Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CCCCCC>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=1)=[O:29]
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)Nc2ccccc2-c2cc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of commercially available 2-(1H-indol-2-yl)benzenamine (62 mg, 0.3 mmol) in dichloromethane (1.5 mL) at rt was added 4-tert-butylphenyl isocyanate (30 mg, 0.171 mmol). The reaction was stirred overnight at rt. Hexane (1 mL) was added to the reaction mixture and the reaction was allowed to set for ˜5 min. Example 1 was the solid formed which was collected by filtration (47.3 mg). (M+H)+=384.37.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[N:4]=1
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Reactant: C1CCNC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1nc(N2CCCC2)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A solution of Example C2 (0.15 g, 0.36 mmol) in DCM (5 mL) was treated with mCPBA (0.11 g, 0.43 mmol), stirred at RT for 2 h, treated with pyrrolidine (0.5 mL) and stirred at RT overnight. The mixture was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain 4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(pyrrolidin-1-yl)pyrimidine (100 mg, 63%). MS (ESI) m/z: 444.2 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:14](=[O:23])[CH2:13][C:12]2=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:29][CH2:30][CH2:31][NH2:32].N1C(C)=CC=CC=1C>C(O)(C)C>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([C:12]3[NH:32][CH2:31][CH2:30][CH2:29][C:13]=3[C:14](=[O:23])[N:15]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCBr
Reactant: O=C1CC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1
Agent: Br
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: O=C1C2=C(NCCC2)C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1
Temperature: 80 °C

Procedure:
To a solution of 8-benzyl-1-(3-fluorophenyl)-1,8-diazaspiro[4.5]decane-2,4-dione (Intermediate 1A.4-1, 300 mg, 0.85 mmol) in isopropanol (4.3 ml) were added 3-bromopropylamine hydrobromide (205 mg, 0.94 mmol) and 2,6-lutidine (0.22 ml, 1.87 mmol). The reaction vessel was sealed and heated at 80° C. for 3 days. The reaction was concentrated in vacuo and partitioned between dichloromethane and 1N NaOH. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography (silica, 0-5% methanol (10% NH4OH)/dichloromethane) to yield 1-benzyl-6′-(3-fluorophenyl)-1′,2′,3′,4′-tetrahydrospiro[piperidine-4,7′-pyrrolo[3,4-b]pyridin]-5′(6′H)-one. LCMS (M+H) 392.1. 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 6H), 7.03 (td, J=8.2, 2.0 Hz, 1H), 6.97 (d, J=7.9 Hz, 1H), 6.92 (dt, J=9.9, 2.1 Hz, 1H), 3.46 (s, 2H), 3.33 (m, 2H), 2.52 (t, J=6.1 Hz, 41H), 2.33 (t, J=6.2 Hz, 2H), 2.06 (quint, J=6.9 Hz, 2H), 1.84 (m, 4H).
Reaction SMILES: [Cl:1][C:2]([Cl:14])=[CH:3][CH2:4][CH:5]([CH:11]([CH3:13])[CH3:12])[C:6]([O:8]CC)=[O:7].C(=O)([O-])[O-].[K+].[K+].CO>O>[Cl:1][C:2]([Cl:14])=[CH:3][CH2:4][CH:5]([CH:11]([CH3:12])[CH3:13])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(CC=C(Cl)Cl)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)C(CC=C(Cl)Cl)C(=O)O
Temperature: 25 °C
Yield: 88.8 %

Procedure:
A mixture of 67.0 g (0.28 mol) of ethyl 5,5-dichloro-2-isopropyl-4-pentenoate, 77.35 g (0.56 mol) of anhydrous potassium carbonate, 2128 ml of methanol, and 708 ml of water was refluxed 4 days under nitrogen. The reaction mixture was then cooled to room temperature and about two-thirds of the solvent removed on the rotary evaporator. The residue was taken up in three times its volume of water, extracted twice with ether, and acidified with conc. HCl. The acidified reaction mixture was extracted into ether, the ether solution washed with water, dried (MgSO4), and removed. The residue was vacuum distilled to give 52.5 g (89% yield) of 5,5-dichloro-2-isopropyl-4-pentenoic acid, b.p. 91°-96° C./0.30 mm.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[CH3:28][S:29][CH2:30][CH2:31][NH2:32]>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:4]([O:26][CH3:27])=[CH:3][C:2]=1[NH:32][CH2:31][CH2:30][S:29][CH3:28]
Reactant: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CSCCN
Product: COc1cc(NCCSC)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 76 %

Procedure:
As described for example 26, 2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (300 mg, 0.81 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using 2-(methylthio) ethylamine instead of thiomorpholine to the title compound (273 mg, 76%) which was obtained as an off-white solid. MS: m/e=441.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13]C)=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.[Na+].[I-]>C(#N)C>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:11]2[CH:12]=[C:7]([O:6][C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=[CH:9][C:10]2=[O:13])=[CH:20][CH:19]=1
Reactant: COc1ccc(Oc2ccc(F)cc2)cn1
Reactant: ClCc1ccc(Cl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1ccc(Oc2ccc(F)cc2)cn1Cc1ccc(Cl)cc1
Yield: 27 %

Procedure:
According to Scheme 32 Step 1: 5-(4-Fluorophenoxy)-2-methoxypyridine (2.37 mmol, 520 mg), 4-chlorobenzylchloride (3.55 mmol, 603 mg), NaI (2.37 mmol, 356 mg) in acetonitrile (15 mL) was heated at 150° C. for 20 minutes under microwave conditions. The cooled crude reaction washed with water, extracted with AcOEt. The organic layer was collected, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified in a manifold (vac.) using a Sep-Pak silica cartridge (heptane/AcOEt, 90:10 to CH2Cl2) and then CH2Cl2/acetone 90:10), following HPLC purification yielding 1-(4-chlorobenzyl)-5-(4-fluorophenoxy)pyridin-2(1H)-one (211 mg, 27%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14]Cl)[CH:6]=1)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[NH:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][C:24]1=[NH:32]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[NH:25][C:24]2=[NH:32])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(OCCCCl)c1
Reactant: N=c1[nH]c2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OCCCn2c(=N)[nH]c3ccccc32)c1
Temperature: 50 °C
Yield: 69.7 %

Procedure:
To a solution of 3-(3-chloro-propoxy)-benzoic acid ethyl ester (5.50 g, 22.7 mmol) in DMF (150 ml) at rt was added Cs2CO3 (14.8 g, 45.5 mmol) and 1,3-dihydro-benzoimidazol-2-ylidene amine (2.75 g, 20.7 mmol). The reaction was heated to 50° C. for 12 h. After this time, the resulting mixture was cooled to rt and partitioned between EtOAc and H2O. The organic layer was separated and the aqueous phase was extracted with additional EtOAc. The combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated under redcued pressure. The crude product was purified by chromatography on silica eluting with 2% MeOH/dichloromethane to give 3-[3-(2-imino-2,3-dihydro-benzoimidazol-1-yl)-propoxy]-benzoic acid ethyl ester (4.9 g g, 64%). HPLC-MS 340 [M+1]+.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:31]1([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: OB(O)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccccc1
Yield: 56 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and phenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (56% yield); 1H-NMR (d6-DMSO) 1.04 (9H, s), 3.68 (2H, m), 4.09 (2H, m), 6.38 (1H, s), 7.18-7.20 (3H, m), 7.27-7.29 (2H, m); 13C-NMR (CDCl3) 27.7, 41.5, 66.8, 125.0, 126.3, 128.0, 132.2; MS ES(+) 206.0 (M+-tBu); HRMS m/z calcd for C15H19NO3+H+ 262.1443 [M+H+]. Found 262.1447. IR λmax=3441, 1701, 1367, 1355, 1163 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1cccc(OCc2ccccc2)c1)Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(NCCc2cccc(OCc3ccccc3)c2)cc1Cl
Temperature: 80 °C
Yield: 96.3 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-2-[3-(phenylmethoxy)phenyl]acetamide (4.5 g, 0.012 mol) in THF (20 ml) on ice was added the borane-tetrahydrofuran complex (15 ml, 0.023 mol). The reaction was allowed to reflux at 80° C. for six hours. The reduction reaction was placed on ice, acidified using 4 N HCl, then stirred for twenty minutes. The reaction was then basified with an aqueous solution of potassium hydroxide. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound (4.3 g, 99% yield): ES−MS (m/z) 372 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCNCC
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Product: CCOC(=O)c1c(N(CC)CC)nc2ccc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
This compound was prepared in analogy to example 29 step D from 6-chloro-4-(2-chloro-benzyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 29 step C, 100 mg, 0.2 mmol) and diethyl amine (0.047 ml, 0.39 mmol). Pale yellow solid (52 mg, 61%). LC-MS (ESI): 431 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].O[Li].O>C1COCC1.O>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)CCCOc1ccc(Cl)cc1Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCOc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.3 %

Procedure:
To a solution of ethyl 4-(2,4-dichlorophenoxy)-butyrate (57 g, crude from last step, about 0.2 mol) in THF (500 mL) and water (500 mL) was added LiOH.H2O (12.6 g, 0.3 mol), and the reaction mixture was stirred for 5 h at RT. The mixture was washed with Et2O (3×200 mL), and the aqueous layer was acidified by addition of HCl (20%) to pH ˜2. The mixture was extracted with EtOAc (3×400 mL), the combined organic extracts were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the butyric acid (37 g, 74.3% from 2,4-dichlorophenol) as a white solid. 1H-NMR (CDCl3): δ 7.36 (d, 1H, J=8.8 Hz), 7.18 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 6.84 (d, 1H, J=8.8 Hz), 4.07 t, 2H, J=7.2 Hz), 2.64 (t, 2H, J=7.2 Hz), 2.17 (p, 2H, J=6.4 Hz).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[C:17]([O:21][C:22](=[O:27])[NH:23][C:24](Cl)=[O:25])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:17]([O:21][C:22](=[O:27])[NH:23][C:24](=[O:25])[NH:2][CH2:3][CH2:4][O:5][N:6]1[C:7](=[O:16])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]1=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: NCCON1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)NC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=O)NCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(2-aminoethoxy)-1H-isoindole-1,3(2H)-dione hydrochloride 75 (0.40 g, 1.65 mmol, EP 1674452 A1, 2006), tert-butyl(chlorocarbonyl)carbamate 82 (1.70 g crude, US 2005/187277 A1) in DCM (10 mL) was added triethylamine (0.69 mL, 4.95 mmol) slowly at 0° C. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 83 (0.56 g, 96° A) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[O:24]2)[CH2:20][CH2:19]1)=[O:17].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([NH:40][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[O:24]2)[CH2:20][CH2:19]1)=[O:17])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)OC(=O)c3ccccc34)cnc12
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)OC(=O)c3ccccc34)cnc12
Yield: 76.8 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(3-oxo-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.160 g, 0.352 mmol) obtained in step 2 and benzylamine (0.100 mL, 0.881 mmol), the title compound (0.142 g, 76%) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.Cl>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]5)=[CH:32][CH:31]=4)[N:7]=3)=[CH:12][NH:11][N:10]=2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: Cl
Product: CN1CCN(c2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
The solution of 150 mg (0.515 mMol) of 2-chloro-4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidine in 5 mL of 1,4-dioxanes (Merck p.a. 9671) at rt is treated with 99 mg of 4-(4-methyl-piperazin-1-yl)-phenylamine (0,515 mMol, 1 Eq.) and 235 mg (2.06 mMol; 202 μl; 4 Eq.) of HCl (32%) (Fluka puriss 84416). The yellow suspension is stirred for 24 h at 100° C. After cooling to rt, the supernatant is decanted and discarded. The smeary residue is treated with 10 ml of NaHCO3 satd. solution and 10 ml of ethyl acetates. The precipitated crude product is filtered off and dried at 60° C. under reduced pressure. The combined organic layers are re-extracted with water, dried (Na2SO4), and evaporated to obtain additional crude product. The combined crude products are purified by means of column chromatography over silica gel (Si60 (0,040-0,063 mm) Merck); eluting with CH2Cl2/CH3OH/NH4OH (9:1:0.1). Final purification is done by suspending the obtained beige crystals in CH2Cl2/CH3OH (1:1) to obtain {4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as pure crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:14]=[CH:13][NH:12][CH:11]=2)=O)=[CH:6][CH:5]=[C:4]([Cl:15])[N:3]=1.O.[NH2:17][NH2:18]>C(O)C>[Cl:15][C:4]1[N:3]=[C:2]2[NH:17][N:18]=[C:8]([C:10]3[CH:14]=[CH:13][NH:12][CH:11]=3)[C:7]2=[CH:6][CH:5]=1
Reactant: O=C(c1cc[nH]c1)c1ccc(Cl)nc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: Clc1ccc2c(-c3cc[nH]c3)n[nH]c2n1
Temperature: 90 °C

Procedure:
A mixture of (2,6-dichloro-pyridin-3-yl)-(1H-pyrrol-3-yl)-methanone (300 mg) and hydrazine hydrate (0.2 mL) in ethanol (10 mL) was heated at 90° C. for 20 hours. The reaction was concentrated to 6 mL, diluted with water (2 mL) and cooled. The precipitate was collected and dried to give 160 mg of the titled compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])=[O:36])=[CH:29][C:25]=1[C:26]([OH:28])=O.[Br:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49](=[O:59])[C:50]2[CH:55]=[C:54]([NH2:56])[CH:53]=[CH:52][C:51]=2[O:57][CH3:58])=[CH:44][CH:43]=1>CN(C=O)C>[CH3:58][O:57][C:51]1[CH:52]=[CH:53][C:54]([NH:56][C:26](=[O:28])[C:25]2[CH:29]=[C:30]([CH2:33][NH:34][C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])=[O:36])[CH:31]=[CH:32][C:24]=2[Cl:23])=[CH:55][C:50]=1[C:49]([NH:48][C:45]1[CH:46]=[CH:47][C:42]([Br:41])=[CH:43][CH:44]=1)=[O:59]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: COc1ccc(N)cc1C(=O)Nc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cc(CNC(=O)C(C)(C)C)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Reaction time: 0.08 h

Procedure:
TBTU (40 mg, 0.125 mmol) in 0.25 mL DMF was added to 2-chloro-5-(tert-butylcarbonylamino)methyl-benzoic acid (34 mg, 0.125 mmol), followed by 50 μL TEA and the mixture was stirred for 5 min. Then N-(4-bromophenyl)-2-methoxy-5-amino-benzoic acid amide in 0.25 mL DMF was added and it was stirred overnight. The crude mixture was filtered through aluminium oxide and the solid phase was washed 4× with 1 mL DMF/MeOH 9:1. The combined organic phase was concentrated i.vac. dissolved in Acetonitrile/HCOOH, filtered and dried via lyophilisation to furnish the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:5][C:6]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][CH:7]=1)[CH3:4].[CH2:13](Br)[CH3:14]>C1(C)C=CC=CC=1>[CH2:3]([N:5]([CH2:13][CH3:14])[C:6]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][CH:7]=1)[CH3:4]
Reactant: CCBr
Reactant: CCNc1cccc(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CC)c1cccc(C)n1
Temperature: 93 °C
Reaction time: 1 h

Procedure:
To a 3000 ml dry toluene were added 185 g of 60% sodium hydride. A solution of 632 g of 6-ethylamino-2-picoline and 500 ml of toluene was dropwise added at 90° C. over about 2 hours to the resulting dispersion and stirred at 93° C. for additional one hour. Ethyl bromide of 554 g were dropwise added at 90° C. over about 2 hours to the resulting mixture and stirred for additional one hour. The reation mixture was added to 3000 ml of ice water. The organic phase was extracted and the extract was washed two times with water, concentrated and dried. The product obtained above was evaporated under reduced pressure (7 mmHg). Thus, 630 g of 6-diethylamino-2-picoline (bp7 103-108) were obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23][CH3:24])=[O:22])[CH2:12][CH2:11]2)=[CH:2]1.[H-].[Na+].[CH2:31]([O:33][CH2:34][CH2:35]Br)[CH3:32]>CN(C=O)C>[CH2:31]([O:33][CH2:34][CH2:35][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23][CH3:24])=[O:22])[CH2:12][CH2:11]2)=[CH:2]1)[CH3:32]
Reactant: CCOCCBr
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCn1cc(C2CCN(CCOc3ccccc3C(=O)OC)CC2)c2ccccc21
Reaction time: 4 h

Procedure:
8.0 g (0.021 mol) of methyl 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoate were dissolved in 125 ml of DMF and, at room temperature, 1.12 g (0.028 mol) of 60% sodium hydride was carefully added. This mixture was stirred for half an hour. 2.9 ml (0.023 mol) of 2-bromoethyl ethyl ether were dropwise added and the stirring was continued for 4 h. The solvent was evaporated under reduced pressure and the residue was worked-up as usual. The crude mixture was purified by flash-chromatography over silica gel affording 4.12 g (54% of yield) of methyl 2-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoate
Reaction SMILES: CC([N:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31](=[O:39])[CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:25][CH:24]=1)=[O:22])C(=O)[O-])(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:5][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21](=[O:22])[C:23]1[CH:24]=[CH:25][C:26]([CH2:29][NH:30][C:31](=[O:39])[CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)N(C(=O)[O-])c1ccc(-c2cccs2)cc1NC(=O)c1ccc(CNC(=O)Cc2cccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CNC(=O)Cc2cccnc2)cc1
Reaction time: 0.33 h

Procedure:
1,1-dimethylethyl[2-{[(4-{[(pyridin-3-ylacetyl)amino]methyl}phenyl)carbonyl]amino}-4-(2-thienyl)phenyl]carbamate was stirred in 10 mL of TFA/DCM (1:1 v/v) for 2 hours. Then 20 mL of saturated NaHCO3 was added to the reaction mixture and the resulted solution was stirred for 20 minutes, 50 mL of DCM was added to the reaction mixture and the organic layer was separated and the aqueous phase was extracted with DCM (50 mL×2), the combined organic layers were washed with brine, dried over Na2SO4, the solvent was removed and the residue was washed with 10 mL of anhydrous ethyl ether, filtered to give N-[2-amino-5-(2-thienyl)phenyl]-4-{[(pyridin-3-ylacetyl)amino]methyl}benzamide as a beige solid. 1H NMR (MeOD, 600 MHz) δ 8.49 (s, 1H), 8.43 (d, J=5.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.0 Hz, 1H), 7.40 (m, 5H), 7.21 (m, 2H), 7.02 (m, 1H), 6.90 (d, J=8.4 Hz, 1H), 4.48 (s, 2H), 3.64 (s, 2H). MS: cal'd 443 (MH+), exp 443 (MH+).