Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])[OH:4].[Na+].[I-:14]>CC(C)=O>[I:14][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])[OH:4]
Reactant: O[C@H](CCl)c1ccc(Cl)cc1Cl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O[C@H](CI)c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
(S)-2-Chloro-(2′,4′-dichlorophenyl)-1-ethanol (4 g, 17.74 mmol) was dissolved in 100 mL of anhydrous acetone (4 Å molecular sieves). The solution was flushed with nitrogen, and NaI (12.75 g, 85.10 mmol) was added to the solution and the solution refluxed for 3.5 hours under nitrogen. Upon cooling to room temperature, the solution was poured into about 320 mL of hexanes/ethyl acetate (3:1), with stirring. The solution was then filtered to remove excess NaI which had precipitated. The filtrate was evaporated to dryness in vacuo to yield a yellow oil. The oil was decanted, the residue treated with ether, and the ether washings decanted from the solid NaI. The ether solutions were combined and evaporated to dryness. Upon removal of ether, the product was obtained as a yellow crystalline solid. Yield: 4.70 g (84%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:5]([O:7]C)=[O:6].[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(N2CCOCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1N1CCOCC1
Temperature: 50 °C
Yield: 9.6 %

Procedure:
To a stirred solution of methyl 3-methyl-4-morpholin-4-ylbenzoate obtained in step 1 (4 g, 169.3 mmol) in THF (100 mL) and water (5 mL) was added lithium hydroxide (2 g, 84.6 mol). The resulting mixture was heated at 50° C. for 12 h. Solvents were removed under vacuum and the resulting mass was diluted with water. The aqueous layer was washed with DCM (2×50 mL) and was acidified with conc HCl (pH=4). It was extracted with EtOAc (2×100 mL). The EtOAc layer was washed with brine and dried over sodium sulfate, affording the title compound as a yellow solid (3.6 g, 97%). 1H NMR (DMSO-d6, 400 MHz) δ 12.5 (bs, 1H), 7.72-7.74 (m, 2H), 7.04-7.06 (m, 1H), 3.72-3.75 (m, 4H), 2.88-2.90 (m, 4H), 2.33 (s, 3H). LC/MS (Method A): 222.1 (M+H)+. HPLC (Method B) Rt 1.42 min (Purity: 98.3%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>ClCCl>[CH2:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:19][CH2:20][C@H:21]([NH:24][C:28]([NH:27][CH2:25][CH3:26])=[O:29])[CH2:22][CH2:23]4)[CH2:14][CH2:15]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCN=C=O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3CCC4)CC2)CC1
Solvent: ClCCl
Product: CCNC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3CCC4)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.4 g (1 mmol) trans-4-{2-[4-(indan-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine was dissolved in dry dichloromethane (30 ml), ethylisocyanate (0.1 ml, 1.3 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was recrystallized from acetonitrile giving the title compound (0.22 g, 55%), melting at 198-200° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([Cl:24])[CH:18]=2)=[O:15])[C:5]2[N:9]=[C:8]([N:10]([CH3:12])[CH3:11])[NH:7][C:6]=2[CH:13]=1.C(N(CC)C(C)C)(C)C.[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:36]=1[C:37](Cl)=[O:38]>C1COCC1.C(OCC)(=O)C>[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:36]=1[C:37]([NH:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([Cl:24])[CH:18]=2)=[O:15])[C:5]2[N:9]=[C:8]([N:10]([CH3:11])[CH3:12])[NH:7][C:6]=2[CH:13]=1)=[O:38]
Reactant: Cc1ccc(NC(=O)c2cc(N)cc3[nH]c(N(C)C)nc23)cc1Cl
Reactant: O=C(Cl)c1c(F)cccc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cc(NC(=O)c3c(F)cccc3Cl)cc3[nH]c(N(C)C)nc23)cc1Cl

Procedure:
To a solution of 6-amino-N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (50 mg) in THF (1.5 mL), was added N,N-diisopropylethylamine (37 μL) and the mixture was stirred under ice-cooling. To the mixture was added slowly 2-chloro-6-fluorobenzoyl chloride (24 μL), and it was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (30 mg) as pale yellow powder. This was then suspended in MeOH (1 mL), 2N hydrogen chloride/MeOH (1 Eq) was added to obtain a homogeneous solution, and MeOH was removed under reduced pressure. The residue was triturated in n-hexane/ethyl acetate (1:1), and the precipitate was collected by filtration and dried to obtain the titled compound (24 mg) as pale purple powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([O:17][CH:18]([CH2:21][F:22])[CH2:19][F:20])[CH:11]=2)=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[N:30]1([C:34]([C:36]2[CH:37]=[C:38]([Cl:43])[C:39](Cl)=[N:40][CH:41]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1>C(#N)C>[N:30]1([C:34]([C:36]2[CH:37]=[C:38]([Cl:43])[C:39]([O:16][C:14]3[CH:15]=[C:10]([CH:11]=[C:12]([O:17][CH:18]([CH2:19][F:20])[CH2:21][F:22])[CH:13]=3)[C:9]([NH:8][C:4]3[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=3)=[O:23])=[N:40][CH:41]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: Cc1cc(NC(=O)c2cc(O)cc(OC(CF)CF)c2)nn1C
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(OC(CF)CF)c2)nn1C
Temperature: 120 °C
Yield: 55.2 %

Procedure:
A solution of N-(1,5-dimethyl-1H-pyrazol-3-yl)-3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxybenzamide (0.61 mmol) in acetonitrile (5 mL), was treated with the potassium carbonate (1.23 mmol) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (0.68 mmol), before being heated to 120° C. in a microwave reactor for 4 hours. The mixture was filtered and evaporated in vacuo before being chromatographed on silica, eluting with 0-5% methanol in ethyl acetate, to give the desired compound as a white foam (175 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[N:12]([CH3:13])[N:11]=[C:10]([CH3:14])[C:4]=2[N:5]=[C:6]([CH2:8][CH3:9])[N:7]=1.[NH2:15][CH2:16][CH:17]([OH:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][N:12]1[C:3]2[C:2]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])=[N:7][C:6]([CH2:8][CH3:9])=[N:5][C:4]=2[C:10]([CH3:14])=[N:11]1
Reactant: CCc1nc(Cl)c2c(n1)c(C)nn2C
Reactant: CC(O)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc(NCC(C)O)c2c(n1)c(C)nn2C
Temperature: 25 °C
Reaction time: 60 h
Yield: 76 %

Procedure:
A mixture of 10.5 g (0.05 mol) of 7-chloro-5-ethyl 1,3-dimethylpyrazolo[4,3-d]pyrimidine (Ex. 11) 7.5 g (0.1 mol) of 1-amino-2-propanol and 8 ml of triethylamine in 75 ml of methylene dichloride is stirred at room temperature for 60 hours and filtered. The hygroscopic solid is stirred in 50 ml of saturated sodium bicarbonate solution to give 9.5 g (76%) of 1-[1,3-dimethyl-5-ethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]amino-2-propanol, a hemihydrate melting at 116°-119° C. from ethyl acetate-pet ether.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C=O.F[C:14](F)(F)C([O-])=O.C[NH2+]C1C=CC=CC=1.C(OCC)C>C1COCC1>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH2:14])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=C([O-])C(F)(F)F
Agent: C=O
Agent: C[NH2+]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
The mixture of 4-hydroxyacetophenone (2.719 g, 20 mmol), paraformaldehyde (2.702 g, 90 mmol) and N-methylanilinium trifluoroacetate (6.603 g, 30 mmol) in 20 mL of anhydrous THF was refluxed for 3.5 h and cooled to room temperature. To the red solution was added 60 mL of diethyl ether and the mixture was vigorously stirred for 15 min. The resultant yellow solution was decanted and residual brown-red sticky mud was repeatedly extracted with 50 mL portions of diethyl ether until it turned into yellow solid. The combined organic extracts were washed with half saturated sodium bicarbonate solution (2×) and the aqueous wash was extracted with ether (2×). The combined organic layers were dried over anhydrous sodium sulfate prior to concentration. Flash chromatography on silica gel with 5:1 hexanes/ethyl acetate as the eluent afforded product 27 (1.21 g, 41%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 5.89 (dd, J=1.8, 10.6 Hz, 1H), 5.91 (s, 1H), 6.43 (dd, J=1.6, 16.9 Hz, 1H), 6.92 (d, J=8.4 Hz, 2H), 7.17 (dd, J=10.6, 17.2 Hz, 1H), 7.93 (d, J=8.4 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]#[C:21][CH2:22][OH:23])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][C:30](Cl)=[O:31]>C1COCC1>[CH3:19][O:18][C:17]1[CH:16]=[CH:15][NH:14][C:13]=1/[CH:12]=[C:5]1\[C:6](=[O:11])[NH:7][C:8]2[C:4]\1=[C:3]([C:20]#[C:21][CH2:22][OH:23])[C:2]([NH:1][C:30](=[O:31])[CH2:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)=[CH:10][CH:9]=2
Reactant: O=C(Cl)Cc1cccs1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(C#CCO)c21
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(NC(=O)Cc3cccs3)c(C#CCO)c21

Procedure:
Using Method M above, (Z)-5-amino-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (20 mg, 0.065 mmol) (from Example 32 above) was acylated with 2-thiopheneacetyl chloride (21 mg, 0.13 mmol) (Aldrich) in THF (2 mL) at RT for 2 h to give (Z)-N-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-4-(3-hydroxy-1-propynyl)-1H-indol-5-yl]-2-thiopheneacetamide. (Yield 18.2 mg, 65%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>N1C=CC=CC=1.CCOC(C)=O>[CH3:32][O:31][C:29](=[O:30])[NH:25][C:23]1[S:24][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:15][C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:26])([F:1])[F:27])=[CH:4][CH:5]=4)[N:14]=[CH:13][N:12]=3)[C:21]=2[N:22]=1
Reactant: COC(=O)Cl
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65) (100 mg, 0.26 mmol) in pyridine (2 mL) was added methyl chloroformate (28 mg, 0.29 mmol, Aldrich) at 0° C. The reaction mixture was stirred at room temperature for 2 h, diluted with EtOAc and washed with 1 N NaOH and water. The EtOAc layer was separated, dried over Na2SO4, filtered and evaporated in vacuum. Purification of the residue by silica gel chromatography with gradient: 40 to 80% EtOAc in hexanes gave the title compound as an off white solid. MS (ESI, pos. ion.) m/z: 447 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8](C(O)=O)([C:17]([OH:19])=[O:18])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].C(O)=O>C(OCC)(=O)C>[C:13]([O:12][C:10](=[O:11])[CH2:9][CH:8]([C:17]([OH:19])=[O:18])[CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:23])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)CC(CC(=O)OC(C)(C)C)(C(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CC(C)(C)OC(=O)CC(CC(=O)OC(C)(C)C)C(=O)O
Temperature: 80 °C

Procedure:
The compound of Example 166 (170 mg, 0.512 mmol) was dissolved in ethyl acetate. Formic acid (61 μL, 1.53 mmol) was added and the mixture was heated at 80° C. for 3 h. After cooling to room temperature, the reaction mixture was extracted three times with water, dried (sodium sulfate), filtered and evaporated to dryness. 1H NMR(CDCl3, 300 MHz): 1.43(s, 18H); 2.50, 2.65(2dd, J1=16.7 Hz, J2=6.2 Hz, 4H); 3.20(p, J=6.2 Hz, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([N:13]2[C:17]3([CH2:21][CH2:20][CH2:19][CH2:18]3)[C:16](=[O:22])[NH:15][C:14]2=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:25][C:26]([NH:28][C:29]1[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[CH:38]([CH3:40])[CH3:39])=[O:27].O>CN(C)C=O>[CH:38]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([CH:35]([CH3:36])[CH3:37])[C:29]=1[NH:28][C:26](=[O:27])[CH2:25][N:15]1[C:16](=[O:22])[C:17]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[N:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:14]1=[O:23])([CH3:39])[CH3:40]
Reactant: O=C1NC(=O)C2(CCCC2)N1c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1C(=O)N(c2ccccc2)C2(CCCC2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.6 %

Procedure:
80 mg (0.57 mmol) of potassium carbonate are added to a solution of 120 mg (0.52 mmol) of 1-phenyl-1,3-diazaspiro[4.4]nonane-2,4-dione and 145 mg (0.57 mmol) of 2-chloro-N-(2,6-diisopropylphenyl)acetamide in 20 ml of dimethylformamide. The reaction medium is stirred at room temperature for 24 hours. It is then poured into water and extracted with ethyl acetate. The organic phases are collected, washed with water and dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane and then heptane/ethyl acetate 80/20, v/v). 120 mg of N-(2,6-diisopropylphenyl)-2-(2,4-dioxo-1-phenyl-1,3-diazaspiro[4.4]non-3-yl)acetamide are obtained in the form of a white solid. Yield=51%, m.p.=275-7° C.
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.BrC1C=CC(C(Cl)=O)=CC=1.Br[C:35]1[CH:65]=[CH:64][C:38]([C:39]([N:41]([CH2:62][CH3:63])[C:42]2[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=2[CH:50]2[CH2:59][CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[C:55]([O:60][CH3:61])[CH:56]=3)[CH2:51]2)=[O:40])=[CH:37][CH:36]=1.[NH2:66][CH2:67][CH2:68][N:69]1[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:62]([N:41]([C:42]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=1[CH:50]1[CH2:59][CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[C:55]([O:60][CH3:61])[CH:56]=2)[CH2:51]1)[C:39](=[O:40])[C:38]1[CH:64]=[CH:65][C:35]([NH:66][CH2:67][CH2:68][N:69]2[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]2)=[CH:36][CH:37]=1)[CH3:63]
Reactant: NCCN1CCCCC1
Reactant: CCN(C(=O)c1ccc(Br)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CC(C)(C)[O-]
Agent: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: O=C(Cl)c1ccc(Br)cc1
Solvent: C1COCCO1
Product: CCN(C(=O)c1ccc(NCCN2CCCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Synthesized from ethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and 4-bromobenzoyl chloride according to an analogous synthetic method to Preparation Example 86, to a suspension of the resulting 4-bromo-N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (299 mg) in 1,4-dioxane (10 ml) were sequentially added 1-(2-aminoethyl)piperidine (0.13 ml), sodium tert-butoxide (88 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (23 mg) and tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (13 mg), and the solution was stirred overnight at 100° C. The solution was let to cool, then the insoluble material was filtered through celite pad, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate-tetrahydrofuran system) to provide the title compound (253 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.Cl.C(=O)(O)[O-].[K+].[CH:31](O)([CH3:33])[CH3:32]>O>[CH3:32][CH:31]([O:15][C:14]([CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)=[O:16])[CH3:33]
Reactant: CC(C)O
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CC(C)OC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C

Procedure:
Bendamustine HCl×H2O (1 g, 2.83 mmol) was suspended iso-propanol (5 mL). Hydrochloric acid (0.3 mL; 8N in iso-propanol) was added and the stirred mixture was heated to reflux temperature for 5 h. After that the product solution was added to potassium bicarbonate (0.6 g) in RO-water (50 mL); final pH value was between 7 and 8. An oil forms. The emulsion was extracted twice with ethyl acetate (30+20 mL), the combined organic extracts were dried over sodium sulphate and concentrated under reduced pressure with a rotary evaporator (0.9 g, crystalline, crude material). The solid was slurried with methyl-tertiary butyl-ether (5 mL), isolated by filtration, washed with cold methyl-tertiary butyl-ether (2×0.8 mL) and dried in the fumehood. Yield: 0.47 g.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19]C)=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][NH:6]3.[CH3:22]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:22]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To 9.5 g (33 mmol) of pyridocinnoline (5) obtained in Example 1, 95 ml of dimethylsulfate was added, and the mixture was heated at 100° to 120° C. for 8 hours. After air-cooled, the solution was added to 900 ml of water containing 137 g of anhydrous potassium carbonate, and the solution was stirred at room temperature for 30 minutes. The solution was extracted with 800 ml of chloroform and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was purified by silica gel chromatography (250 g of silica gel, eluent solvent: chloroform), and the obtained crystal was filtered off and washed with ether to obtain 5.3 g of the subject compound (6) in a 56% yield. The result of the analysis of this compound was as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[N:6][CH:7]=1.[C:10]([O-])([O-])=O.[K+].[K+].BrCBr.CCOC(C)=O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:10][O:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Br)cnc1O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: BrCBr
Product: Brc1cnc2c(c1)OCO2
Temperature: 90 °C

Procedure:
To a suspension of 5-Bromo-pyridine-2,3-diol (10.0 g, 52.63 mmol, commercially available, CAS 34206-49-0) in NMP (100 mL) was added K2CO3 (21.97 g, 158 mmol) and dibromo methane (10.97 g, 63.16 mmol). The reaction mixture was heated to 90° C. for 16 h. EtOAc was added and the salts were filtered off. Water was added, the phases were separated and the aq layer was extracted with more ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4 and concentrated under vacuo to get the crude compound. The crude compound was purified by silica gel chromatography (eluent 5% ethyl acetate in petrol ether). Yield of 6-Bromo-[1,3]dioxolo[4,5-b]pyridine 2:2 g (21%) pure by 1H NMR (400 MHz, DMSO) δ 7.71 (d, 1H, J=2 Hz), 7.55 (d, 1H, J=2 Hz), 6.20 (s, 2H). Mp 69-71 C.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4([C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)=[O:29])[CH2:27][CH2:26]4)=[O:24])=[C:18]([F:38])[CH:17]=3)[CH:12]=[CH:11][N:10]=2)=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)=[O:29])[CH2:27][CH2:26]3)=[O:24])=[C:18]([F:38])[CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Yield: 42.3 %

Procedure:
A mixture of N-(4-(2-(4-methoxybenzylamino)pyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (160 mg, 0.29 mmol) in CH2Cl2 (0.2 mL) was treated with trifluoroacetic acid (0.4 mL, 5.26 mmol) and the resultant mixture was stirred overnight at RT. The reaction mixture was concentrated to dryness and the residue was purified by reverse-phase silica gel chromatography (25-95% acetonitrile in water, 0.1% TFA). The desired fractions were partitioned between saturated aqueous NaHCO3 and EtOAc. The organics were washed with saturated aqueous NaHCO3, water, and brine and were dried over Na2SO4 and concentrated in vacuo to provide N-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (52 mg, 39% yield). MS (ESI) m/z: 425.1 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10](N)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.N([O-])=O.[Na+].[BrH:18]>O>[Br:18][C:10]1[CH:11]=[CH:12][C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:8][CH:9]=1
Reactant: Nc1ccc(C2CCOCC2)cc1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1ccc(C2CCOCC2)cc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(tetrahydro-2H-pyran-4-yl)benzenamine (1.79 g, 10.10 mmol) in 15 mL of HBr and 5 mL of water was stirred at 0° C. for 10 minutes, then 0.77 g of NaNO2 was added to the mixture at −5° C.˜0° C. The mixture was stirred at −5° C. for 30 minutes. Then the solution of CuBr in 3 mL of HBr was added to the mixture, after that the mixture was heated at 100° C. for 2 hours. The mixture was cooled to room temperature, partitioned between 2N NaOH and EA, washed with water and aqueous NaCl, dried over Na2SO4. The volatiles were removed in vacuo, and the residue was purified by chromatography with PE/EA (10:1˜4:1) to give 1.11 g of title compound.