixture was stirred for 1 hour at room temperature, and then quenched with ice and extracted with EtOAc (50 mL). The organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (EtOAc-hexane, 1:9) give 6-bromo-5-fluoro-1-methyl-1H-indole as a colorless solid (0.97 g, 99%). 1H NMR (CDCl3, 400 MHz): 3.66 (s, 3H), 6.43 (d, J=2.7 Hz, 1H), 7.05 (d, J=2.7 Hz, 1H), 7.34 (d, J=9.3 Hz, 1H), 7.44 (d, J=5.4 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:23]([F:26])([F:25])[F:24])=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:23]([F:26])([F:25])[F:24])=[C:13]2[C:17]=1[N:16]([CH3:29])[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCc3ccccc3)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCc3ccccc3)c2n1C

Procedure:
The reaction was carried out in a manner similar to Reference Example 18 a) except for using 8.00 g (22.0 mmol) of ethyl 7-benzyloxy-4-trifluoromethyl-2-indolecarboxylate, 0.88 g (22.0 mmol) of 60% sodium hydride, 6.25 g (44.0 mmol) of methyl iodide and 150 ml of dimethylformamide. Ethyl 7-benzyloxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate was thus obtained in the yield of 7.40 g (89.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[C:11](/[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)=[N:12]/[S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)[NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14]
Reactant: COc1ccc(/C(=N/S(=O)C(C)(C)C)c2cccc(C)n2)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(NS(=O)C(C)(C)C)c2cccc(C)n2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
The product of Step B (2.41 g, 6.69 mmol) was dissolved in MeOH (60 mL), cooled to 0° C., and NaBH4 (0.51 g, 13.37 mmol) was added portionwise. The reaction was aged for 45 min and was quenched with saturated aq NH4Cl. The reaction was concentrated. The resulting paste was diluted in EtOAc and washed with brine. The organic portion was isolated, dried with Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0 to 100% EtOAc/hexane, affording a mixture of two diastereomers.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]([OH:10])=[O:9])[C@H:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:16](OC(OC)=O)(OC)=O>CO>[O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]([O:10][CH3:16])=[O:9])[C@H:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC[C@H]1C(=O)CC[C@H]1CC(=O)O
Reactant: COC(=O)OC(=O)OC
Solvent: CO
Product: CCCCC[C@H]1C(=O)CC[C@H]1CC(=O)OC
Yield: 90 %

Procedure:
104 Mg (0.49 mmole) of (+)-cis-3-oxo-2-pentyl-1-cyclopentaneacetic acid (97:3 cis/trans ratio) in 0.5 ml of methanol were treated with 76 μl of dimethyl dicarbonate [CH3O(CO)O(CO)OCH3, origin: Bayer; 96 mg, 0.72 mmole, 1.5 eq.]. The resulting solution was heated to 45° during 16 h and then evaporated under vacuum. After distillation of the residue in a bulb-to-bulb apparatus (oven t. 150°/10 Pa), there were obtained 100 mg (0.44 mmole, yield 90%) of pure methyl (±)cis-3-oxo-2-pentyl-1-cyclopentaneacetate (97:3 cis/trans ratio).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])=[CH:4][CH:3]=1.CS(O[CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:39]([O:38][C:37]([NH:36][CH2:35][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=2)[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])=[O:11])=[CH:4][CH:3]=1)=[O:43])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: CC(C)c1ccc(O[C@@H](Cc2ccc(O)cc2)C(=O)OCC[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)c1ccc(O[C@@H](Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2)C(=O)OCC[Si](C)(C)C)cc1
Yield: 91.2 %

Procedure:
In a similar manner to that described in Reference example 25, a reaction was carried out using 2-trimethylsilylethyl (S)-3-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)propionate (4.80 g), which is the product of Reference example 29(e), t-butyl 2-methanesulfonyloxyethylcarbamate (7.17 g) and potassium carbonate (8.28 g) and the reaction mixture was treated to afford the desired compound (5.94 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C@H:9]([CH3:12])[CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[F:13].[F-].[Cs+].[CH2:16]([Sn](CCCC)(CCCC)C=C)[CH2:17]CC>O1CCOCC1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[F:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C@H:9]([CH3:12])[CH2:10][CH3:11])=[CH:7][C:2]=1[CH:16]=[CH2:17]
Reactant: CC[C@@H](C)Oc1ccc(F)c(Cl)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=Cc1cc(O[C@H](C)CC)ccc1F
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-1-fluoro-4-{[(1R)-1-methylpropyl]oxy}benzene (1.75 g, 8.64 mmol) in dioxane (28.8 ml) under argon were added bis(tri-t-butylphosphine) palladium(0) (0.221 g, 0.432 mmol) and cesium fluoride (2.89 g, 19.0 mmol). Argon was bubbled through the reaction for 2 min. To the reaction was added tributyl (vinyl) tin (3.03 ml, 10.4 mmol) and the argon bubbled for another 5 min. The reaction was sealed and heated to 100° C. overnight. The reaction was partitioned between H2O and EtOAc. The aqueous phase was extracted with EtOAc (3 times). The combined organics were dried with MgSO4, filtered, and concentrated. The residue was purified by column chromatography on a silica gel cartridge (0% EtOAc/hexanes to 4% EtOAc/hexanes) to give the desired product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH3:9].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Cl-].[Na+]>ClCCl>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:1][CH2:2][CH2:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH3:9]
Reactant: Cc1ncsc1CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncsc1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
2.09 ml of 5-(2-hydroxyethyl)-4-methylthiazole 93 is introduced into 150 ml of dichloromethane, 7.8 ml of 2,3-dihydropyran and 400 mg of pyridinium-p-toluenesulfonate are added, and it is stirred for 5 days at room temperature. Then, sodium chloride solution is added, extracted with ethyl acetate, the organic phase is washed with sodium bicarbonate solution and sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 3.8 g of 5-[2-[(tetrahydro-2H-pyran-2-yl)oxy]ethyl]-4-methylthiazole 94 is obtained as a colorless oil.
Reaction SMILES: [CH2:1]([PH:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].CN([CH2:13][C-:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19]N(C)C)C.[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28]>C(O)(=O)C>[CH2:1]([P:5]([CH2:13][C-:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][P:5]([CH2:6][CH:27]([CH3:26])[CH3:23])[CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28]
Reactant: CC(C)CPCC(C)C
Reactant: CN(C)Cc1ccc[c-]1CN(C)C
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Product: CC(C)CP(Cc1ccc[c-]1CP(CC(C)C)CC(C)C)CC(C)C

Procedure:
The title compound was prepared in accordance with the procedure of Example 10 employing di-iso-butylphosphine (Strem 486 mg, 3.33 mmol), 1,2-bis(dimethylaminomethyl)ferrocene (0.5 g, 1.66 mmol) and anhydrous acetic acid (100 ml). Yield 0.372 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[NH:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[NH:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1c[nH]c(Sc2ccc(Cl)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Sc2ccc(Cl)cc2)c1

Procedure:
Methyl 5-(4-chlorophenylthio)pyrrole-3-carboxylate (1.4 g.) was combined with 20 ml. of methanol and 20 ml. of 1 N sodium hydroxide and heated on a steam bath for 2 hours. The reaction was cooled, acidified with conc. hydrochloric acid. and the crude product which precipitated, collected by filtration. Two recrystallizations from acetone/hexane afforded purified 5-(4-chlorophenylthio)pyrrole-3-carboxylic acid (740 mg., m.p. 171°-173° C.).
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=2)[CH:14]=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][C:18]#[N:19]>>[CH:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:16]=[C:13]([CH:14]([OH:15])[CH2:17][C:18]#[N:19])[CH:12]=[N:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cncc(/C=C/C2CCCCC2)c1
Reactant: CC#N
Product: N#CCC(O)c1cncc(/C=C/C2CCCCC2)c1

Procedure:
Addition of CH3CN to (E)-5-(2-cyclohexylvinyl)nicotinaldehyde following the method used in Example 3 gave (E)-3-(5-(2-cyclohexylvinyl)pyridin-3-yl)-3-hydroxypropanenitrile as a yellow oil. Yield (0.9 g, 95%); 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.41 (s, 1H), 7.93 (s, 1H), 6.42 (s, 2H), 5.05 (t, J=5.6 Hz, 1H), 2.98-2.82 (m, 2H), 2.24-2.12 (m, 1H), 1.88-1.66 (m, 5H), 1.42-1.18 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[CH2:11]([NH2:14])[CH2:12][CH3:13]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:14][CH2:11][CH2:12][CH3:13])[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CCCN
Solvent: C1CCOC1
Product: CCCNc1ccc(C#N)cc1Cl
Temperature: 50 °C
Yield: 93.8 %

Procedure:
Step AR1. A mixture of 3-chloro-4-florobenzonitrile (312 mg, 2 mmol) and propylamine (236 mg, 4 mmol) in THF (4 mL) was heated at 50° C. overnight. After the solvent was removed, the residue was purified by flash chromatography with DCM to give 3-chloro-4-(propylamino)benzonitrile (365 mg, 94%).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[CH2:33][O:32][CH2:31][CH2:30][NH:29]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[CH2:33][O:32][CH2:31][CH2:30][N:29]4[C:37](=[O:38])[CH2:36][N:35]([CH3:40])[CH3:34])[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c(CC3COCCN3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCOCC1Cc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-(morpholin-3-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.23 mmol), N,N-dimethylglycine (25 mg, 0.24 mmol), EDCl (48 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol), and N,N-diisopropylethylamine (119 μL, 0.68 mmol) in DMF (1.2 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 50 mg (42%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.52-8.57 (m, 1 H), 7.88-7.96 (m, 1H), 7.76-7.84 (m, 1 H), 7.48-7.55 (m, 1 H), 7.26-7.39 (m, 5 H), 7.04-7.11 (m, 1 H), 6.58-6.63 (m, 1 H), 5.64 (s, 2 H), 4.43-4.89 (m, 1 H), 3.69-4.12 (m, 3 H), 3.24-3.57 (m, 4 H), 3.09-3.23 (m, 1 H), 2.72-2.99 (m, 1 H), 2.15-2.27 (m, 1 H), 1.88-1.99 (m, 6H); ES-MS m/z 525.15 [M+H]+, HPLC RT (min) 2.17.
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[CH3:21])[CH2:6]1)C.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[NH:37])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:21][C:13]1[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=1[N:7]1[CH2:8][CH2:9][C:10]2[N:37]=[C:36]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[CH:34][CH:33]=3)[N:38]=[CH:4][C:5]=2[CH2:6]1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCC(=O)C(=CN(C)C)C1
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2C1
Temperature: 25 °C

Procedure:
To a solution of 3-Dimethylaminomethylene-1-(2-methyl-5-nitrophenyl)-piperidin-4-one (12.06 gm, 41.7 mmol)[as prepared in reference 1] in Ethanol (250 ml) were added N-[4-(4-Methyl-piperazin-1-yl)-phenyl]-guanidine (38.9 gm, 167 mmol) and sodium acetate (27.32 gm, 334 mmol) and solution was heated under reflux for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was washed with brine, dried [sodium sulfate] and concentrated under vacuum. The crude product obtained was further purified by silica gel chromatography using 5-10% Methanol/Chloroform as eluent to give pure desired product [47] i.e., [6-(2-Methyl-5-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as yellow solid. (Yield: 3.65 gm, 19.0%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:33])[C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])=[CH:14][C:13]=2[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:6][CH:5]=1.CO>[Pd].C1COCC1>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:33])[C:12]2[CH:17]=[C:16]([NH2:18])[C:15]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])=[CH:14][C:13]=2[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:6][CH:5]=1
Reactant: CC(C)(O)CNc1cc(N2CCOCC2)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)CNc1cc(N2CCOCC2)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1N
Reaction time: 8 h

Procedure:
A mixture of N-(4-trifluoromethoxyphenyl)-2-(morpholinyl)-4-(2-hydroxy-2-methyl-propylamino)-5-nitro-benzoic acid amide (100 mg, 0.20 mmol), Pd/C (50 mg), MeOH (3.5 mL) and THF (10 mL) is stirred under 4 bar H2-atmosphere overnight. The mixture is filtered, and the filtrate is concentrated. Yield: 94 mg. HPLC Rt=1.36 min (method H). MS m/z: 468 [M+H]+.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21](OCC)=[O:22])[CH:14]=1.Cl>CCCCCC.O1CCCC1>[O:22]=[C:21]([CH2:20][O:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: CCOC(=O)COc1cccnc1
Reactant: COP(C)(=O)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)COc1cccnc1)OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyl-lithium (4.76ml. of a 2.1M solution in hexane) was added to a solution of dimethyl methylphosphonate (1.24g.) in dry tetrahydrofuran at -78° C. in an atmosphere of nitrogen. After 10 minutes, a solution of ethyl 3-pyridyloxyacetate (0.90g.) in dry tetrahydrofuran (5ml.) was added dropwise, and the mixture was stirred for 1 hour at -78° C. The reaction mixture was taken to pH 1-2 with 2N hydrochloric acid and the solvents were removed under reduced pressure. The residue was shaken with water (10ml.) and extracted with ether (3 × 10ml.). The extracts were discarded, and the aqueous solution was adjusted to pH 7-8 with sodium bicarbonate solution and extracted with chloroform (6 × 10ml.). The combined extracts were evaporated, to give dimethyl [2-oxo-3-(pyrid-3-yloxy)propyl]phosphonate as an oil, RF = 0.2 (10% methanol in ethyl acetate).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14].[CH2:15](S)C.[OH-].[K+]>>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:11])([CH3:10])[CH3:12])=[N:5][N:4]=[C:3]1[S:13][CH2:14][CH3:15]
Reactant: CSc1nnc(C(C)(C)C)c(=O)n1N
Reactant: CCS
Agent: [K+]
Agent: [OH-]
Product: CCSc1nnc(C(C)(C)C)c(=O)n1N
Temperature: 10 °C

Procedure:
A mixture of 230 g (1 mole of 93% active ingredient) of 4-amino-6-t-butyl-3-methylthio-1,2,4-triazin-5-one and 310 g (5 moles) of ethyl mercaptan and 0.5 g of crushed solid KOH was stirred and refluxed onto a 10° C. condenser. The vapors which pass through the condenser (methyl and ethyl mercaptans) were collected in a dry ice or caustic trap. The reaction was continued until thin layer chromatography indicated that the starting material was gone (usually 2-8 hours). The unreacted ethyl mercaptan was then distilled off while ~600 ml of warm (40° C.) water was added at such a rate that the water addition was complete when ~2/3 of the mercaptan had distilled. Distillation was continued until ~100 ml of water distilled at 100° C. The solution was then allowed to cool with rapid stirring. The product crystallized at 60°14 70° C. and at 20° C. was filtered and washed with water, then dried. The final product, 4-amino-6-t-butyl-3-ethylthio-1,2,4-triazin-5-one, was obtained in nearly quantitative yield and contained less than 1% of the starting 3-methylthio compound.
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([F:13])[CH:5]=1)([OH:3])[OH:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[F:13][C:6]1[CH:5]=[C:4]([B:1]([OH:2])[OH:3])[CH:12]=[CH:11][C:7]=1[C:8]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:10]
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccc(B(O)O)cc1F)N1CCOCC1
Yield: 90 %

Procedure:
A solution of 4-borono-2-fluorobenzoic acid (1.000 g, 5.44 mmol), morpholine (0.951 mL, 10.87 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.103 g, 5.53 mmol) in DMF (10 mL) was stirred at room temperature for 16 h and quenched with 1 N HCl (20 mL). Attempted extraction with EtOAc did not remove all of the product from aqueous phase. The two phases were combined, concentrated and purified by reverse phase HPLC (Sunfire S10 30×250 mm column, 30-45% solvent B gradient) to give the expected product as white solid (1.2385 g, 90% yield). MS (ES+) m/z: 254 (M+H); LC retention time: 2.06 min (analytical HPLC Method A).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:8]([O:19][CH2:20][CH2:21][OH:22])=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH:6]=1)C.[CH2:32]([NH2:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[CH2:32]([NH:44][C:4](=[O:3])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:8]([O:19][CH2:20][CH2:21][OH:22])=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH:6]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCOC(=O)c1cc(-c2cccc(OC)c2)c(OCCO)c(-c2cccc(OC)c2)c1
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCNC(=O)c1cc(-c2cccc(OC)c2)c(OCCO)c(-c2cccc(OC)c2)c1
Yield: 66.1 %

Procedure:
In a manner similar to Example 1, Step 2, the title compound (0.386 g, 65%) was prepared from 3.5-bis-(3-methoxyphenyl)-4-(2-hydroxyethoxy) benzoic acid ethyl ester (0.44 g, 1.04 mmol) and dodecylamine (0.676 g, 3.65 mmol), 1H NMR (CDCl3) δ 7.75 (s, 2H), 7.38 (m, 2H), 7.19 (m, 4H), 6.94 (m, 2H), 6.21 (t, 1H), 3.85 (s, 6H), 3.41 (m, 4H), 3.28 (m, 2H), 1.60 (m, 2H), 1.23 (m, 18H), 0.85 (t, 3H).