Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH2:17])[N:11]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)[C:3]=1[C:28]#[N:29].C(N(CC)CC)C.Br[CH2:38][CH2:39][C:40](Cl)=[O:41]>CS(C)=O.C(Cl)(Cl)Cl>[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:4]2[C:3]([C:28]#[N:29])=[C:2]([NH2:1])[N:7]=[C:6]([S:8][CH2:9][C:10]3[N:11]=[C:12]([CH2:16][NH:17][C:40](=[O:41])[CH:39]=[CH2:38])[CH:13]=[CH:14][CH:15]=3)[N:5]=2)=[CH:19][CH:20]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Nc1ccc(-c2nc(SCc3cccc(CN)n3)nc(N)c2C#N)cc1
Reactant: O=C(Cl)CCBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C=CC(=O)NCc1cccc(CSc2nc(N)c(C#N)c(-c3ccc(NC(C)=O)cc3)n2)n1
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
The compound of Example 32 (0.5 g) and triethylamine (0.3 mL) was dissolved in 5 mL of DMSO, to the solution at ice temperature added 0.17 g of 3-bromopropionyl chloride, and the mixture was stirred for 30 minutes. The reaction mixture was diluted with chloroform, washed with water (twice) and brine (once), and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed, and the resulting crude crystal was washed with diethyl ether to give 0.12 g of N-{6-[4-(4-acetylaminophenyl)-6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl]pyridin-2-ylmethyl}acryl-amide as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[Cl:17].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C(OCC)(=O)C.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>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[C:16]([Cl:17])[CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
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: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cnc(Cl)nc1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
A mixture of 20 g 2,4-dichloro-5-fluoropyrimidine, 22.86 g 3,4-dichlorophenylboronic acid, 33.11 g potassium carbonate and 6.92 g tetrakis(triphenylphosphine)palladium were in 500 mL THF and 500 mL water was heated to reflux for 4 h. The reaction mixture was cooled to room temperature diluted with water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel with dichloromethane to yield 24.640 g (74.13%) of the title compound as white solid, MS 279.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[CH3:15][O-:16].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:11]([O:16][CH3:15])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: Nc1nc2cc(Cl)c(Cl)cc2nc1Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc2cc(Cl)c(Cl)cc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To 2-amino-3,6,7-trichloroquinoxaline (1.54 g, 6.20 mmol) dissolved in tetrahydrofuran (40 ml), 25 wt % sodium methoxide (2.01 g, 9.30 mmol) in methanol was added at room temperature and stirred further at room temperature for 1 hour. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 1.21 g of the titled compound (yield, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][NH2:26])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].Cl.[N:29]1([C:34]([NH2:36])=O)C=CC=N1>CO>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][NH:26][C:34]([NH2:36])=[NH:29])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCON)ccc21
Reactant: NC(=O)n1cccn1
Agent: Cl
Solvent: CO
Product: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCONC(=N)N)ccc21
Reaction time: 120 h
Yield: 97 %

Procedure:
3-[5-(2-aminooxy-ethoxy)-indol-1-yl]-3-phenyl-propionic acid ethyl ester (0.28 g, 0.75 mmol) and 1H-pyrazole-1-carboxamide hydrochloride (0.99 g, 0.67 mmol) were dissolved in methanol (3 mL) and stirred for 5 days. The solvent was evaporated under vacuum and the crude mixture was purified via column chromatography with silica gel, eluting with 10% methanol/dichloromethane to afford the title compound (97% yield). 1H NMR (CDCl3), δ 7.11-7.26 (m, 7H), 7.00 (d, 1H, J=2.3 Hz), 6.75 (dd, 1H, J=2.3, 8.8 Hz), 6.43 (d, 1H, J=3.2 Hz), 5.98 (t, 1H, J=7.6 Hz), 4.08 (m, 2H), 3.99 (m, 4H), 3.23 (m, 2H), 1.05 (t, 3H, J=7.2 Hz).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13]([S:16][CH3:17])=[N:14][N:15]=3)[CH:9]=2)[NH:4][CH:3]=1.[CH3:18][C:19]([CH3:22])([O-:21])[CH3:20].[K+].CN([CH:27]=[O:28])C>>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13]([S:16][CH3:17])=[N:14][N:15]=3)[CH:9]=2)[N:4]([C:27]([O:21][C:19]([CH3:22])([CH3:20])[CH3:18])=[O:28])[CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)[O-]
Reactant: CSc1nnc(-c2ccc3[nH]cc(I)c3c2)s1
Agent: [K+]
Product: CSc1nnc(-c2ccc3c(c2)c(I)cn3C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 2-(3-iodo-1H-indol-5-yl)-5-(methylthio)-1,3,4-thiadiazole (21 g, 56.3 mmol) in DMF (210 mL) was added potassium tert-butoxide (12.6 g, 112.6 mol) and followed by di-tert-butyl-di-cabonate (24.5 g, 112.6 mmol). The reaction was stirred at RT for 2 h, and ice/H2O was added. The resulting precipitate was filtered and washed with H2O to give tert-butyl 3-iodo-5-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-1H-indole-1-carboxylate (20 g, 75%). MS (ESI, pos. ion) m/z: 473.8 (M+1). 1HNMR (DMSO-d6, 300 MHz): δ 2.8 (s, 3H), 7.5 (d, 1H), 7.7 (m, 2H), 12.0 (s, 1H).
Reaction SMILES: [C:1]([N:8](C)[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.Br[C:42]1[CH:43]=[N:44][C:45]([N:48]([CH3:50])[CH3:49])=[N:46][CH:47]=1>>[ClH:27].[ClH:27].[CH3:49][N:48]([CH3:50])[C:45]1[N:44]=[CH:43][C:42]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:29]([CH:30]=2)[CH2:28][N:15]([CH:12]2[CH2:13][CH2:14][CH:9]([NH:8][CH3:1])[CH2:10][CH2:11]2)[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])=[CH:47][N:46]=1
Reactant: CN(C)c1ncc(Br)cn1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CNC1CCC(N(Cc2cc(-c3cnc(N(C)C)nc3)ccc2OC)C(=O)c2sc3ccccc3c2Cl)CC1
Product: Cl

Procedure:
The title compound is prepared from boronic acid 5 (25 mg, 43 μmol) and 5-bromo-2-(dimethylamino)pyrimidine (7.2 mg, 36 μmol) in accordance with Method L2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1.F[C:16]1[CH:32]=[CH:31][C:19]([O:20][CH2:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:18][C:17]=1[N+:33]([O-])=O.[C@@H:36]12[C:45](=O)[O:44][C:42](=[O:43])[C@@H:37]1[CH2:38][CH2:39][CH2:40][CH2:41]2>>[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][O:20][C:19]1[CH:31]=[CH:32][C:16]2[N:14]([CH2:13][C:10]3[CH:11]=[CH:12][C:7]([C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:8][CH:9]=3)[C:45]([C@H:36]3[CH2:41][CH2:40][CH2:39][CH2:38][C@H:37]3[C:42]([OH:44])=[O:43])=[N:33][C:17]=2[CH:18]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: O=[N+]([O-])c1cc(OCc2nc3ccccc3s2)ccc1F
Reactant: NCc1ccc(-c2ncccn2)cc1
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(-c2ncccn2)cc1

Procedure:
The title compound was prepared using analogous conditions described in Example 208 using (4-(pyrimidin-2-yl)phenyl)methanamine and 2-((4-fluoro-3-nitrophenoxy)methyl)benzo[d]thiazole in step B and cis-1,2-cyclohexanedicarboxylic anhydride in step D. MS (ESI): mass calcd. for C33H29N5O3S, 575.69; m/z found, 576.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.91-8.78 (d, J=4.9, 2H), 8.50-8.29 (d, J=8.4, 2H), 8.17-7.89 (d, J=8.0, 2H), 7.59-7.57 (d, J=9.2, 1H), 7.57-7.52 (m, 1H), 7.49-7.44 (ddd, J=8.2, 7.2, 1.2, 1H), 7.44-7.43 (d, J=2.4, 1H), 7.39-7.35 (m, 1H), 7.35-7.31 (dd, J=9.1, 2.4, 1H), 7.29-7.26 (d, J=8.5, 2H), 5.95-5.80 (m, 2H), 5.71-5.63 (s, 2H), 3.71-3.62 (dt, J=12.1, 3.9, 1H), 3.04-2.94 (q, J=3.7, 1H), 2.40-2.26 (m, 1H), 2.25-2.14 (m, 1H), 2.11-2.04 (m, 1H), 2.01-1.94 (m, 1H), 1.88-1.73 (m, 1H), 1.73-1.64 (m, 1H), 1.61-1.47 (m, 2H).
Reaction SMILES: [O:1]=[C:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:9]([Si](C)(C)C)[CH:10]=C.Cl[CH2:17]Cl>[Ti](Cl)(Cl)(Cl)Cl>[OH:1][C:2]([CH3:17])([CH2:8][CH:9]=[CH2:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)=O
Reactant: C=CC[Si](C)(C)C
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: C=CCC(C)(O)C(=O)OCC
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
Ethyl 2-oxopropanoate (1 g, 8.61 mmol) was taken in to DCM (5M) and cooled to −78 C. To this titanium tetrachloride (8.61 mL, 8.61 mmol) in dichloromethane (5 mL) was added and stirred the reaction mixture for 30 min at this temperature. To this reaction mixture allyltrimethylsilane (1.279 g, 11.20 mmol) was added drop wise at −78° C. and stirring was continued for 2 h. Then it was brought to 0° C. and quenched with saturated aq. sodium bicarbonate solution and stirred for 15 min, and filtered through celite bed and filtrate was evaporated under reduced pressure to afford colorless oil. The residue was purified by flash chromatography (silica, 230-400, 10% EtoAc/Pet ether) to obtain ethyl 2-hydroxy-2-methylpent-4-enoate B-37a (0.8 g, 5.06 mmol, 58.7% yield) as yellow liquid. 1H NMR (CDCl3, δ=7.26 ppm, 400 MHz): δ 5.84-5.72 (m, 1H), 5.15-5.09 (m, 2H), 4.29-4.19 (m, 2H), 2.56-2.37 (m, 2H), 1.43 (s, 3H), 1.31 (t, J=9.6 Hz, 3H).
Reaction SMILES: [C:1]([Cl:4])(=O)[CH3:2].[N:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][C:21]([OH:23])=[O:22])=[N+]=[N-].O.C(Cl)Cl>C(O)C>[ClH:4].[NH2:5][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][C:21]([O:23][CH2:1][CH3:2])=[O:22]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCC(=O)O
Reactant: CC(=O)Cl
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COCCOCCOCCOCCN
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of anhydrous hydrogen chloride in ethanol was prepared by slow addition of acetyl chloride (100 mL) to anhydrous ethanol (500 mL), followed by stirring at room temperature for one hour. 3 (44 g) was added and the solution stirred for one hour. Water (1 L) was added and the solution -extracted with methylene chloride (3×). The solvent was removed on a rotovap and the residue dissolved in ethanol. Activated charcoal was added and the mixture stirred for approximately half an hour after which it was filtered through celite. The solvent was then removed on a rotovap. The residue was dissolved in ethanol/water (50:50) (200 mL). Formic acid was added (16 g) followed by 10% palladium/carbon (2.7 g). The solution was warmed to 60° C. and stirred until evolution of gas had ceased. The mixture was filtered through celite. The filtrate was neutralized with aqueous sodium bicarbonate until samples diluted with water were neutral (pH˜7) by analysis with pH paper. The solvent was then removed on a rotovap. Residual water and salt were removed by filtration and azeotropic distillation with ethanol (2×), yielding crude 4 as a yellow oil (33 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([NH2:29])[CH:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])[CH:20]=4)[C:9]3=N[CH:11]=2)[N:3]=[N:2]1.N1C=CC=C[CH:31]=1.[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:31][C:9]3[N:12]([C:15]4[CH:16]=[C:17]([NH:29][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])[CH:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])[CH:20]=4)[CH:13]=[N:14][C:8]=3[CH:7]=2)[N:3]=[N:2]1
Reactant: c1ccncc1
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4c[nH]nn4)cnc32)c1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4c[nH]nn4)ccc32)c1
Yield: 2.3 %

Procedure:
To a solution of 5-(6-(1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (70 mg, 0.18 mmol) in DCM was added pyridine (42 mg, 0.54 mmol, 3.0 eq.) followed by ethanesulfonyl chloride (27 mg, 0.216 mmol, 1.2 eq.). The reaction was monitored by LCMS. After completion of the reaction the solvent was distilled off and the crude product was purified by preparative HPLC to give the product in 2.3% yield (2 mg).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15](=[N:23][OH:24])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)[C:27]([N:29]=C=O)=[O:28].N.C(#N)C>O1CCCC1>[NH2:29][C:27]([O:24]/[N:23]=[C:15](/[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1)\[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:28]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(C(Cc2ccccc2)=NO)cc1OC1CCCC1
Agent: N
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc(/C(Cc2ccccc2)=N/OC(N)=O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a magnetically-stirred solution of 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl ethanone oxime (4.51 mmol, 1.48 g) in dry tetrahydrofuran (45 mL) at 0° C. is added trichloroacetyl isocyanate (5.00 mmol, 0.943 mg; 0.596 mL) dropwise over 2 minutes and the resulting solution is allowed to stir as the temperature rises slowly from 0° C. to room temperature overnight. The reaction mixture is then cooled to 0° C. and saturated NH3 /acetonitrile solution (25 mL; prepared by bubbling gaseous ammonia through CH3CN at room temperature for 1 hour) is added dropwise to the reaction mixture. The solution is allowed to stir as it warms slowly from 0° C. to room temperature. After 1.5 hours, the tetrahydrofuran is removed in vacuo and the residue is partitioned between methylene chloride (200 mL) and water (200 mL). The aqueous phase is extracted with ethyl acetate (200 mL) and the combined organics are washed with water (200 mL), dried (Na2SO4), and concentrated in vacuo to afford a mixture of product and oxime (~1:1). The residue is purified via flash chromatography (SiO2 : 1) 2% ethyl acetate/methylene chloride, 2) 5% ethyl acetate/methylene chloride, 3) 7% ethyl acetate/methylene chloride) to give a white solid which is triturated with ether/hexane and dried in vacuo at 50° C. to afford analytically-pure title compound (1.22 mmol, 0.450 g; 27%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]([NH:17][C:18](=[O:30])[C@@H:19]([NH2:29])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:16][C:9]([NH:17][C:18](=[O:30])[C@@H:19]([NH:29][C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:8])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(NC(=O)[C@@H](N)COCc1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(NC(=O)[C@H](COCc1ccccc1)NC(=O)c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
3.2 g of an oily substance [which had been obtained by the treatment of the (2S)-N-(α,α-dimethylbenzyl)-3-benzyloxy-2-aminopropionamide trifluoroacetate (prepared as described in Preparation 5) with triethylamine] were dissolved, together with 1.5 g of triethylamine, in 150 ml of methylene chloride. 1.5 g of benzoyl chloride was dropped onto this solution in an ice bath, and the reaction solution was stirred for 30 minutes, after which the methylene chloride layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off and recrystallization of the residue from a mixture of diethyl ether and hexane gave 4.1 g of the title compound melting at 88°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[O:5][CH2:6][CH2:7]Br.[CH2:13]([NH2:16])[CH2:14][CH3:15].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[O:5][CH2:6][CH2:7][NH:16][CH2:13][CH2:14][CH3:15]
Reactant: Clc1cc(Cl)cc(OCCBr)c1
Reactant: CCCN
Agent: Cl
Product: CCCNCCOc1cc(Cl)cc(Cl)c1

Procedure:
The title compound was prepared by the method of Preparation 34 from 2-(3,5-dichlorophenoxy)-1-bromoethane, n-propylamine and hydrogen chloride. The free base was obtained as an oil. The hydrochloride salt melted at 185°-186° C.
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1B(O)O>>[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Reactant: OB(O)c1ccco1
Agent: OB(O)c1ccccc1
Product: COc1cc2c(cc1-c1ccco1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 41 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used furan-2-boronic acid. The title compound (40 mg) was obtained as a white solid, (yield=41%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]3[CH2:12][CH2:11]3)[C:5]=2[CH:13]=[C:14](Br)Br)[CH2:3][CH2:2]1.[CH2:17]([NH2:20])[CH2:18][NH2:19]>>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]3[CH2:12][CH2:11]3)[C:5]=2[CH2:13][C:14]2[NH:19][CH2:18][CH2:17][N:20]=2)[CH2:3][CH2:2]1
Reactant: NCCN
Reactant: BrC(Br)=Cc1c(C2CC2)cccc1C1CC1
Product: c1cc(C2CC2)c(CC2=NCCN2)c(C2CC2)c1

Procedure:
2-(2,6-Dicyclopropyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from 1,3-dicyclopropyl-2-(2,2-dibromo-vinyl)-benzene and ethylenediamine in analogy to Example 1e): light yellow crystals; MS (ISP): 241.4 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:3][CH2:4][CH2:5][NH2:6].[CH3:19][C:20]([CH3:22])=O>[Pt]=O.C(O)C>[CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:3][CH2:4][CH2:5][NH:6][CH:20]([CH3:22])[CH3:19]
Reactant: COc1ccc(CCN(C)CCCN)cc1OC
Reactant: CC(C)=O
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(CCN(C)CCCNC(C)C)cc1OC
Yield: 100 %

Procedure:
3.87 g of N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-1,3-propanediamine and 15 ml of acetone were dissolved into 50 ml of ethanol. To this was added 0.1 g of platinum oxide and then hydrogenetion was made at room temperature and under pressure of 3 kg/cm2. At the end of 3 hours catalyst was concentrated after filtering and 4.52 g of marked compound was obtained as yellow oily matter (yield: 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][NH2:27])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][NH:27][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:12])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: NCC1CCN(Cc2ccccc2)CC1
Product: O=C(NCC1CCN(Cc2ccccc2)CC1)c1c[nH]c2ccccc12
Yield: 60 %

Procedure:
Indole-3-carboxylic acid was converted to its acid chloride and then reacted with (1-benzyl-4-piperidyl)methylamine (D10) as in the method of Description 1b to afford N-[(1-benzyl-4-piperidyl)methyl] indole-3-carboxamide as a white solid (60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.Cl[C:21]1[N:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:21]1[N:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: N#Cc1cccnc1Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2ncccc2C#N)c(OC)c1
Temperature: 80 °C
Yield: 72.2 %

Procedure:
2,4-Dimethoxybenzylamine (2.90 g, 17.3 mmol) and triethylamine (1.75 g, 17.3 mmol) were added sequentially to a solution of 2-chloronicotinonitrile (2.0 g, 14.4 mmol) in N,N-dimethylacetamide (29 mL). The reaction was heated at 80° C. for 4 h, quenched with water and extracted with diethyl ether (3×). The combined organic extracts were washed water, saturated brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 0-5% ethyl acetate (with 0.1 triethylamine) in dichloromethane gradient elution) to produce the title compound (2.80 g). MS 270.3 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[CH:9]=[C:8]([C:12]([O:14]C)=[O:13])[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:3]12.[Li+].[OH-].C1COCC1.O>CO>[O:1]=[C:2]1[NH:11][C:10]2[CH:9]=[C:8]([C:12]([OH:14])=[O:13])[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:3]12
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C1CCCCN21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)NC(=O)C1CCCCN21
Temperature: 25 °C
Reaction time: 8 h
Yield: 1008.2 %

Procedure:
Methyl 6,6a,7,8,9,10-hexahydro-6-oxo-5H-pyrido[1,2-a]quinoxaline-3-carboxylate (0.762 g, 0.29 mmole) and LiOH (0.25 g) were suspended in MeOH (5 mL), THF (5 ml) and Water (2 mL). The mixture was stirred at room temperature overnight. The reaction was evaporated to near dryness, and 2N HCl was added to adjust the PH about 2. The solid was filtered and dried to provide 6,6a,7,8,9,10-hexahydro-6-oxo-5H-pyrido[1,2-a]quinoxaline-3-carboxylic acid as white solid (0.72 g, 100%).
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[K+].[K+].[Br:9][C:10]1[CH:24]=[N:23][C:13]2[NH:14][C:15](=[S:22])[N:16]([CH2:19][CH2:20][CH3:21])[C:17](=[O:18])[C:12]=2[CH:11]=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[Br:9][C:10]1[CH:24]=[N:23][C:13]2[N:14]=[C:15]([S:22][CH3:3])[N:16]([CH2:19][CH2:20][CH3:21])[C:17](=[O:18])[C:12]=2[CH:11]=1
Reactant: CCCn1c(=S)[nH]c2ncc(Br)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCn1c(SC)nc2ncc(Br)cc2c1=O
Yield: 75.2 %

Procedure:
A mixture of iodomethane (1.33 g, 0.58 mL), 8.7 g potassium carbonate and 1.88 g of the title compound of Step B was stirred at room temperature in 50 mL of dimethylformamide for 3 h. A 1 mL portion of saturated aqueous NaHCO3 was added and the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was partitioned between 200 mL each of methylene chloride and water, and the organic layer was removed. Further washing of the organic phase with water and saturated aqueous NaCl followed by drying (Na2SO4) and concentration under reduced pressure delivered 1.8 g of the crude product. This material was then subjected to silica gel chromatography using 70:30 hexane:ethyl acetate as eluant to afford 1.48 g of the title compound of Step C, a compound of the invention, as a white solid melting at 124-127° C. 1H NMR (400 MHz, CDCl3): δ 1.03 (t,3H), 1.76-1.90 (m,2H), 2.7 (s,3H), 4.1 (t,2H), 8.63 (s,1H), 8.89 (s,1H).