Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].Cl[CH2:17][C:18]1[C:19]([CH3:34])=[N:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[CH:22][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:17][C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1
Product: CCOC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c(C)c1

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 1N]) to give 3-{3-methyl-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][C@@H:5]([NH:8]C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C([Cl:19])(=O)C.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C>[ClH:19].[NH2:8][C@@H:5]1[CH2:6][NH:7][C:2](=[O:1])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC(=O)NC1
Reactant: CC(=O)Cl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: N[C@H]1CCC(=O)NC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
N-((3S)-6-Oxo(3-piperidyl))(tert-butoxy)carboxamide (3.9 mmol, 0.83 g) were dissolved in ethanol (10 mL) and cooled to 0° C. Acetyl chloride (2 mL) was added and the reaction was allowed to reach room temperature. The reaction was stirred for 1 hour after which the solvent was removed in vacuo to yield the title compound (725 mg, 99% yield) as the dihydrochloride salt. ES-MS: 115 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][CH:29]=1)[C:14]([C:16](=[CH:19]NC1C=CC=CC=1)[C:17]#[N:18])=[O:15]>C(O)C.CCCCCC>[NH2:18][C:17]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:19][C:16]=1[C:14](=[O:15])[C:13]1[CH:27]=[CH:28][CH:29]=[C:11]([Br:10])[CH:12]=1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(Br)c1
Reactant: NNc1ccc(F)cc1
Solvent: CCO
Solvent: CCCCCC
Product: Nc1c(C(=O)c2cccc(Br)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
A mixture of 4-fluorophenylhydrazine (4.25 g, 33.7 mmol) and 2-(3-bromobenzoyl)-3-phenylaminoacrylonitrile (10.0 g, 30.7 mmol) in ethanol (100 ml) was heated at reflux under a nitrogen atmosphere. After 4 h, the reaction mixture was cooled to room temperature, diluted with hexane to give 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (9.7 g) as a solid.
Reaction SMILES: C(N(CC)CC)C.[O:8]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=O)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[C:26]1([C:32]2[CH:33]3[C:46](=O)[CH:37]([CH:38]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CCCCCC.[Zn]>[O:8]([C:16]1[CH:17]=[C:18]([CH2:19][O:21][CH:22]=[C:36]2[CH2:35][CH2:34][CH:33]3[CH2:46][CH:37]2[CH:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:39]=[C:32]3[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=C1C2CCCC1C(c1ccccc1)C=C2c1ccccc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(COC=C2CCC3CC2C(c2ccccc2)C=C3c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Into a 1000 mL three-neck flask equipped with magnetic stirrer, pressure-equalizing addition funnel and nitrogen line was charged with 200 mL of anhydrous THF. Ttitanium tetrachloride (17 mL) was added dropwise over a period of 30 minutes. The suspension was stirred for 20 minutes and 25.5 parts of zinc was added in small portions . The reaction mixture was heated under reflux for 2 hours and 42.5 mL of triethylamine was added dropwise. After refluxing one hour, 9 parts of a solution of methyl 3-tert-butyldimethylsiloxybenzoate and 4 parts of ketone (77) in 100 mL of dry THF was added over a period of 60 minutes and the reaction mixture was heated for one hour. The mixture on TLC silica gel plate showed the presence of the starting ester. An additional 1 part of starting ketone (77) in 35 mL of dry THF was added dropwise over 45 minutes and refluxed for two hours. The mixture was cooled to room temperature, diluted with 600 mL of hexane and decanted. The residue was washed with 3×250 mL of hexane. The combined hexane layer was filtered and evaporated under reduced pressure to give an oily material which was purified by chromatography on silica gel column using 5% ethyl acetate/hexane as an eluant. The fractions were checked by TLC on silica gel plate and the desired fractions were combined. The solvent was evaporated under reduced pressure to give an oil, yield 9.6 parts.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15]/[CH:16]=[C:17]3\[C:18](=[O:31])[NH:19][C:20](=[O:30])[C:21]4[C:26]\3=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)=[CH:11][CH:10]=2)[CH2:3]1.BrC1C=C2C(=CC=1)[C:39](=[O:43])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[CH3:39][O:43][CH:16]=[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=2)[C:20](=[O:30])[NH:19][C:18]1=[O:31].[CH3:8][CH:6]1[NH:7][CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5]1
Reactant: CC1CN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc([N+](=O)[O-])cc43)cc2)CC(C)N1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Product: CC1CN(c2ccc(N)cc2)CC(C)N1
Product: COC=C1C(=O)NC(=O)c2ccc([N+](=O)[O-])cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, 0.032 g (12.8% yield) of dark brown solid is obtained from 0.15 g (0.60 mmol) of 4-methoxymethylene-6-nitro-4H-isoquinoline-1,3-dione and [4-(3,5-dimethylpiperazin-1-yl)phenyl]amine (0.15 g, 0.72 mmol): mp >300° C.; MS (ESI) m/z 422.2 (M+H)+1
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27](N3CCOCC3)[CH2:28][Br:29])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:36])[CH:10]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:7])[CH2:3][CH2:2]1.Cl.C[OH:50]>C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27]([OH:50])[CH2:28][Br:29])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:36])[CH:10]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:7])[CH2:2][CH2:3]1
Reactant: CO
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(CBr)N2CCOCC2)C1SC(=O)OCC1CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1SC(=O)OCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidine-1-yl]-α-[2-bromo-1-(morpholin-4-yl)ethylidene]acetate (300 mg) in a mixture of methanol (22 ml) and methylene chloride (3.5 ml), and the mixture is stirred at room temperature under nitrogen atmosphere after addition of 10% hydrochloric acid (4 ml). After 2 hours, the reaction mixture is poured into ice water, and is extracted with chloroform. The extract solution is washed with water, dried, and evaporated to give p-nitrobenzyl 4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxo-α-(2-bromo-1-hydroxyethylidene)azetidine-1-acetate (252 mg). Foam. Yield: 92.8%. IR: νmaxCHCl3 3426, 1781, 1710, 1690, 1601 cm-1. NMR: δCDCl3 0.23-1.33m5H, 3.84-4.36m4H, 4.55s2H, 5.10-5.32m3H, 5.88d(5 Hz)1H, 6.83-8.33m9H, 12.0s1H.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.C([Li])CCC.[Cl-].[CH3:19][Ga+:20][CH3:21]>CCOCC.CCCCCC.CCCCCC>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Ga:20]([CH3:21])[CH3:19]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: C[Ga+]C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Ga](C)Cc1ccccc1C(F)(F)F
Reaction time: 0.25 h

Procedure:
5.25 g (22 mmol) of o-trifluoromethylbenzyl bromide in 10 ml of ether/hexane are added at -50° to a mixture of 45 ml of ether/hexane (2:1) and 14.7 ml (1.5N =22 mmol) of n-butyllithium. After stirring for 15 minutes, 2.1 g (16 mmol) of dimethylgallium chloride in 20 ml of hexane are added. Then the reaction mixture is allowed to come to room temperature, it is stirred for 24 hours, and the LiCl is filtered off and the solvent removed. After sublimation in vacuo, o-trifluoromethylbenzyldimethylgallium is obtained with a Mp. 35°-38°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10](OC)=[N:9]2)=[CH:2]1.[Cl-:17].[NH4+:18]>>[ClH:17].[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH:8]2[NH:9][C:10](=[NH:18])[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:2]1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC1=NC(CCc2ccoc2)CCCC1
Product: Cl
Product: N=C1CCCCC(CCc2ccoc2)N1

Procedure:
The product of Example 171 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([CH2:18][C:19](OC(C)(C)C)=[O:20])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.[NH2:33][C:34]1[N:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][N:43]([C:46](=[O:48])[CH3:47])[CH2:42][CH2:41]2)=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[C:46]([N:43]1[CH2:42][CH2:41][N:40]([C:37]2[CH:36]=[CH:35][C:34]([NH:33][C:19](=[O:20])[CH2:18][C:11]3[CH:12]=[C:13]([C:14]([F:16])([F:17])[F:15])[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[N:9][CH:10]=3)=[N:39][CH:38]=2)[CH2:45][CH2:44]1)(=[O:48])[CH3:47]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Cc1cc(-c2ncc(CC(=O)OC(C)(C)C)cc2C(F)(F)F)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(-c4ccnc(C)c4)c(C(F)(F)F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of tert-butyl 2-(2′-methyl-3-(trifluoromethyl)-2,4′-bipyridin-5-yl)acetate 189-4 (230 mg, 0.65 mmol) and TFA (1 mL) in DCM (5 mL) was stirred at room temperature for 5 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2-(2′-methyl-3-(trifluoromethyl)-2,4′-bipyridin-5-yl)acetic acid 189-5, was dissolved in DMF (4 mL). 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone (173 mg, 0.78 mmol) and DIEA (910 uL, 5.22 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (372 mg, 0.98 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2′-methyl-3-(trifluoromethyl)-2,4′-bipyridin-5-yl)acetamide 189. MS m/z 499.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.78(s, 1H), 8.48(d, 1H), 8.26(s, 1H), 7.99(s, 1H), 7.88(d, 1H), 7.42-7.36(m, 2H), 7.31(d, 1H), 3.92(s, 2H), 3.69(t, 2H), 3.65(t, 2H), 3.16(t, 2H), 3.11(t, 2H), 2.57(s, 3H), 2.09(s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)=[O:7].C(N(CC)C(C)C)(C)C.[CH3:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>C(Cl)Cl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:25]([NH:26][C:39](=[O:40])[C:38]4[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=4[CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1NC(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
A mixture of 1.0 g of 5-(3-methoxy-4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.47 g of N,N-diisopropylethylamine and 0.56 g of 2-methylbenzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water and saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. Hexane is added at the boil to give 1.27 g of the desired product as a crystalline solid, m.p. 209°-210° C.
Reaction SMILES: C(O[C:4](=[O:14])[C:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH:6]O)C.[NH:15]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1)[NH2:16].C([O-])C.[Na+].Cl>C(O)C>[CH3:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([N:15]2[C:4](=[O:14])[C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[CH:6][NH:16]2)[CH:22]=1
Reactant: Cc1ccnc(NN)c1
Reactant: CCOC(=O)C(=CO)c1cccnc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.53 g (7.90 mmol) of the compound from Example 2A and 2.92 g (23.7 mmol) of the compound from Example 1A are dissolved 2 ml anhydrous ethanol under argon and the mixture is stirred at RT for 16 h. 537 g (7.90 mmol) sodium ethanolate are added, the reaction solution becoming dark red in color. The mixture is subsequently stirred at RT for 30 min and 7.9 ml 1 M hydrochloric acid are then added. The solution is partly concentrated, a precipitate separating out. This is filtered off, washed with water (twice with 5 ml each time) and with MTBE (5 ml) and dried in vacuo. 435 mg (22% of th.) of the title compound are obtained.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]([O:14]CC)=[O:13])=[O:11])[S:7][CH:8]=1)[CH3:3].O.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[CH3:3][CH:2]([C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]([OH:14])=[O:13])=[O:11])[S:7][CH:8]=1)[CH3:1]
Reactant: CCOC(=O)C(=O)Nc1nc(C(C)C)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1csc(NC(=O)C(=O)O)n1

Procedure:
Ethyl 4-(2-propyl)thiazol-2-ylcarbamoylcarboxylate was combined with 50 ml. of water and 6.2 ml. of 1 N potassium carbonate. The mixture was clarified, cooled, acidified with acetic acid and product extracted into 150 ml. of ethyl acetate in three portions. The combined extracts were dried over anhydrous sodium sulfate, filtered and evaporated to an oil, which partially crystallized on standing. The gummy solid was recrystallized from isopropyl alcohol, affording 4-(2-propyl)thiazol-2-ylcarbamoylcarboxylic acid [216 mg.; m.p. 195°-197° C. (dec.)].
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C(O)C>[CH2:15]([N:17]([CH2:18][CH3:19])[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:16]
Reactant: CCNCC
Reactant: Clc1nc2ccccc2n2ccnc12
Solvent: CCO
Product: CCN(CC)c1nc2ccccc2n2ccnc12

Procedure:
A mixture of 2,8 g of 4-chloroimidazo[1,2-a]quinoxaline (example 1) and 9.8 ml of diethylamine in 40 ml of ethanol is refluxed for 4 h. After evaporating the solvent, the residue is taken up in chloroform and washed with water and saturated NaCl, then dried and evaporated, thereby obtaining 2.2 g of raw product that is subsequently chromatographed on SiO2 (eluent: CH2Cl2): after recrystallization from n-hexane there are obtained 1.3 g of 4- diethylaminoimidazo[1,2-a]quinoxaline. m.p. (DSC)=91.7° C. (onset); IR (KBr): 2976, 1518, 1425, cm-1 ; 1H-NMR (CDCl3): δ7.9 (1H,s), 7.7÷7.4 (3H,m), 7.35÷7.05 (2H,m), 4.15 (4H,q), 1.3 (6H,t); UV (EtOH): λmax =231, 250, 293, 305, 332, 348 nm. Elementary analysis for C14H16N4 (m.w. 240.31): calcd. C 69.97, H 6.71, N 23.31%; found C 69.99, H 6.80, N 23.13%.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=CC=N[C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[CH3:28][N:29]([CH3:39])[CH2:30][C:31]1[N:32]=[C:33]([N+:36]([O-])=O)[NH:34][CH:35]=1.CO.[CH2:42]1[CH2:46]OC[CH2:43]1.CO>[Ni].C(Cl)Cl.CO>[CH3:28][N:29]([CH2:30][C:31]1[N:32]=[C:33]([NH:36][C:4]([C:6]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[F:27])=[C:12]3[C:7]=2[N:8]=[CH:46][CH:42]=[CH:43]3)=[O:3])[NH:34][CH:35]=1)[CH3:39]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: C1CCOC1
Reactant: CN(C)Cc1c[nH]c([N+](=O)[O-])n1
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(CN(C)C)c[nH]3)c3ncccc23)c1F
Temperature: 70 °C
Reaction time: 7 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), stirring the reaction mixture for 7 h at 70° C., and using dimethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 22.1) instead of 2-nitroimidazole in Step 14.3, and Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. The title compound: ESI-MS: 468.1 [M+H]+; tR=3.29 min (System 1); TLC: Rf=0.18 (DCM/MeOH/NH3aq, 91.5:7.5:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].CO>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)/[C:16](=[N:1]\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)/[NH2:17]
Reactant: N#Cc1cccc(Br)c1
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: N/C(=N/c1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
Aniline (5.12 g, 55.0 mmol) was charged into the reaction flask with 100 mL of toluene. This solution was chilled using a wet ice bath. A 2.0 M toluene solution of trimethylaluminum (41.2 mL, 82 mmol) was added dropwise to the chilled reaction mixture over a 15 min period. The cooling bath was removed and the reaction mixture was stirred at room temperature for 2 h. 3-bromobenzonitrile (10.01 g, 55 mmol) was dissolved in 80 mL of toluene and was added dropwise to the reaction mixture. The reaction mixture was then stirred at 75° C. for 18 h. The reaction mixture was cooled to room temperature then was slowing poured into a beaker containing 75 g of silica gel and 150 mL methanol/300 mL DCM. This mixture was stirred at room temperature for 30 min then was filtered through a pad of Celite®. The pad was rinsed with DCM/methanol. The filtrate was stripped under vacuum and the crude residue was triturated with hexanes yielding (E)-3-bromo-N′-phenylbenzimidamide (6.95 g, 25.3 mmol, 45.9%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22]([O:24]C)=O)[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11]1.[CH:26]1([Mg]Br)[CH2:28][CH2:27]1.O.O1[CH2:36][CH2:35][CH2:34]C1>>[CH:26]1([C:22]([CH:34]2[CH2:35][CH2:36]2)([C:18]2[C:17]3[N:13]4[CH2:12][CH2:11][N:10]([C:3]5[C:4]([CH3:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])[C:14]4=[N:15][C:16]=3[CH:21]=[CH:20][CH:19]=2)[OH:24])[CH2:28][CH2:27]1
Reactant: COC(=O)c1cccc2nc3n(c12)CCN3c1c(C)cc(Cl)cc1Cl
Reactant: Br[Mg]C1CC1
Reactant: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)cc(Cl)c1N1CCn2c1nc1cccc(C(O)(C3CC3)C3CC3)c12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 39 %

Procedure:
To a solution of methyl 1-(2,4-dichloro-6-methylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole-5-carboxylate (90 mg, 0.239 mmol) in tetrahydrofuran (2.4 mL) was added a solution of cyclopropyl magnesium bromide in tetrahydrofuran (1.0 M, 1.4 mL, 1.4 mmol) at room temperature. The mixture was stirred at 60° C. for 1.5 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-60% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/diisopropyl ether to give the title compound (40.2 mg, 0.094 mmol, 39%) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:30])[CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1.O>C1C=CC=CC=1>[Cl:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][CH:13]([CH3:30])[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:28][CH:29]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: c1ccccc1
Solvent: O
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)c1cccc(Cl)c1
Reaction time: 8 h
Yield: 13.3 %

Procedure:
A solution of 2.5 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8) and 3.58 g of 5-[4-(2-oxopropoxy)benzyl]thiazolidine -2,4-dione in 50 ml of benzene was heated under reflux for 1.5 hours, whilst the water being formed during the reaction was continuously removed. At the end of this time, the benzene used was removed by distillation under reduced pressure. The resulting residue was dissolved in 100 ml of absolute methanol, and then 3 g of sodium borohydride were added to the resulting solution. The reaction mixture was allowed to stand overnight at room temperature, after which it was concentrated by evaporation under reduced pressure, and the concentrate was mixed with water. The resulting aqueous mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using ethyl acetate, followed by a 10:1 by volume mixture of ethyl acetate and ethanol, as the eluent. The product was recrystallized from ethyl acetate, to give 0.74 g of the title compound as crystals, melting at 100°-125° C.
Reaction SMILES: O[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:6][C:3]=1[C:4]#[N:5].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1ccc(-c2cc(C#N)c(O)nc2-c2ccccc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2cc(C#N)c(Cl)nc2-c2ccccc2)cc1

Procedure:
A solution of 2-hydroxy-6-phenyl-5-p-tolylnicotinonitrile (Compound 114, 528 mg, 1.9 mmol) in POCl3 (5 ml) was heated to 110° C. overnight. POCl3 was removed and the residue was purified by MPLC column chromatography (silica gel, 10% ethyl acetate in hexane) to obtain the title compound as an oil-foam.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][N:28]([CH3:36])[C:29](=[O:35])[CH2:30][CH2:31][C:32](O)=[O:33]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[CH2:31][CH2:30][C:29]([N:28]([CH3:36])[CH3:27])=[O:35])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CN(C)C(=O)CCC(=O)O
Agent: Cl
Product: CN(C)C(=O)CCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (87 mg, 77%), MS (ISP) m/z=456.3 [(M+H)+], mp 205° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-(dimethylamino)-4-oxobutanoic acid.