Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11]=[CH:12]N(C)C)=[CH:7][N:6]=1)=[O:4].Cl.[OH2:17].[Cl-].[Na+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][CH:12]=[O:17])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(C=CN(C)C)cn1
Reactant: O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1cnc(CC=O)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A solution of 5-(2-dimethylamino-vinyl)-pyrazine-2-carboxylic acid methyl ester (prepared as in Example 41, 600 mg, 2.9 mmol) in benzene (5 mL) was treated with a solution of a 1M aqueous hydrochloric acid solution (5 mL) and water (5 mL) and then stirred vigorously at 50° C. for 60 min. The mixture was cooled and then treated with sodium chloride (2 g). The mixture was extracted with benzene (3×25 mL). Each extract was washed with a saturated aqueous sodium chloride solution (2×20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-(2-oxo-ethyl)-pyrazine-2-carboxylic acid methyl ester (295 mg, 56%) as yellow crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH:10]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1.CCCCCC>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH:10]=[C:6]([CH2:4][OH:3])[CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)C1=CCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(CO)C1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of 5.43 g (22.5 mmol) 2,5-dihydro-pyrrole-1,3-dicarboxylic acid 1-tert.-butylester 3-ethyl ester in 50 ml THF, cooled to -78° C. was dropwise added 50 ml of a 1N DIBAL-H solution in hexane. The mixture was allowed to warm to room temperature overnight. As TLC analysis indicated complete consumption of starting material, the mixture was cooled in an ice bath and 1.90 g water were cautiously added, followed by 1.90 g 15% aqueous NaOH and 5.70 g water. The white precipitate was filtered off, washed thoroughly with ether and the combined filtrates were evaporated. Bulb-to-bulb distillation of the residual pale yellow oil gave 4.13 g (93%) 3-hydroxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert.-butylester as a colorless oil, b.p. 130° C. (0.2 mbar).
Reaction SMILES: C(O)(=O)CC.[NH4+:6].[OH-].[CH3:8][C:9]1[C:14](NC(=O)CC)=[C:13]([CH3:20])[N:12]=[C:11]([NH:21][C:22](=O)[CH2:23][CH3:24])[CH:10]=1>>[CH3:20][C:13]1[N:12]=[C:11]2[N:21]=[C:22]([CH2:23][CH3:24])[NH:6][C:10]2=[C:9]([CH3:8])[CH:14]=1
Reactant: [NH4+]
Reactant: CCC(=O)Nc1cc(C)c(NC(=O)CC)c(C)n1
Agent: [OH-]
Solvent: CCC(=O)O
Product: CCc1nc2nc(C)cc(C)c2[nH]1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a mixture of 8.44 g of a 55:45 mixture of 2-Amino-3-nitro-4,6-dimethylpyridine and 2-Amino-4,6-dimethyl-5-nitropyridine in MeOH (1.2 L) was added 10% Pd/C (2.4 g). The reaction vessel was evacuated then purged with H2 at 1 atm. and stirred vigorously for 18 hours. Filtration (celite), and concentration gave 6.65 g of a mixture of 2,3-diamino-4,6-dimethylpyridine and 2,5-diamino-4,6-dimethylpyridine as a dark solid. To 5.40 g (39.4 mmol) of this mixture was added propionic acid (8.80 mL, 118 mmol) followed by polyphosphoric acid (100 mL). This stirred mixture was heated to 90° C. for 3 hours then to 100° C. for 1 hour. After the reaction was complete, the warm mixture was poured onto 300 g of ice and the mixture was made basic with NH4OH. The mixture was extracted (4×50 mL CH2Cl2), dried (K2CO3) and concentrated to give a mixture of the title compound and 4,6-dimethyl-2,5-bis(propionamido)pyridine. Purification (SiO2, 5% MeOH/EtOAc) gave 1.66 g of the title compound as the slower eluting component. 1H NMR (CD3OD, 300MHz) δ 6.95 (s, 1H), 2.92 (q, 2H, J=7.8 Hz), 2.54 (apparent s, 6H), 1.40 (t, 3H, J=7.8 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH:12][S@](C(C)(C)C)=O)[CH2:9][CH:10]=[CH2:11])[CH:3]=1.Cl.CCN(CC)CC.[O:27](C(OC(C)(C)C)=O)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=O>CO.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH:12][C:28](=[O:27])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:9][CH:10]=[CH2:11])[CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=CC[C@H](N[S@@](=O)C(C)(C)C)c1cc(Cl)ccn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.8 %

Procedure:
1B (75 g, 261 mmol) was dissolved in methanol (1500 mL). Hydrochloric acid (6N) (750 ml, 4.5 mol) was added. The reaction was stirred at rt for 2-3 hrs and then was concentrated. The residue was diluted with water (2 L), washed with ethyl acetate (500 ml). The aqueous layer was basified with saturated sodium carbonate solution, extracted into ethyl acetate (3×1 L). The combined organic layers were washed with water (1×1 L) and brine (1×1 L), dried over sodium sulfate, filtered and conc. under vacuum at 50-55° C. to give crude product (43 g, 90%). MS (ESI) m/z: 183.2 (M+H)+. The crude product (42 g, 230 mmol) was dissolved in dichloromethane (420 mL), Et3N (32.1 mL, 230 mmol) was added followed by dropwise addition of BOC2O (53.4 mL, 230 mmol). The reaction was stirred at rt for 2-3 hrs. The reaction was diluted with excess DCM (1 L), washed with water (1×500 ml) and brine (1×500 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was then purified using silica gel chromatography to give 1C (61 g, 86%) as a pale yellow solid. MS (ESI) m/z: 283.2 (M+H)+.
Reaction SMILES: [Br:1]Br.[C:3]1([CH2:9][CH2:10][CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][CH:10]([CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:11]=[O:12]
Reactant: BrBr
Reactant: O=CCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=CC(Br)Cc1ccccc1
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A solution of bromine (15.2 g, 95.1 mmol) in 30 mL of dichloromethane was added to a solution of 3-phenyl-propionaldehyde (13.4 g, 100 mmol) in dichloromethane (150 mL) at 0° C. over 20 minutes. The reaction mixture was allowed to stir for 2 hours and then a saturated aqueous solution of sodium bicarbonate (100 mL) was added to the mixture. The organic layer was separated and the aqueous layer was washed with dichloromethane (50 mL). The combined organic layers were washed with water, a saturated aqueous solution of sodium chloride, and then evaporated to dryness to give an orange oil (14.2 g), which was used directly in the next step.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.C(OC([N:26]1[CH2:33][CH2:32][CH:31]2[CH:28]([NH:29][CH2:30]2)[CH2:27]1)=O)(C)(C)C.Cl[C:35]1[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([C:42]([F:45])([F:44])[F:43])[N:36]=1.ClC1C=NC2C(=CC=CC=2)N=1>>[CH3:41][C:39]1[N:38]=[C:37]([C:42]([F:45])([F:43])[F:44])[N:36]=[C:35]([N:29]2[C@@H:28]3[C@@H:31]([CH2:32][CH2:33][NH:26][CH2:27]3)[CH2:30]2)[CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Reactant: Cc1cc(Cl)nc(C(F)(F)F)n1
Agent: Clc1cnc2ccccc2n1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: Cc1cc(N2C[C@@H]3CCNC[C@@H]32)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, substituting (1R,6S)-(3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester for 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester and 4-chloro-2-trifluoromethyl-6-methyl-pyrimidine for 2-chloro-quinoxaline in Step A. MS (ESI) mass calcd. for C12H15F3N4, 272.27; m/z found 273.0 [M+H]+. 1H NMR (CDCl3): 6.29 (s, br, 1H), 6.13 (s, 1H), 4.52 (d, J=8.0, 1H), 4.08-3.94 (m, 1H), 3.87-3.75 (m, 1H), 3.64 (t, J=19.8, 1H), 3.39-3.26 (m, 1H), 3.11 (dd, J=14.2, 3.5, 1H), 3.00-2.77 (m, 2H), 2.38 (s, 3H), 2.22-2.07 (m, 1H), 1.92-1.79 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)O)=[CH:5][CH:4]=1.N1C=CC=CC=1.P(Br)(Br)[Br:26]>C1(C)C=CC=CC=1>[Br:26][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(Br)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
Bis(4-methoxyphenyl)methanol (2.0 g, 8.2 mmol) was dissolved in toluene (60 mL) and pyridine (661 μL, 8.2 mmol)) was added. The solution was cooled to 0° C. PBr3 (768 μL, 8.2 mmol) was added dropwise over 15 min. The reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was washed with K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo to give the crude product 4,4′-(bromomethylene)bis(methoxybenzene) (780 mg, 31%), as a colourless oil. This was used in the next reaction step without further purification. Sodium ethoxide (133 mg, 1.96 mmol) was added to DMF (5 mL) at 0° C., and the suspension was stirred for 10 min. 7-hydroxy-4-methylcoumarin (345 mg, 1.96 mmol) was slowly added and resulting mixture was stirred at this temp for 0.5 h. To this mixture 4,4′-(bromomethylene)bis(methoxybenzene (500 mg, 1.63 mmol) was added portionwise. Resulting reaction mixture was stirred at room temperature for 16 h. DMF was evaporated off in-vacuo and the residue was taken up in EtOAc, and washed with brine, water and 1M NaOH (2×30 mL). The organic layer was dried (MgSO4) and product was purified by flash chromatography, eluting with hexane:EtOAc (2:1) to give 49 (100 mg, 15%) as a white solid. Mpt=142-145° C. m/z=403 (M+H). H1 NMR (500 MHz, acetone-d6): δ=7.60 (1H, d, ArH), 7.45 (4H, d, ArH), 7.04 (1H, d, ArH), 6.94 (5H, d, ArH), 6.56 (1H, s ArH), 6.10 (1H, s, qCH), 3.78 (6H, s, 2×CH3O), 2.39 (3H, s, CH3). 13C NMR (500 MHz, acetone-d6, DEPT 135): δ=206.3 (qC), 134.1 (2×qC), 129.3 (2×CH), 129.2 (2×CH), 129.0, (2×CH), 126.9 (Ar CH), 114.4 (Ar CH), 114.7 (Ar CH), 115.1 (Ar CH), 112.5 (Ar CH), 104.0 (Ar CH), 81.7 (CH), 55.6 (2×CH3), 18.2 (CH3).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[N:14][CH:15]=2)=[N:7][CH:8]=1.[I-].C([Si](C)(C)[O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32](N2C=C[N+](C)=C2)=[O:33])[CH2:28][CH2:27]1)(C)(C)C.C(N(CC)CC)C>C(#N)C>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:32]([N:29]3[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]3)=[O:33])=[N:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cn1
Reactant: C[n+]1ccn(C(=O)N2CCC(O[Si](C)(C)C(C)(C)C)CC2)c1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cn1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
A solution of 5-(5-trifluoromethyl-pyridin-2-yloxy)-pyridin-2-ol (180 mg, 0.70 mmol), 3-[4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carbonyl]-1-methyl-3H-imidazol-1-ium iodide (317 mg, 0.70 mmol) and triethylamine (98 μL) in acetonitrile (10 mL) was stirred at room temperature overnight. The solvent was evaporated in vacuo. The residue was redissolved in some dichloromethane, filtered over a short pad of silicagel and washed with ethyl acetate:heptane 50:50. The solvent was evaporated in vacuo and the residue was dissolved in 3.2N HCl in ether (10 mL). After stirring for 1 hour at room temperature the solvent was evaporated in vacuo and the residue was dissolved in dichloromethane. Triethylamine (0.5 mL) was added and the solution was extracted with water. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo to yield the title compound (174 mg, 65% yield) as a thick oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
A solution of 2-bromo-1-(4-fluorophenyl)ethanone (5.00 g, 23.0 mmol) and potassium thiocyanate (2.24 g, 23.0 mmol) in ethanol (50 ml) was stirred at 80° C. for 3 hours. After cooling to room temperature, water (60 ml) was poured into the reaction solution, and a crystal was separated by filtration, which was washed with 50% aqueous ethanol solution to give the desired product (3.71 g, 82.5%) as a solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[N:56]=[CH:55][C:54]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:53][N:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[N:52]=[CH:53][C:54]([C:57]2[CH:58]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=[CH:61][CH:62]=2)=[CH:55][N:56]=1
Reactant: COc1ncc(-c2cccc(N)c2)cn1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 19.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methoxy-pyrimidin-5-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.005 g of product in 20% yield: LCMS (ESI) m/z 390 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH2:18]1[NH:23][CH2:22][CH2:21][N:20]2[CH2:24][CH2:25][CH2:26][CH:19]12.COCCO.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:18]1[N:23]([C:2]2[C:3]3[CH2:13][CH2:12][CH2:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=4[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[CH2:22][CH2:21][N:20]2[CH2:24][CH2:25][CH2:26][CH:19]12
Reactant: C1CC2CNCCN2C1
Reactant: Nc1nc(Cl)c2c(n1)-c1ccccc1CCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Solvent: ClCCl
Product: Nc1nc2c(c(N3CCN4CCCC4C3)n1)CCCc1ccccc1-2
Temperature: 115 °C

Procedure:
The product from Example 68A (40 mg, 0.16 mmol) was treated with octahydro-pyrrolo[1,2-A]pyrazine (31 mg, 0.24 mmol), and to this was added 2-methoxyethanol (0.65 mL) and N,N-diisopropylethylamine (0.20 mL, 1.2 mmol); the reaction was heated at 115° C. for 16 hours, cooled, diluted with CH2Cl2 (25 mL) and washed with 1 M NaOH (10 mL). The aqueous layer was extracted with CH2Cl2 (15 mL). The combined organic layers were dried (MgSO4), filtered, concentrated and purified by chromatography (eluting with 2, 3.5, 5 and 10% (9:1 MeOH:saturated aqueous NH4OH) in CH2Cl2) to provide the title compound. 1H NMR (CDCl3) δ 1.43-1.57 (m, 1H), 1.71-1.94 (m, 3H), 2.13-2.29 (m, 4H), 2.30-2.45 (m, 3H), 2.66 (t, J=6.78 Hz, 2H), 2.81 (dd, J=12.21, 10.17 Hz, 1H), 3.06-3.23 (m, 3H), 3.81-3.89 (m, 1H), 3.98 (dt, J=12.29, 2.33 Hz, 1H), 4.76 (s, 2H), 7.20-7.24 (m, 1H), 7.31-7.39 (m, 2H), 7.71-7.76 (m, 1H); MS (M+H)+ m/z 336.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N:10]([O-])=[O:11].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[C:7]=1[N:10]=[O:11]
Reactant: O=N[O-]
Reactant: Cc1cc(C)cc(O)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(O)cc(C)c1N=O
Temperature: 0 °C
Yield: 71.6 %

Procedure:
750 ml of concentrated HClare added to a solution of 3,5-dimethyl phenol (80.6 g) in 750 ml of 95% ethyl alcohol. The mixture is cooled to 0° C. in an ice/methanol bath. While maintaining the temperature of the reaction mixture below 5° C. a solution of NaNO2 (69.0 g) in 150 ml of H2O is added dropwise to the reaction mixture. The mixture is stirred at 0° C. for more than an hour and then poured into 9 liters of water. The aqueous mixture is filtered to give a yellow solid which is recrystallized from hot methanol and filtered to give 71.45 grams of a yellow solid, M.P. 180°-181° C. (dec).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:10][CH:9]2[CH:5]1[CH:6]=[CH:7][CH2:8]2>C(OCC)(=O)C>[NH2:2][CH2:3][C:4]1([CH2:11][C:12]([OH:14])=[O:13])[CH2:10][CH:9]2[CH:5]1[CH:6]=[CH:7][CH2:8]2
Reactant: CC(C)(C)OC(=O)CC1(CN)CC2CC=CC21
Agent: Cl
Solvent: CCOC(C)=O
Product: NCC1(CC(=O)O)CC2CC=CC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
A 4 N solution of hydrochloric acid in ethyl acetate (10 mL) was added to tert-butyl [6-(aminomethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (0.99 g, 4.17 mmol), and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure. The residue was suspended by the addition of dichloromethane. To the suspension, triethylamine was then added dropwise, and the resulting powder was collected by filtration. The obtained powder was washed with dichloromethane and then dried under reduced pressure to obtain the compound of interest as a white powder (211.6 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1.CCN(CC)CC>CS(C)=O.O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: OCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: OCC1CCN(c2cc(Cl)nnc2Cl)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of 3,4,6-trichloro-pyridazine (59) (364 mg, 2 mmol) and piperidin-4-yl-methanol (35) (253 mg, 2.2 mmol) in DMSO (5 mL) was added Et3N (404 mg, 4 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give [1-(3,6-dichloro-pyridazin-4-yl)-piperidin-4-yl]-methanol (60) (292.3 mg, 1.12 mmol, yield 75.99%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:14][C:15]([CH3:17])=[O:16]>CCO.O.[OH-].[Na+]>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:11]/[C:4](=[O:3])/[CH:5]=[CH:6]/[C:7]2[CH:10]=[CH:17][C:15]([O:16][C:2]([F:1])([F:12])[F:13])=[CH:14][CH:8]=2)=[CH:6][CH:5]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1ccc(OC(F)(F)F)cc1)/C=C/c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
A colorless solution of 4-(trifluoromethoxy)-benzaldehyde (0.75 mL, 5.3 mmol) in acetone (0.19 mL, 2.6 mmol), EtOH (5 mL) and H2O (1 mL) was treated with aq. 10% NaOH solution (˜12 drops). The reaction mixture was stirred for 2 h at room temperature and the colorless solution turned into a yellow suspension. The precipitate was filtered, washed with H2O and dried in vacuo to obtain NW254 as a pale yellow solid (275 mg, 25%). mp: 112-115° C. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.74 (d, 3J=16.1 Hz, 2H, Hvin), 7.67 (d, 3J=8.5 Hz, 4H, HAr), 7.28 (d, 3J=8.2 Hz, 4H, HAr), 7.06 (d, 3J=15.9 Hz, 2H, Hvin.). 13C NMR (75 MHz, CDCl3) δ (ppm): 188.2 (C), 150.6 (C), 141.8 (CH), 133.3 (C), 129.8 (CH), 126.0 (CH), 121.2 (CH). MS (EI) m/z: 402.1 (M+). Anal. calcd for C19H12F6O3: C, 56.73; H, 3.01. Found: C, 56.44; H, 3.10%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[CH3:8][N:9]([CH3:34])[C:10]([C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[C:24]3[CH:25]=[C:26]([CH3:28])[O:27][C:23]=3[CH:22]=[C:21]([C:29](OCC)=[O:30])[CH:20]=2)=[CH:14][N:13]=1)=[O:11]>>[CH3:34][N:9]([CH3:8])[C:10]([C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[C:24]3[CH:25]=[C:26]([CH3:28])[O:27][C:23]=3[CH:22]=[C:21]([C:29](=[O:30])[NH:7][C:4]3[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=3)[CH:20]=2)=[CH:14][N:13]=1)=[O:11]
Reactant: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)C)nc2)c2cc(C)oc2c1
Reactant: Cn1ccc(N)n1
Product: Cc1cc2c(Oc3cnc(C(=O)N(C)C)nc3)cc(C(=O)Nc3ccn(C)n3)cc2o1

Procedure:
The title compound (4) was prepared by a method analogous to that described in Example 1 using 1-methyl-1H-pyrazol-3-amine and ethyl 4-(2-(dimethylcarbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (I-2a)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:9](=[O:16])[NH:8][C:7]2=[O:17].[CH3:18]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:9](=[O:16])[N:8]([CH3:18])[C:7]2=[O:17]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)c2cc(Cl)c([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
NaH (5.30 g, 0.132 mol) was added in portions to a solution of 5-chloro-6-nitroisoindoline-1,3-dione (20.0 g, 88.27 mmol) in 100 mL of anhydrous DMF at 0° C. under argon. The reaction mixture was then stirred at rt for 3 h. MeI (15.0 g, 106 mol) was added dropwise via a syringe at rt under argon. The resulted mixture was stirred for 6 h at rt, hydrolyzed by adding 200 mL of water. The brown precipitate was isolated, washed with water and dried under vacuum. The solid was purified by column chromatography (silica-gel, CH2Cl2/Acetone=19/1 v/v) to give a yellow solid product, 15.6 g, 73.6% yield. MS: 239.2 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 8.54 (s, 1H), 8.32 (s, 1H), 3.07 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:19][C:14]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=2)[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: Oc1ccc(Cl)c(Cl)c1
Product: O=Cc1ccc(Br)cc1Oc1ccc(Cl)c(Cl)c1
Yield: 46.9 %

Procedure:
In the same manner, reaction of 12.06 g of 4-bromo-2-fluorobenzaldehyde and 9.68 g of 3,4-dichlorophenol gave 9.64 g of 4-bromo-2-(3,4-dichlorophenoxy)-benzaldehyde as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23](O)=[O:24])=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.[N:32]1(OC(N(C)C)=[N+](C)C)[C:36]2C=[CH:38][CH:39]=[CH:40][C:35]=2N=N1.CN1CCOCC1.C(N)CCCC>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:21])([CH3:22])[O:20][C:16]=3[C:15]([C:23]([NH:32][CH2:36][CH2:35][CH2:40][CH2:39][CH3:38])=[O:24])=[CH:14][C:12]=2[N:13]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCNC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Yield: 20.4 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.050 g, 0.127 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.082 g, 0.225 mmol), N-methyl morpholine (0.5 mL), DMF (1.0 mL), THF (5.0 mL) and n-pentyl amine (0.022 g, 0.254 mmol) to afford 0.012 g of the desired product. 1HNMR (DMSO-d6): δ 1.29 (t, J=6.3 Hz, 3H), 1.64 (s, 3H), 1.71 (s, 6H), 1.91 (s, 3H), 3.42 (s, 2H), 3.68-3.74 (m, 2H), 7.62 (s, 1H), 8.10 (m, 1H), 8.84 (s, 2H), 11.23 (s, 1H), 11.81 (s, 1H); MS [M+H]+: 462.43.