Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-])=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>O>[C:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][CH:3]=1)([O:12][CH3:13])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)Cl)cc1

Procedure:
Monomethyl terephthalate (10.2 g, 0.057 mol) and thionylchloride (50 ml) were mixed in a 100 ml three-necked flask and stirred under gentle reflux overnight. The cooling water was shut off and excess thionylchloride swept away in a stream of nitrogen. By raising the temperature, the product then was distilled and collected as white crystals of high purity.
Reaction SMILES: [C:1]1([CH:41]2[C:54]3[CH2:53][CH2:52][C:51]4[C:46](=[N:47][C:48]([C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=5)=[CH:49][C:50]=4[C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[C:45]=3[NH:44][C:43]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[C:42]2[C:73]#[N:74])[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[C:20]3[CH2:19][CH2:18][C:17]4[C:12](=[N:13][C:14]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:15][C:16]=4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[NH:10][C:9]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:8]2[C:39]#[N:40])[CH:2]=1.C(Cl)Cl>C(O)COCCO.[Pd]>[C:3]1([C:7]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:13]4)[N:10]=[C:9]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:8]=2[C:39]#[N:40])[CH:4]=[CH:5][CH:6]=[C:1]([C:41]2[C:54]3[C:45](=[C:46]4[C:51](=[CH:52][CH:53]=3)[C:50]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:49][C:48]([C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)=[N:47]4)[N:44]=[C:43]([C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)[C:42]=2[C:73]#[N:74])[CH:2]=1
Reactant: N#CC1=C(c2ccccc2)NC2=C(CCc3c(-c4ccccc4)cc(-c4ccccc4)nc32)C1c1cccc(C2C(C#N)=C(c3ccccc3)NC3=C2CCc2c(-c4ccccc4)cc(-c4ccccc4)nc23)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: OCCOCCO
Product: N#Cc1c(-c2ccccc2)nc2c(ccc3c(-c4ccccc4)cc(-c4ccccc4)nc32)c1-c1cccc(-c2c(C#N)c(-c3ccccc3)nc3c2ccc2c(-c4ccccc4)cc(-c4ccccc4)nc23)c1
Temperature: 25 °C

Procedure:
suspension of 4,4′-(1,3-phenylene)bis(2,7,9-triphenyl-1,4,5,6-tetrahydro-1,10-phenanthroline-3-carbonitrile) (5) in 2 L diethyleneglycol was heated until total dissolution. 10 g Pd/C was then slowly added, and the reaction was refluxed for 72 hours with argon bubbling directly in the solution. The reaction was monitored by TLC (Silica Gel; CH2Cl2). The starting material's spot (rf: 0.8, blue-green under 366 nm) converted into a blue fluorescent spot (rf: 0.9). Once the starting material spot has disappeared, the reaction was stopped, and the suspension cooled to room temperature.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17](=[O:20])[CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CCO.O.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1
Reactant: CCC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCC(=O)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Reaction time: 2 h

Procedure:
To a solution of 5-[2-benzyloxy-4-((E)-3-oxo-pent-1-enyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (130 mg, 0.325 mmol) in 7 mL of EtOH/water (2:5) is added K2CO3 (53 mg, 0.39 mmol) and 10% Pd/C (65 mg). The mixture is hydrogenated at 1 atm for 2 h then the catalyst is filtered and the solvent removed under reduced pressure. The residue is purified by preparative HPLC to give the title compound as a white solid: (M−1)−=311. HPLC retention time: 1.31 min (Method A).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:32])[C@H:10]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[NH3:33]>C1COCC1>[CH2:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([NH2:33])=[O:32])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Solvent: C1CCOC1
Product: NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To THF (150 mL) solution of Nα-benzyloxycarbonyl-L-tryptophan-2,5-dioxopyrrolidin-1-yl ester (5.0 g) was added dropwise a 30% aqueous ammonia (3.3 mL) at 0° C., and thereafter the mixture was stirred for 2 hours at room temperature. The crystals were distilled off, and thereafter to the residue obtained by distilling off the solvent of the filtrate under a reduced pressure was added petroleum ether and a small amount of diethyl ether, and the crystals precipitated were filtered, to give the captioned compound (3.6 g, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]([OH:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[C:15]([CH3:27])[CH:14]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:28].[H-].[Na+].[CH3:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].C(OCC)(=O)C>CN(C=O)C>[CH3:27][C:15]1[CH:14]=[C:13]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:3]([CH3:28])[CH:4]=2)([CH2:9][CH3:10])[CH2:11][CH3:12])[CH:18]=[CH:17][C:16]=1[O:19][CH2:20][CH:21]([OH:26])[C:22]([CH3:23])([CH3:25])[CH3:24]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Reactant: CC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of the compound of example 7 (100 mg, 0.26 mmol) in DMF (2.5 mL) was added NaH (7.0 mg, 0.29 mmol). The reaction mixture was stirred at ambient temperature for 30 min, then pinacolone (39 mg, 0.29 mmol) was added. The reaction was stirred at ambient temperature for I h or until judged complete by TLC (20% ethyl acetate in hexanes). The reaction mixture was quenched with water, and diluted with ethyl acetate. The organic fraction was separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo. Chromatography (silica, 10% ethyl acetate in hexanes) afforded 117 mg (0.24 mmol, 92%) of 11. 1HNMR (CDCl3) δ: 6.91 (m, 4 H, Ar—H), 6.69 (d, J=8.3 Hz, 1 H, Ar—H), 6.49 (d, J=8.3 Hz, 1 H, Ar—H), 4.83 (s, 2 H, CH2), 4.09 (dd, J=11.3 Hz, J=3.3 Hz, 1 H, CH2), 3.85 (t, J=11.3 Hz, 1 H, CH2), 3.69 (d, J=11.3 Hz, 1 H, CH2), 2.23 (s, 3 H), Ar—CH3), 2.18 (s, 3 H, Ar—CH3), 2.00 (q, J=7.3 Hz, 4 H, CH2CH3), 1.24 (s, 9 H, t-Bu), 1.00 (s, 9 H, t-Bu), 0.58 (t, J=7.3 Hz, 6 H, CH2CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH2:15][CH:16]=O)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[NH2:18][C@H:19]1[CH2:23][N:22]([C:24]2[CH:25]=[CH:26][C:27]3[O:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=3[N:33]=2)[C:21](=[O:35])[CH2:20]1.C(OC(=O)N[C@@H]1CC(=O)NC1)(C)(C)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH2:15][CH2:16][NH:18][C@H:19]3[CH2:23][N:22]([C:24]4[CH:25]=[CH:26][C:27]5[O:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=5[N:33]=4)[C:21](=[O:35])[CH2:20]3)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1
Reactant: N[C@@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: COc1cnc2ccc(=O)n(CCC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N[C@H]1CNC(=O)C1
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cnc2ccc(=O)n(CCCN[C@@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Reaction time: 8 h
Yield: 9 %

Procedure:
To a solution of 3-(3-methoxy-6-oxopyrido[2,3-b]pyrazin-5 (6H)-yl)propanal (Reference Example 24, 120 mg, 0.515 mmol) in N,N-dimethylformamide (1.6 ml) were added 6-[(4R)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (synthesized using [(3R)-5-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester synthesized with reference to WO2004/22536 in the same manner as in Reference Examples 20, 21, 22; 166 mg, 0.66 mmol) and acetic acid (0.04 ml, 0.66 mmol) and the mixture was stirred at room temperature for 30 minutes. The reaction solution was then cooled on ice and sodium triacetoxyborohydride (141 mg, 0.66 mmol) was added thereto. After stirring overnight, sodium triacetoxyborohydride (282 mg, 1.32 mmol) was added to the reaction solution, which was further stirred at room temperature for 2 days. A sodium hydrogen carbonate aqueous solution was added to the reaction solution, which was then extracted with ethyl acetate and the obtained organic layer was washed with water and saturated sodium chloride solution. The layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained crude product was purified by thin layer chromatography (dichloromethane/methanol) to yield 21 mg (9%) of the title compound.
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:15][CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[I:17]I.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([C:5]2[C:14]([I:17])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:15][CH3:16])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCc1cc(C2CCC2)ccc1C(=O)OC
Reactant: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1cc(C2CCC2)c(I)cc1C(=O)OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a solution of methyl 4-cyclobutyl-2-ethylbenzoate (compound 181.3, 7.70 g, 35.3 mmol, 1.00 equiv) in acetic acid (80 mL) was added iodine (8.98 g, 35.4 mmol, 1.00 equiv), NaIO4 (3.78 g, 17.7 mmol, 0.50 equiv), and sulfuric acid (0.870 g, 8.87 mmol, 0.25 equiv). The reaction mixture was stirred at 60° C. overnight. After cooling to room temperature, the reaction was slowly quenched with Na2S2O3 (aq., sat.). The mixture was extracted with 200 mL of ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:50) to furnish 10.5 g (86%) of the desired product as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:36])[N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[N:22]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=[CH:20]5)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:36])[N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][CH:21]=[CH:20]5)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(N3CCc4nc(-c5ccc(Cl)cc5)sc4C3=O)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1c2sc(-c3ccc(Cl)cc3)nc2CCN1c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
Mix 2-(4-chloro-phenyl)-5-(1-triisopropylsilanyl-1H-indol-5-yl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (4.23 g, 7.89 mmol) in THF (50 mL) and add tetrabutyl-ammonium fluoride (1.0M in THF, 10 vmL, 10 mmol). Stir the red solution at room temperature for 2 h, then quench with aqueous 2M NH4Cl (50 mL) and extract with CH2Cl2 (3×50 mL). Dry, filter, and concentrate the organic solution. Purify the crude material by flash chromatography, using 8% MeOH (2N NH3)/CHCl3 as eluent, then triturate the resulting yellow solid with ether to give the title compound (2.68 g, 89%). MS (ES+) 380.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 11.20 (s, 1H), 8.05 (d, 2H, J=8.4 Hz), 7.62 (d, 2H, J=8.4 Hz), 7.53 (d, 1H, J=1.8 Hz), 7.43-7.38 (m, 2H), 7.09 (dd, 1H, J=8.6, 2.0 Hz), 6.45-6.43 (m, 1H), 4.11 (t, 2H, J=7.0 Hz), 3.28 (t, 2H, J=7.0 Hz).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([OH:27])[CH2:7][S:8]([CH2:11][CH2:12][C:13]([NH:16]C(OCC1C=CC=CC=1)=O)([CH3:15])[CH3:14])(=[O:10])=[O:9])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][CH2:5][CH:6]([OH:27])[CH2:7][S:8]([CH2:11][CH2:12][C:13]([NH2:16])([CH3:14])[CH3:15])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(O)CS(=O)(=O)CCC(C)(C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)OCC(O)CS(=O)(=O)CCC(C)(C)N
Reaction time: 1.5 h

Procedure:
To a solution of 3-(3-(benzyloxycarbonylamino)-3-methylbutylsulfonyl)-2-hydroxypropyl acetate (368.7 mg, 0.9184 mmol) in methanol (10 ml) was added palladium on carbon (10%, 37 mg). The solution was purged with nitrogen gas, and then put under a blanket of hydrogen gas (1.3 atm). The suspension was stirred for 1.5 hours, filtered through a 0.45 um PTFE filter, and concentrated in vacuo. The residue was used without any further purification. LRMS (ESI/APCI) m/z 268 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.Br.Br.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:26])[F:27])[CH:14]=3)[CH2:25][CH2:24]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: FC(F)(F)c1cccc(NC2CCNCC2)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cccc(NC2CCN(c3ccc(Cl)nn3)CC2)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
A mixture of 3 parts of 3,6-dichloropyridazine, 6.1 parts of N-[3-(trifluoromethyl)phenyl]-4-piperidinamine dihydrobromide, 6.4 parts of sodium carbonate and 180 parts of N,N-dimethylacetamide was stirred for 24 hours at 60° C. After cooling to room temperature, the reaction mixture was poured onto water. The product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.5 parts (47%) of 1-(6-chloro-3-pyridazinyl)-N-[3-(trifluoromethyl)phenyl]-4-piperidinamine; mp. 117.9° C. (compound 148).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:23]([C:28](O)=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28]([C:23]3[C:22]([CH3:21])=[CH:27][CH:26]=[CH:25][N:24]=3)=[O:29])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C(=O)O
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1cccnc1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 3-methyl-2-pyridinecarboxylic acid as starting materials, MS (LC/MS): 422.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH2:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:23][CH3:24])[CH2:32][CH2:33]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: CCc1ccccc1N1CCNCC1
Product: CCc1ccccc1N1CCN(C(=O)Nc2nc3ccccc3nc2OC)CC1
Yield: 75 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(2-ethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[N:8]=1.Cl>[Pd].C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[N:8]=1
Reactant: O=[N+]([O-])c1ccc(-c2noc(-c3ccccn3)n2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(-c2noc(-c3ccccn3)n2)cc1

Procedure:
A mixture of 2.68 g. (0.01 mole) of 5-(2-pyridyl)-3-(4-nitrophenyl)-1,2,4-oxadiazole, from part (a), 10 ml. of 10% HCl, 190 ml. of absolute ethanol, and 0.27 g. of 5% Pd/C is reduced on the Parr hydrogenator at 50 psi. until the required amount of hydrogen is absorbed. The catalyst is removed by filtration followed by removal of the ethanol by distillation in vacuo to yield the 5-(2-pyridyl)-3-(4-aminophenyl)-1,2,4-oxadiazole.
Reaction SMILES: Cl.[CH2:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:23]1[N:24]=[C:25]([S:31][CH3:32])[N:26]=[N:27][C:28]=1[C:29]#[N:30]>C(O)C>[CH3:32][S:31][C:25]1[N:26]=[N:27][C:28]([C:29]#[N:30])=[C:23]([N:4]2[CH2:3][CH2:2][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][CH2:5]2)[N:24]=1
Reactant: c1ccc2c(c1)CCNCC2
Reactant: CSc1nnc(C#N)c(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.5 %

Procedure:
A solution of 395 mg (2.7 mmol) of 2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride [J. Heterocycl. Chem. 1971, 8(5), 779-83] in 5 ml of ethanol was treated at room temperature with 0.92 ml (5.4 mmol) of Huenig's base and, thereupon, with a solution of 501 mg (2.7 mmol) of crude 5-chloro-3-methylsulfanyl-[1,2,4]triazine-6-carbonitrile in 5 ml of ethanol. The dark brown reaction mixture was stirred during 18 h at room temperature. For the working-up, the product, partially precipitated in pure form, was filtered and the resulting mother liquor evaporated under reduced pressure. The residue was chromatographed on silica gel with a 2:1 v/v mixture of hexane and ethylacetate as the eluent. In total, 470 mg (58.5% of theory) of 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile were obtained in the form of a beige powder; MS: 298 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[N:10]([CH3:12])[CH3:11].[N:16]([O-])=O.[Na+].[ClH:20]>C(OCC)C.[Fe].O>[ClH:20].[ClH:20].[CH3:6][C:7]1[C:8]([NH2:16])=[C:9]([N:10]([CH3:12])[CH3:11])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(N(C)C)c1
Reactant: O=N[O-]
Agent: [Fe]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(N(C)C)c1N
Reaction time: 2 h
Yield: 60 %

Procedure:
To a 250 cm3 round bottom flask was added water (100 cm3) and the temperature was reduced to 5° C. with an ice bath. To this cooled solution was carefully added sulphuric acid (98%, 22.5 g). To this solution was added 3-methyl-N,N-dimethylaniline (10 g, 74 mmol) and then sodium nitrite (5.6 g, 81.4 mmol), and the solution was stirred at room temperature for 1 hour. Iron (Fe) filings (12.8 g, 229 mmol) were added and the mixture stirred for a further 2 hours. The solution was filtered and then neutralized with saturated sodium hydrogen carbonate solution and the organics were extracted into ethyl acetate (3×100 cm3). The extracts were dried over magnesium sulphate, filtered, and concentrated to give a brown oil. The oil was dissolved in diethyl ether (100 cm3) and concentrated hydrochloric acid (50 cm3) was added. The solution was evaporated to dryness to give the title compound (10 g, 60%) as a light tan solid. νmax (KBr)/cm−1: 2849 (CH), 2821 (CH), 2543 (CM, 2444 (CA), 1586 (C═N), 1487 (CH), 1445 (CH), 1415 (CH), 1138 (CH); δH (250 MHz; D2O): 7.59 (1H, s, ArH), 7.50 (2H, s, ArH), 3.24 (6H, s, CH3), 2.39 (3H, s, CH3); δC (62.9 MHz; D2O) 18.9 (CH3), 48.8 (CH3), 122.1 (ArC), 126.2 (ArC), 127.6 (ArC), 133.7 (ArC), 137.4 (ArC), 144.4 (ArC).
Reaction SMILES: Cl.[N:2]1([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([CH3:20])[CH:14]=3)[N:10]=[C:9]2[CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:5][CH2:4][CH2:3]1.[Cl:27][C:28]1[C:29]([NH2:35])=[N:30][CH:31]=[N:32][C:33]=1Cl>>[N:2]1([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([CH3:20])[CH:14]=3)[N:10]=[C:9]2[CH:21]2[CH2:22][CH2:23][N:24]([C:33]3[N:32]=[CH:31][N:30]=[C:29]([NH2:35])[C:28]=3[Cl:27])[CH2:25][CH2:26]2)[CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Reactant: Nc1ncnc(Cl)c1Cl
Agent: Cl
Product: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4Cl)CC3)n2)ccc1F

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “1” by using 4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidine hydrochloride and 5,6-dichloro-pyrimidin-4-ylamine as starting materials. LC-MS (M+H=471, obsd=471). 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.66-7.58 (m, 1H), 7.53 (ddd, J=7.8, 5.0, 2.3 Hz, 1H), 7.47 (s, 1H), 7.06 (dd, J=9.7, 8.6 Hz, 1H), 6.79 (s, 2H), 4.13 (d, J=13.0 Hz, 2H), 3.88 (t, J=6.2 Hz, 2H), 3.11 (t, J=6.9 Hz, 4H), 3.07-2.93 (m, 3H), 2.69 (t, J=6.1 Hz, 2H), 2.29-2.19 (m, 3H), 2.01-1.81 (m, 6H).
Reaction SMILES: [ClH:1].Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:55][C@@H:56]([N:58]2[CH2:63][CH2:62][C@H:61]([OH:64])[C@@H:60]([CH3:65])[CH2:59]2)C)CC1>>[ClH:1].[ClH:1].[OH:64][C@H:61]1[CH2:62][CH2:63][N:58]([C@@H:56]([CH3:55])[CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:59][C@@H:60]1[CH3:65]
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Reactant: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c2cc1C
Agent: Cl
Product: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CC[C@H](O)[C@@H](C)C6)CC5)cc34)c2cc1C

Procedure:
This compound is synthesized from 4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (127, see example 104) and amine 56 analogously to the method described in example 1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[N:8]1([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][N:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[I-].[K+].Cl[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1>C(#N)C>[N+:35]([C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH2:26][N:11]2[CH2:12][CH2:13][N:8]([C:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[S:16][N:15]=3)[CH2:9][CH2:10]2)=[CH:30][CH:31]=1)([O-:37])=[O:36]
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCCN2CCN(c3nsc4ccccc34)CC2)cc1
Temperature: 150 °C
Yield: 114.9 %

Procedure:
Excess dried, −325 mesh potassium carbonate (257 mg, 1.86 mmol) was diluted in 4 mL acetonitrile and 3-piperazin-1-yl-benzoisothiazole hydrochloride (395 mg, 1.55 mmol), catalytic potassium iodide, and 1(2-chloroethoxy)-4-nitrobenzene (250 mg, 1.20 mmol) were added. This mixture was sealed in a Smith microwave vial and heated on the Smith Workstation at 150° C. for 1.5 h. After cooling, the salts were filtered off and washed with acetonitrile and the filtrate was concentrated. The residue was taken up in methylene chloride and washed with water. The organic layer was dried over sodium sulfate, and concentrated to afford 530 mg of a yellow solid. Yield 89%; 92% HPLC purity at 214 nm; mp 115° C.; MS (APCI): 385 [M+H]+.