Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[CH3:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[CH:21][C:20]=1[CH2:30][C:31](O)=[O:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:31](=[O:32])[CH2:30][C:20]2[CH:21]=[N:22][N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19]=2[CH3:18])[CH2:7]1
Reactant: Cc1c(CC(=O)O)cnn1-c1ccccc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: Cc1c(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cnn1-c1ccccc1

Procedure:
Example 34 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.056 g) and (5-methyl-1-phenyl-1H-pyrazol-4-yl)acetic acid (0.0439) to give the title compound (0.014 g).
Reaction SMILES: C(N1CCN(C2C=CC([NH:20][C:21]3[C:26]([F:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=3)=CC=2)CC1)C1C=CC=CC=1.[CH2:29]1[CH2:39][O:38][C:37]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=2[O:30]1>>[CH2:29]1[CH2:39][O:38][C:37]2[CH:36]=[CH:35][C:33]([NH:34][C:23]3[N:22]=[C:21]([NH2:20])[C:26]([F:27])=[CH:25][N:24]=3)=[CH:32][C:31]=2[O:30]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Product: Nc1nc(Nc2ccc3c(c2)OCCO3)ncc1F
Yield: 127.1 %

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine, the reaction of N4-[4-(N-benzylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine (50 mg, 0.12 mmol) and 3,4-ethylenedioxyaniline (0.045 mL, 0.36 mmol) gave N4-[4-(N-benzylpiperazino)phenyl)]—N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (40 mg, 63%). 1H NMR (CDCl3): δ 2.64 (t, J=4.8 Hz, 4H), 3.20 (t, J=4.8 Hz, 4H), 3.59 (s, 2H), 4.24 (m, 4H), 6.61 (d, 1H, NH), 6.68 (br, 1H, NH), 6.76 (d, J=8.7 Hz, 1H), 6.88 (dd, J=2.4 and 8.7 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 7.19 (d, J=2.4 Hz, 1H), 7.28-7.36 (m, 5H), 7.47 (d, J=8.7 Hz, 2H), 7.87 (d, J=3.3 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ −168.66; LCMS: ret. time: 18.05 min.; purity: 100%; MS (m/e): 513.10 (MH+).
Reaction SMILES: [F:1][C:2]1([F:16])[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:17]([NH:24][CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2]1([F:16])[F:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)(F)C1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(F)(F)C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (0.250 g, 1.06 mmol) in CH2Cl2 (4.5 mL) was added benzylamine (0.13 mL, 1.17 mmol) and sodium triacetoxyborohydride (0.356 g, 1.59 mmol) and the solution was stirred at rt for 22 h. The reaction mixture was treated with sat. aq. Na2CO3 and extracted with EA (3×50 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Heptane/EA, 1:1) to give tert-butyl 4-(benzylamino)-3,3-difluoropiperidine-1-carboxylate. LC-MS-conditions 08: tR=0.65 min; [M+H]+=327.32.
Reaction SMILES: Br[C:2]([CH3:18])=[CH:3][C:4]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1)=[O:5].OCC1SC(B(O)O)=CC=1.Br[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>>[O:5]=[C:4]([C:6]1[CH:7]=[C:8]([O:16][CH3:17])[C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=1)[CH:3]=[C:2]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1)[CH3:18]
Reactant: O=Cc1ccc(Br)cc1
Reactant: COc1cc(C(=O)C=C(C)Br)cc(OC)c1OC
Agent: OCc1ccc(B(O)O)s1
Product: COc1cc(C(=O)C=C(C)c2ccc(C=O)cc2)cc(OC)c1OC
Yield: 81 %

Procedure:
When the product of Step A and 4-carbaldehyde-boronic acid were substituted for 5-(hydroxymethyl)thiophen-2-ylboronic acid and 4-bromobenzaldehyde, respectively, in Example 22, Step A, the similar process afforded the title compound in 81% yield, as creamy gum. 1H-NMR (CDCl3) 10.05 (s, 1H); 7.92 (d, 2H, J=8.25 Hz); 7.68 (d, 2H, J=8.28 Hz); 7.23 (s, 2H); 7.10 (s, 1H); 3.91 (s, 9H); 2.55 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1(/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([O:33][CH2:34][CH2:35][CH2:36][C:37]#[CH:38])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C>C1COCC1.[Cu]I.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>[C:1]([O:5][C:6]([NH:8][C:9]1(/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([C:38]#[C:37][CH2:36][CH2:35][CH2:34][O:33][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(/C=C/c2ccc(Br)cc2)COC(C)(C)OC1
Reactant: C#CCCCOCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(/C=C/c2ccc(C#CCCCOCc3ccccc3)cc2)COC(C)(C)OC1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
To a solution of 17 (0.21 g, 0.51 mmol) and 5-benzyloxy-1-pentyne (133 mg, 0.77 mmol) in N,N-diisopropylethylamine (1 mL, 5.7 mmol) and dry THF (5 mL) were added CuI (9.7 mg, 51 μmol) and tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 25.5 μmol) under nitrogen. The mixture was heated at reflux under nitrogen for one day, and then was cooled to room temperature and filtered through a short pad of silica gel to remove insoluble and very polar components in the mixture. The filtrate was concentrated and dissolved in CH2Cl2 (50 mL). The solution was washed with water (2×20 mL) and brine (2×20 mL), and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified by column chromatography (hexanes/EtOAc 20:1 to 6:1) to give 18 (0.14 g, 53%). 1H NMR δ 7.43-7.19 (m, 4H), 6.49 (d, 1H, J=16.4 Hz), 6.21 (d, 1H, J=16.4 Hz), 5.43 (s, 1H), 4.50 (s, 2H), 3.98 (d, 2H, J=11.2 Hz), 3.87 (d, 2H, J=11.2 Hz), 3.59 (t, 2H, J=6.0 Hz), 2.53 (t, 2H, J=6.8 Hz), 1.89 (m, 2H), 1.45 (s, 15H); 13C NMR δ 154.4, 138.1, 135.5, 131.3, 129.3, 127.9, 127.2, 127.1, 125.9, 122.8, 97.8, 90.1, 80.6, 79.0, 72.5, 68.3, 65.6, 52.7, 28.5, 28.0, 27.1, 19.3, 15.9. HRMS m/z: calcd for C31H39NNaO5 (MNa+), 528.2720; found, 528.2727.
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:21]([O:23][CH3:24])=[O:22])[C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C1COCC1>[O:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([C:21]([O:23][CH3:24])=[O:22])[C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCCCCI
Reactant: COC(=O)C(C(=O)OC)c1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCC(C(=O)OC)(C(=O)OC)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a suspension of NaH (144 mg of 60% in mineral oil washed with hexanes, 86.4 mg, 3.6 mmol) in dry THF (20 mL) was carefully added dimethyl 2-(4-phenoxyphenyl)malonate (900 mg, 3.0 mmol). The resulting mixture was stirred at room temperature for 1 hour and then 1-iodohexane (1.27 g, 0.89 mL, 6.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then heated to reflux overnight . The reaction was cooled to room temperature and quenched with 1N HCl (20 mL) and extracted with ether (2×40 mL). The combined organic extracts were washed with saturated Na2S2O3, water, then brine, dried (Na2SO4), concentrated, and purified by chromatography using a Chromatotron with a silica gel plate (4000 micron) eluted with 13% EtOAc/hexanes to give 950 mg of dimethyl 2-(4-phenoxyphenyl)-2-n-hexylmalonate as a viscous oil. 1H NMR (200 mHz, CDCl3) δ 7.39-6.92 (9H, m), 3.75 (6H, s), 2.10 (2H, t), 1.29 (8H, m), 0.87 (3H, t).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)(O)=O.S(N)([NH2:17])(=O)=O.S(Cl)(Cl)=O.O>S1(CCCC1)(=O)=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)#[N:17]
Reactant: O=C(O)c1ccc2c(c1)COC2=O
Reactant: NS(N)(=O)=O
Solvent: O=S1(=O)CCCC1
Solvent: O
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc2c(c1)COC2=O
Temperature: 135 °C
Reaction time: 0.25 h

Procedure:
5-Carboxyphthalid (50 g, 0.28 mole) and sulfamide (31 g, 0.32 mole) were suspended in sulfolane (150 mL). Thionylchloride (41 g, 0.34 mole) was added and the temperature was raised to 130-140° C. for 2 hours. At about 90° C., gas evolution took place. The mixture was allowed to cool to 90° C. and water (150 mL) was added. The temperature was held at 85-90° C. for 15 min and then the solution was cooled to 35° C. The crystals were filtered off and washed with water (250 mL). The title compound was crystallised from acetic acid.Yield: 34.5 g, 77%. DSC onset: 203° C. Purity: 98.5% (hplc, peak area). 1H NMR (DMSO-d6, 500 MHz): 5.48 (2H, s), 8.03 (2H, s), 8.22 (1H, s). 13C NMR (DMSO-d6, 125 MHz): 70.0, 116.1, 188.0, 126.0, 127.5, 129.0, 132.8, 147.7, 169.3.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.[SH:18][C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:27][C:21]=2[N:20]=1>C(O)(C)C>[ClH:2].[ClH:1].[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][S:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][S:18][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]([F:33])([F:31])[F:32])=[CH:27][C:21]=3[N:20]=2)[C:9]=1[CH3:10]
Reactant: FC(F)(F)COc1ccc2[nH]c(S)nc2c1
Reactant: Cc1c(SCc2ccco2)ccnc1CCl
Agent: Cl
Solvent: CC(C)O
Product: Cc1c(SCc2ccco2)ccnc1CSc1nc2cc(OCC(F)(F)F)ccc2[nH]1

Procedure:
Following the procedure described in Example 12, the reaction of 2-chloromethyl-4-(2-furylmethylthio)-3-methylpyridine hydrochloride with 2-mercapto-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole in isopropanol gives the title compound as a colorless solid; m.p. 161-163° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1.C(N(CC)CC)C.[CH2:19]([CH:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:30](Cl)=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>CN1CCCC1=O.C1COCC1.C(OCC)(=O)C>[CH2:19]([CH:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:30]([NH:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1)=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Nc1ccc2c(c1)=NC(=O)N=2
Reaction time: 8 h

Procedure:
5-Aminobenzimidazolone (2.93 g, 19.6 mmol, obtained from TCI America, Oregon, USA) and triethylamine (4 mL, 28.7 mmol) were dissolved in 20 mL N-methylpyrrolidinone in a 250 mL round-bottom flask under inert atmosphere. To this solution, a second solution of 2-decyltetradecanoyl chloride from Step 1 dissolved in dry THF (150 mL) was slowly added. After stirring overnight, deionized water was added and the mixture was poured into 300 mL ethyl acetate and washed with three 100 mL portions of deionized water. The organic layer was then concentrated by rotary evaporation until a white slurry was obtained. The solid was collected by filtration and washed with cold ethyl acetate to give 5-(2′-decyltetradecanamido)-2-benzimidazolone as a white solid (7.18 g). The product was identified by 1H and 13C NMR spectroscopy and ESI-MS and was of satisfactory purity. The compound was believed to be of the formula
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C@H:20]4[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:10][N:9]=2)=[CH:4][C:3]=1[F:29].[Cu][C:31]#[N:32].CN1C(=O)CCC1.Cl>O>[C:31]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([C@H:20]4[CH2:21][CH2:22][C@H:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]4)=[CH:18][CH:19]=3)=[CH:12][N:13]=2)=[CH:4][C:3]=1[F:29])#[N:32]
Reactant: N#C[Cu]
Reactant: CCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(Br)c(F)c4)nc3)cc2)CC1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(C#N)c(F)c4)nc3)cc2)CC1
Temperature: 60 °C

Procedure:
3.5 g (0.008 mol) of 2-(4'-bromo-3'-fluorophenyl)-5-[4'-(trans-4"-propylcyclohexyl)phenyl]pyrimidine and 1.1 g (0.012 mol) of copper (I) cyanide were added to 31 cm3 of NMP and the solution was refluxed for 2 hours using a mantle heater. The solution was cooled to 60° C. and added to a solution of 4.2 g of FeC13.6H2 o, 1.3 cm3 of concentrated hydrochloric acid and 6 cm3 of water. The resulting solution was maintained on a warm water bath at 60° C. for one hour. The crystals deposited were filtered, washed with water and treated through a silica gel column with chloroform as the solvent. The chloroform was distilled off and the residue was recrystallized from acetone to yield 1.9 g (0.005 mol) of 2-(4'-cyano-3'-fluorophenyl)-5-[4'-(trans-4"-propylcyclohexyl)phenyl]pyrimidine. The phase transition temperature of this compound measured by DSC, was: ##STR32##
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=O.[NH2:23][C:24]([NH2:26])=[S:25].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:12][C:8]1[N:7]=[C:6]([C:4]2[N:23]=[C:24]([NH2:26])[S:25][C:3]=2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(C(=O)C(Br)c2ccc3ncccc3c2)n1
Reactant: NC(N)=S
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cccc(-c2nc(N)sc2-c2ccc3ncccc3c2)n1
Temperature: 25 °C

Procedure:
A solution of 2-bromo-1-(6-methyl-pyridin-2-yl)-2-quinolin-6-yl-ethanone hydrobromide (24.5 mg, 0.072 mmol), thiourea (7.5 mg, 0.094 mmol, 1.3 equiv), and potassium carbonate (0.11 mmol, 1.5 equiv) in ethanol (1 mL) is heated to 80° C. overnight. The resulting reaction mixture is cooled to ambient temperature and concentrated in vacuo. Reverse phase high pressure liquid chromatography (a gradient from 5-30% acetonitrile in 0.1% aqueous formic acid) provides 4-(6-Methyl-pyridin-2-yl)-5-quinolin-6-yl-thiazol-2-ylamine.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[F:22][C:23]1[CH:24]=[C:25]([CH:30]([NH2:32])[CH3:31])[CH:26]=[C:27]([F:29])[CH:28]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:22][C:23]1[CH:24]=[C:25]([CH:30]([NH:32][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=2)[CH3:31])[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: CCCOc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Reactant: CC(N)c1cc(F)cc(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCCOc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Yield: 98.2 %

Procedure:
Following a similar procedure to that described in Example (1a), 790 mg of 3-nitrophenyl 4-propoxyphenyl ketone, 870 mg of 1-(3,5-difluorophenyl)ethylamine, 1.54 ml of triethylamine, 0.37 ml of titanium tetrachloride, 733 mg of sodium cyanoborohydride and 0.24 ml of acetic acid were reacted, to obtain 1.16 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[C:15]([O:17]CC3C=CC=CC=3)[C:14]([O:25][CH3:26])=[CH:13][C:12]=2[CH:27]2[CH:36]3[CH2:37][C:38]4[C:43]([CH:35]3[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:44](=[NH:46])[NH2:45])[CH:33]=3)[NH:28]2)=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:6][CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:47])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[C:15]([OH:17])[C:14]([O:25][CH3:26])=[CH:13][C:12]=2[CH:27]2[CH:36]3[CH2:37][C:38]4[C:43]([CH:35]3[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:44](=[NH:45])[NH2:46])[CH:33]=3)[NH:28]2)=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Oc2cc(OCc3ccccc3)c(OC)cc2C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(Oc2cc(O)c(OC)cc2C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)cc1

Procedure:
A solution of 4-[5-Benzyloxy-2-(2-carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-4-methoxy-phenoxy]-benzoic acid methyl ester (63 mg, 0.1 mmol) in 2 mL of MeOH was hydrogenated overnight using 10%Pd—C (20 mg) to give 4-[2-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5-hydroxy-4-methoxy-phenoxy]-benzoic acid methyl ester that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[NH2:15]>>[NH2:15][C:14]1[CH:13]=[C:12]([O:11][CH3:10])[C:18]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:17][C:16]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: COCCOc1ccc(N)cc1OC
Reactant: O=Cc1ccccc1Cl
Product: COCCOc1cc(C(=O)c2ccccc2Cl)c(N)cc1OC

Procedure:
(2-amino-4-methoxy-5-(2-methoxyethoxy)phenyl)-(2-chlorophenyl)-methanone (Xkk) was prepared by reacting 2-chlorobenzaldehyde with 0.0242 moles of 3-methoxy-4-(2-methoxyethoxy) aniline in a manner analogous to Example 1. MH+/Z=336.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=3[Cl:24])=[O:13])[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.ClC1C(C(F)(F)F)=CC=CC=1C(O)=O.CCN=C=NCCCN(C)C.[CH:50]1[CH:51]=[CH:52][C:53]2[N:58]([OH:59])[N:57]=[N:56][C:54]=2[CH:55]=1>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[C:15]=3[Cl:24])=[O:13])[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:58]1([O:59][C:2]2[C:3]3[CH2:11][CH2:10][N:9]([C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=4[Cl:24])=[O:13])[CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:53]2[CH:52]=[CH:51][CH:50]=[CH:55][C:54]=2[N:56]=[N:57]1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(Cl)ncnc2C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(ncnc2On2nnc3ccccc32)C1
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of the product of Intermediate 3 step a (305 mg, 1.80 mmol) in DCM (9 mL) was added 2-chloro-3-(trifluoromethyl)benzoic acid (404 mg, 1.80 mmol) followed by EDCI (517 mg, 2.70 mmol), HOBt (170 mg, 1.26 mmol) and TEA (0.50 mL, 3.60 mmol). The mixture was stirred overnight and then loaded directly on a column. Chromatography on SiO2 eluting with EtOAc/Hex afforded the desired product (267 mg, 39%) and 4-(1H-benzotriazol-1-yloxy)-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (203 mg, 24%) as a side product. MS (ESI) mass calcd. C15H10Cl2F3N3O, 375.02. m/z found 376.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.89-8.74 (m, 1H), 7.84-7.76 (m, 1H), 7.55-7.45 (m, 2H), 5.13-4.94 (m, 1H), 4.54-4.35 (m, 1H), 4.23-4.06 (m, 1H), 3.64-3.52 (m, 1H), 3.10-2.78 (m, 2H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38][N:37]=1>>[Cl:35][C:36]1[CH:41]=[C:40]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:30])=[O:31])[CH2:27][CH2:28]2)=[O:22])[CH:39]=[CH:38][N:37]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)C(C)C)CC4)cc3c2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)C(C)C)CC2)n3-c2ccnc(Cl)c2)CC1
Yield: 41 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 3.5 days at 35° C., from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-[4-(propane-2-sulfonyl)-piperazin-1-yl]-methanone (example 15) and 2-chloropyridine-4-boronic acid to afford the desired product as a light-brown foam (41%). MS (ISP): 601.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Al](Cl)(C)C.[CH3:13][N:14]([CH3:39])[C:15]([C:17]1[N:22]=[CH:21][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34](OCC)=[O:35])[CH:25]=2)=[CH:19][CH:18]=1)=[O:16]>ClCCCl.C(Cl)Cl>[CH3:39][N:14]([CH3:13])[C:15]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)=[O:35])[CH:25]=2)=[CH:21][N:22]=1)=[O:16]
Reactant: CCOC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2cc(C)oc2c1
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N(C)C)nc3)c3cc(C)oc3c2)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.2 %

Procedure:
To a solution of 5-methylpyridin-2-amine (191 mg, 1.76 mmol) in DCE at 0° C. was added Al(CH3)2Cl drop-wise. After stirring the mixture at room temperature for 20 minutes ethyl 4-({6-[(dimethylamino)carbonyl]pyridin-3-yl}oxy)-2-methyl-1-benzofuran-6-carboxylate (65 mg, 0.18 mmol) was added. The reaction was stirred at room temperature for 14 hours. The sample was diluted with CH2Cl2 and quenched with potassium sodium tartrate tetrahydrate (20% w/w) (1 mL). Caution, addition was done slowly. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude sample was introduced into a silica gel column and eluted with MeOH/CHCl3 (3/97) to provide the product (35 mg, 85% yield) as white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.32 (s, 3 H) 2.48 (s, 3 H) 3.16 (d, J=7.54 Hz, 6 H) 6.26 (s, 1 H) 7.31 (dd, J=8.67, 2.83 Hz, 1 H) 7.48 (d, J=1.13 Hz, 1 H) 7.58 (d, J=6.78 Hz, 1 H) 7.69 (d, J=8.67 Hz, 1 H) 7.87 (s, 1 H) 8.12 (s, 1 H) 8.26 (d, J=8.48 Hz, 1 H) 8.38 (d, J=2.64 Hz, 1 H) 8.53 (s, 1 H); MS (ESI, pos): 431.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:36][CH2:35][CH2:34][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:33])[CH2:21][S:22]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:23])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:36][CH2:35][CH2:34][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:33])[CH2:21][S:22]([C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=1)=[O:23])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CS(=O)c1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: O=C(CS(=O)c1ccc([N+](=O)[O-])cc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 76.5 %

Procedure:
(2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-[1-hydroxy-2-(4-nitrophenylsulfinyl)ethyl]pyrrolidine (883 mg) was subjected to DMSO-DCC oxidation as in Example 1-D) to give 673 mg of the title compound (See Table 3).