Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)[C:2]#[CH:3]>FC(F)(F)C(O)=O.O>[CH2:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[C:2]#[CH:3]
Reactant: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C#CCN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
tert-Butyl 4-propargylpiperazine-1-carboxylate of step 2(ii) above (570 mg, 2.545 mmol) was dissolved in trifluoroacetic acid (10 ml) and water (2.5 ml). The mixture was then stirred at room temperature overnight. The solution was evaporated to dryness in vacuum. The residue was dissolved in water (10 ml) and then basified with Na2CO3 (pH 11), and extracted with Et2OAc (3×50 ml). The organic layer was washed with brine (2×50 ml) and dried over Na2SO4 overnight. Evaporation in vacuum gave N-propargylpiperazine (D7) as white solid. (crude, 193 mg, 62% yield). H1 NMR (250 MHz, CDCl3) 1.64 (s, 1NH), 2.26 (m, 1H), 2.55 (dd, J=4.73, 4.50 Hz, 4H), 2.93 (dd, J=4.96, 4.84 Hz, 4H), 3.29 (d, J=2.44 Hz, 2H).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([CH3:15])[C:3]1=[O:16].[C:17]([NH:24][C@H:25]([C:29](O)=[O:30])[CH2:26][CH2:27][CH3:28])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[C:20]([O:19][C:17]([NH:24][C@H:25]([C:29]([C:2]1([NH2:1])[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([CH3:15])[C:3]1=[O:16])=[O:30])[CH2:26][CH2:27][CH3:28])=[O:18])([CH3:22])([CH3:23])[CH3:21]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1C(=O)C(N)C(=O)N(C)c2ccccc21
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)C1(N)C(=O)N(C)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D using the product from Example 4-R, Step C and Boc-L-norvaline (BACHEM) the title intermediate was prepared. HPLC purification eluting with EtOAc/Hexanes (60:40) afforded the title intermediate as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([CH2:27][CH2:28][CH2:29][CH3:30])[C:15]1=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([CH2:27][CH2:28][CH2:29][CH3:30])[C:15]1=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: CCCCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(Cl)nc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)nc21
Yield: 80.8 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-benzyloxy-1-butyl-7-chloro-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example O-2, 0.16 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) in 20 mL of acetonitrile. The solution was warmed to reflux for 17 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.14 g of the title compound as a solid
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]([NH2:13])=[N:11][C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:9]2)[CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C>C1COCC1>[N:21]1([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:10]3[N:11]=[C:12]([NH2:13])[N:8]([C:4]4[CH:3]=[C:2]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[N:7]=[CH:6][N:5]=4)[N:9]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: Nc1nc(Nc2ccc(N3CCOCC3)cc2)nn1-c1cc(Cl)ncn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Nc2ccc(N3CCOCC3)cc2)nn1-c1cc(N2CCNCC2)ncn1
Yield: 64 %

Procedure:
A mixture of 1-(6-chloro-pyrimidin-4-yl)-N3-(4-morpholin-4-yl-phenyl)-1H-[1,2,4]triazole-3,5-diamine (0.11 g, 0.30 mmol), piperazine ((0.26 g, 3.0 mmol), and di-iso-propylethylamine (0.21 mL) in THF (100 mL) was stirred at reflux for 3 d, then cooled and evaporated. Purification by semi-preparative HPLC provided the title compound (0.13 g, 64% yield) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([CH3:19])[C:5]([NH:7][C:8]1[CH:12]=[C:11]([C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH3:16])[O:10][N:9]=1)=[O:6].[OH-].[K+]>O.C(O)C>[CH3:17][C:13]([C:11]1[O:10][N:9]=[C:8]([N:7]2[CH2:2][CH2:3][CH:4]([CH3:19])[C:5]2=[O:6])[CH:12]=1)([CH3:18])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(C)(C)c1cc(NC(=O)C(C)CCCl)no1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC(C)(C)c1cc(N2CCC(C)C2=O)no1
Yield: 20 %

Procedure:
1-[5-(1,1-Dimethylbutyl)-3-isoxazolyl]-3-methyl-2-pyrrolidinone was prepared by reacting 17.2 g of 4-chloro-N-[5-(1,1-dimethylbutyl)-3-isoxazolyl]-2-methylbutanamide with 6.72 g of potassium hydroxide in 30 ml water and 75 ml ethanol by the general method of Example 3. Weight 4 g (Yield 20%). mp 30°-31° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[S:15][CH2:14][CH2:13][CH2:12]2.C(N(CC)C(C)C)(C)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>C(#N)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[S:15][CH2:14][CH2:13][CH2:12]3)[CH2:36][CH2:35]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: BrCCCCOc1cccc2c1SCCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCCOc2cccc3c2SCCC3)CC1

Procedure:
1.5 g (4.98 mmol) of the compound obtained in Step A are dissolved in 15 cm3 of acetonitrile, under argon. 0.94 g (7.47 mmol) of N,N-diisopropylethylamine diluted in 11 cm3 of acetonitrile is added, followed by 1.44 g (0.747 mmol) of 1-(2-methoxyphenyl)piperazine dissolved in 11 cm3 of acetonitrile.
Reaction SMILES: [C:1]([C:4]1[NH:8][C:7]([CH3:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Br:11]Br>Br>[CH3:9][C:7]1[NH:8][C:4]([C:1](=[O:3])[CH2:2][Br:11])=[C:5]([CH3:10])[N:6]=1
Reactant: CC(=O)c1[nH]c(C)nc1C
Reactant: BrBr
Agent: Br
Product: Cc1nc(C)c(C(=O)CBr)[nH]1
Yield: 71.3 %

Procedure:
A solution of 1.0 g (7.24 mmol) of 5-acetyl-2,4-dimethylimidazole in 15 ml of concentrated hydrobromic acid was warmed to 50° and 1.16 g (7.25 mmol) of bromine was added dropwise over 1 minute. The mixture was then heated at 50°-60° for 1 hour. The mixture was concentraed and the solid residue was triturated with 30 ml of saturated sodium bicarbonate solution. The insoluble material was collected by filtration, washed with water, and dried in vacuo to give 1.12 g (71%) of 1-(2,4-dimethyl-5-imidazolyl)-2bromoethanone as a white solid, mp 128°-132° . nmr (D6DMSO) (δ): 4.40 (s, 2H); 2.27 (s, 3H); 2.13 (s, 3H).
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](I)[CH2:29][CH3:30]>CC(C)=O>[CH2:1]([N:9]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[CH2:28][CH2:29][CH3:30])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(CCNCCc2ccccc2)cc1OC
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN(CCc1ccccc1)CCc1ccc(OC)c(OC)c1

Procedure:
A solution of 8 g of N-phenethyl-3,4-dimethoxyphenethylamine, 8 g of anhydrous potassium carbonate, 11 ml of propyl iodide and 80 ml of acetone was refluxed for 6 hours and the mixture was filtered. The filtrate was evaporated to dryness and the residue was taken up in 50 ml of water. The solution was extracted with methylene chloride and the organic extracts were washed with water, dried over magnesium sulfate, filtered and evaporated to dryness to obtain 9.37 g of raw N-phenethyl-N-propyl-3,4-dimethoxyphenethylamine in the form of an oil which was used as is for the next step.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([O-:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20].[K+].CC(C)([O-])C.[K+]>C1COCC1>[F:11][C:12]1[CH:18]=[CH:17][C:15]([O:16][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: [O-]c1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Oc2ccc(F)c(C(F)(F)F)c2)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium 4-fluoro-3-trifluoromethyl-phenoxide (2.2 mmol) in THF (may be generated by adding the corresponding alcohol to a 1M solution of potassium t-butoxide in THF) was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the reaction mixture was treated with cold H2O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product could be used directly for further transformation.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:17][CH3:18])=[O:4].[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C=O)C>[N:19]([CH2:2][C:3]([C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:17][CH3:18])=[O:4])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(OC)c(C(=O)CBr)c(OC)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)c(C(=O)CN=[N+]=[N-])c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-(bromoacetyl)-3,5-dimethoxybenzoate was dissolved in DMF, sodium azide (96 mg) was added to it, and stirred at room temperature for 1 hour. The reaction liquid was poured into water, extracted with ethyl acetate, the organic layer was washed with water and saturated saline water, and dried with sodium sulfate. Sodium sulfate was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40) to obtain the title compound.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([Si](C(C)(C)C)(C)C)[CH:18]=1)(O)[CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:9]12[NH:8][CH:13]([CH2:14][CH2:15]1)[CH2:12][C:11]([C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[CH:10]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1cn([Si](C)(C)C(C)(C)C)c3ccccc13)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2c[nH]c3ccccc23)CC2CCC1N2
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
To 1.25 g (2.74 mmol) tert-butyl-3-{1-[tert-butyl(dimethyl)silyl]-1H-indol-3-yl}-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate in 25 mL CH2Cl2 is added 6 mL of TFA. After stirring at 23° C. for 45 min, the reaction mixture is poured into sat. aqueous NaHCO3 (300 mL) and extracted with 3×50 mL CH2Cl2. The combined organics are washed with 1×100 mL H2O, 1×100 mL of brine, dried over Na2SO4, filtered and evaporated to give 603 mg (2.24 mmol, an 82% yield) of the title compound as a yellow/orange oil. MS (ES) m/z 269 (MH)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][OH:12])=[CH:6][CH:5]=1.[CH3:23]I>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:11][O:12][CH3:23])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[CH:6][CH:5]=1
Reactant: CI
Reactant: CCCCC(CO)(Cn1cncn1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(COC)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a 100 mL 3 neck flask stirring under nitrogen was charged 0.40 g (0.010 mole) of 60% sodium hydride, prewashed with hexanes, in 30 mL of dimethylformamide. The slurry was cooled to 10° C. and 2.12 g (0.00723 mole) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1-yl)methyl]hexan-1-ol in 15 mL of dimethylformamide was added over 15 minutes. The reaction was warmed to room temperature and 1.17 g (0.00812 mole) of methyl iodide was added directly and the reaction was stirred overnight at room temperature. The reaction was quenched with 10 mL water and 100 mL ether. The organic phase was washed with 2×25 mL water, dried, concentrated and gave 1.53 g (69% yield) of product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].Br[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=1.CC1(C)CCCC(C)(C)N1>CN(C=O)C.CCOC(C)=O>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([N:7]2[CH2:8][CH2:9][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]2)=[N:12][CH:13]=1)#[N:16]
Reactant: COC(=O)C1CCNC1
Reactant: N#Cc1ccc(Br)nc1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ccc(C#N)cn2)C1
Temperature: 130 °C
Yield: 50.9 %

Procedure:
Pyrrolidine-3-carboxylic acid methyl ester (100 mg, 0.77 mmol) was dissolved in dry DMF (0.5 MI) in a shield tube. 6-Bromonicotinonitrile (140 mg, 077 mmol) was added to the reaction mixture, followed by 2,2,6,6-tetramethylpiperadine (110 mg, 0.77 mmol) and the mixture was heated to 130° C. for 3 h, cooled to room temperature, and diluted with EtOAc. The organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 15-18% EtOAc in petroleum ether) to afford methyl 1-(5-cyanopyridin-2-yl)pyrrolidine-3-carboxylate (90 mg, yield 70%). 1H NMR (300 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 7.62-7.59 (dd, J=8.9 Hz, J=2.3 Hz, 1H), 6.36 (d, J=9.0 Hz, 1H), 3.78-3.77 (m, 2H), 3.75 (s, 3H), 3.67 (m, 1H), 3.56-3.52 (m, 1H), 3.28-3.23 (t, J=7.1 Hz, 1H), 2.37-2.30 (q, J=7.1 Hz, 2H). MS (ESI) m/z: Calculated for C12H13N3O2: 231.10. found: 232.2 (M+H)+
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][CH:18]=[C:19]([C:21]([O:23]C)=O)[N:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:26]>CO>[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][CH:18]=[C:19]([C:21](=[O:23])[NH2:26])[N:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1c[nH]c(-c2ccc(OCC(O)CNC(C)(C)C)cc2)n1
Reactant: N
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc(-c2nc(C(N)=O)c[nH]2)cc1

Procedure:
A solution of methyl 2-[4-(3-tert. butyl amino-2-hydroxypropoxy)phenyl]imidazole-4-carboxylate (10 g.) in methanol (100 ml.) is reacted in a bomb with ammonia (44 g.) at 100° C. for about 24 hours. The reaction mixture is concentrated under reduced pressure and the residue is chromatographed on silica gel. The product is eluted with chloroform that is washed with concentrated aqueous ammonia (90%) and methanol (10%) and is recrystallized from acetonitrile to yield the 2-[4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]-4-carbamoylimidazole as a white solid, m.p. 149°-154° C.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[NH:7])=[CH:4][CH:3]=1.C([Li])CCC.Cl[P:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[N:7][P:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(C(=N)Nc2c(C)cccc2C)cc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Product: Cc1ccc(C(=NP(c2ccccc2)c2ccccc2)Nc2c(C)cccc2C)cc1
Reaction time: 1 h

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.19 g of 4-methyl-N1-(2,6-dimethylphenyl)benzamidine (Amidine III, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.93 mL chlorodiphenylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, the oily product was treated with 20 mL of pentane. After 1 hour stiffing at room temperature, a white solid formed. The solution was concentrated to approximately 10 mL and filtered while cold, yielding 1.64 g (78%) after drying.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]([OH:27])=O)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH2:53]([N:56]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([NH2:67])=[CH:63][CH:62]=1)[CH2:57][CH2:58][CH3:59])[CH2:54][CH3:55]>CN(C=O)C>[CH2:53]([N:56]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([NH:67][C:25]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([CH2:14][N:7]([CH2:6][C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)[CH2:8][C:9]3[NH:13][CH:12]=[CH:11][N:10]=3)=[CH:16][CH:17]=2)=[O:27])=[CH:63][CH:62]=1)[CH2:57][CH2:58][CH3:59])[CH2:54][CH3:55]
Reactant: CCCN(CCC)Cc1ccc(N)cc1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (130 mg) obtained in Example 36-4 was dissolved in DMF (3.0 ml) and then added with DCC (60.0 mg) and HOBt (40.0 mg), followed by stirring at room temperature for 2 hours. The compound (50.0 mg) obtained in Example 19-2 was added to the solution at room temperature, and the whole was stirred overnight. After completion of the reaction, insoluble matter was removed from the solution through a G4 glass filter and the solvent was distilled off. The residue was dissolved in chloroform and then washed with 1 mol/l hydrochloric acid. The organic layer was added with hydrochloric acid to separate the solution into layers. Then, the aqueous layer was added with a sodium hydroxide aqueous solution to adjust it to pH 12. The aqueous layer was subjected to extraction with chloroform, and the organic layer was dried with anhydrous sodium sulfate. Then, the solvent was distilled off. Subsequently, the residue was treated with hydrochloric acid and then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (17.4 mg) of the subject compound as a white foamed compound.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].N1CCCCC1>C(O)(=O)C>[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=C1CCc2ccccc21
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1C(=Cc2ccc([N+](=O)[O-])cc2)Cc2ccccc21
Temperature: 95 °C

Procedure:
A mixture of indan-1-one (20.0 g), 4-nitrobenzaldehyde (27.0 g), glacial acetic acid (3.0 g) and piperidine (3.06 g) was heated at 95° C. under nitrogen for 3.5 h. The mixture was cooled to 20° C. and filtered to give a solid which was recrystallized from industrial methylated spirit to give 2-(4-nitrobenzylidene)indan-1-one.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCCCCC.C(OCC)(=[O:23])C>>[O:23]=[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCOC(C)=O
Reactant: COC(=O)Cc1ccc(C(C)C)cc1
Solvent: CCCCCC
Product: COC(=O)C(=O)c1ccc(C(C)C)cc1

Procedure:
Prepared from methyl 4-isopropylphenylacetate by the method described in Example 33a), except that the eluent used was 4:1 hexane:ethyl acetate and the product contained starting material. δH (250 MHz, CDCl3), 1.28 (6H, d, J 6.87), 2.99 (1H, heptet), 3.98 (3H, s), 7.37 (2H, d, J 8.25), 7.95 (2H, d, J 8.33).
Reaction SMILES: NC1C=CC([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][C:14](N)=[CH:13][C:11]=3[N:12]=2)=CC=1.[C:18]1([C@@H:24]2[CH2:26][C@H:25]2[C:27](Cl)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C@@H:24]2[CH2:26][C@H:25]2[C:27]([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc(-c2nc3cc(N)ccc3[nH]2)cc1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Product: O=C(c1nc2ccccc2[nH]1)[C@@H]1C[C@H]1c1ccccc1

Procedure:
Bis-trans-2-phenyl-cyclopropanecarbonyl benzimidazole was prepared by method C from 2-(4-aminophenyl)-6-amino-benzimidazole (0.500 g, 2.23 mmole) and trans-2-phenyl-1-cyclopropanecarbonyl chloride (0.831 ml, 0.966 g, 5.35 mmole). The resulting solid was purified on silica gel (5% MeOH in CH2Cl2). HPLC showed the product was 95.5% pure.
Reaction SMILES: C([C:4]1[C:5]([CH3:13])=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)(=O)C.[ClH:14].[N:15]([O-])=O.[Na+]>O>[ClH:14].[NH2:15][C:4]1[C:5]([CH3:13])=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12
Reactant: O=N[O-]
Reactant: CC(=O)c1c(C)nn2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1nn2ccccc2c1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7 g. 3-Acetyl-2-methylpyrazolo[1,5-a]pyridine (see J. Org. Chem., 42, 443/1977) are dissolved in 140 ml. 6N hydrochloric acid and mixed dropwise at 0° C. with a solution of 5.52 g. sodium nitrite in water. After 2 hours, the ice-bath used for the cooling is removed and the reaction mixture is left to stand overnight at ambient temperature and then adjusted to pH 9. The precipitated nitroso compound (6.4 g.) is filtered off with suction and dissolved in about 150 ml. 2N hydrochloric acid. The nitroso compound is reduced with zinc dust analogously to Example 1.2. The crude product is chromatographed on silica gel with ethyl acetate. The product-containing fractions are evaporated, the residue is dissolved in ethanol and the solution is mixed with ethanolic hydrogen chloride. The precipitate which is obtained after some time is filtered off with suction and dried. There are obtained 3.1 g. (45% of theory) of the title compound; m.p. >275° C.; TLC (silica gel, ethyl acetate/acetone/glacial acetic acid/water 50:25:12.5:12.5 v/v/v/v): Rf =0.6.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([NH:15]C(=O)OC(C)(C)C)=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Br[C:25]1[S:34][C:28]2[C:29](=[O:33])[NH:30][CH2:31][CH2:32][C:27]=2[CH:26]=1>CCCCO.C([O-])([O-])=O.[Na+].[Na+].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>[NH2:15][C:10]1[C:9]([C:25]2[S:34][C:28]3[C:29](=[O:33])[NH:30][CH2:31][CH2:32][C:27]=3[CH:26]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ncccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1NCCc2cc(Br)sc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Nc1ncccc1-c1cc2c(s1)C(=O)NCC2
Temperature: 100 °C
Yield: 88.1 %

Procedure:
A solution of tert-butyl (3-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (416 mg, 1.3 mmol), 2-bromo-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (300 mg, 1.3 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) in n-BuOH (3 mL) and 2M Na2CO3 (3 mL) was degassed under bubbling nitrogen and the reaction was heated 2 h at 100° C. Upon completion, the reaction was filtered and concentrated under reduced pressure, then partitioned between DCM (10 mL) water (10 mL). The layers were separated and the aqueous layer was extracted with DCM (3×10 mL). The combined organics were dried over Na2SO4 and concentrated. The concentrate was slurried in EtOAc, sonicated and filtered to afford 2-(2-aminopyridin-3-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (281 mg, 88% yield) as a white solid. 1H NMR (300 MHz, MeOH) δ ppm 7.99 (dd, J=5.0, 1.3 Hz, 1H), 7.62 (dd, J=7.5, 1.4 Hz, 1H), 7.25 (s, 1H), 6.76 (dd, J=7.5, 5.1 Hz, 1H), 3.61 (t, J=7.0 Hz, 2H), 2.97 (t, J=7.1 Hz, 2H); MS (EI) m/z=246.3 [M+1]+.