Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C=C(Cl)CN(Cl)N1.CN(C)C=O.[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:22]([CH:33](O)[CH3:34])=[CH:21]2.O>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:22]([CH:33]([Cl:1])[CH3:34])=[CH:21]2
Reactant: CC(O)c1cc2cccc(Cl)c2nc1-c1cccc(F)c1
Reactant: ClC1=CN(Cl)NN(Cl)C1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(Cl)c1cc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1,3,5-Trichlorotriazine (94 mg, 510 μmol) was added to dimethylformamide (0.04 mL, 510 μmol) at 25° C. After the formation of a white solid (10 min), DCM (3 mL) was added, followed by 1-(8-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethanol (140.0 mg, 464 μmol), made from procedure K. After the addition, the mixture was stirred at room temperature for 4 h. Water (10 mL) was added, and then diluted with DCM (10 mL), the organic phase was washed with 15 mL of a saturated solution of NaHCO3, followed by water and brine. The organic layers were dried and concentrated. Purification of the residue by flash chromatography over silica gel, using 10% hexane in EtOAc, gave 8-chloro-3-(1-chloroethyl)-2-(3-fluorophenyl)quinoline, Mass Spectrum (ESI) m/e=320.0 (M+1).
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9]([OH:11])=O)[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:47][C@H:48]([C:64]([NH:66][C@H:67]([C:77]([C:79]([O:81][CH3:82])=[O:80])=[O:78])[CH2:68][O:69][CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)=[O:65])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:52][CH:51]=1.FC(C(O)=O)(F)F.CCN(CC)CC>CN(C=O)C>[NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9]([NH:47][C@H:48]([C:64]([NH:66][C@H:67]([C:77]([C:79]([O:81][CH3:82])=[O:80])=[O:78])[CH2:68][O:69][CH2:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)=[O:65])[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:55]=1)=[O:11])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)C(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of Cbz-His (1.00 g, 3.47 mmol) in DMF (15 mL) at 0° C. was added HOBT (0.64 g, 4.16 mmol) and DCC (0.86 g, 4.16 mmol). Tyr(OBn)-Ser(OBn)-CO2Me.TFA (from Step 2 above, 2.0 g, 3.47 mmol) was added followed by Et3N (0.58 mL, 4.16 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered and the filtrate was diluted with CHCl3, washed twice with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated. Flash chromatography (2-5% MeOH/CHCl3) gave 2.14 g of the title compound as a white solid, mp 175°-176°C.; FAB-MS 734 (m+1);
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[C:26]1([NH:36]N)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[C:26]1([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: NNc1cccc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and naphthalen-1-yl-hydrazine according to example 43 gave the desired product. MS: M=449.0 (M+H)+
Reaction SMILES: O[Li:2].O.C([O:6][C:7](=[O:47])[CH2:8][C:9]1[C:10]([CH2:15][CH2:16][C:17]2[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]4)=[CH:30][CH:29]=3)[N:18]=2)=[N:11][CH:12]=[N:13][CH:14]=1)C>C1COCC1.O.CO>[C:43]([O:42][C:40]([N:37]1[CH2:36][CH2:35][CH:34]([C:31]2[CH:30]=[CH:29][C:28]([NH:27][C:19]3[N:18]=[C:17]([CH2:16][CH2:15][C:10]4[C:9]([CH2:8][C:7]([O-:47])=[O:6])=[CH:14][N:13]=[CH:12][N:11]=4)[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=3)=[CH:33][CH:32]=2)[CH2:39][CH2:38]1)=[O:41])([CH3:46])([CH3:44])[CH3:45].[Li+:2]
Reactant: [Li]O
Reactant: CCOC(=O)Cc1cncnc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncncc4CC(=O)[O-])n3)cc2)CC1
Product: [Li+]
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.9 %

Procedure:
LiOH.H2O (0.020 g, 0.468 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(5-(2-ethoxy-2-oxoethyl)pyrimidin-4-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I112) (0.096 g, 0.156 mmol) in THF (7 mL), water (1.5 mL) and methanol (1 mL) and the resulting mixture was allowed to stir at room temperature for 18 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (70 mL) and 2 M aqueous NaOH (80 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×70 mL), the combined organics were washed with brine (70 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (I113) (0.096 g, quantitative) as a pale yellow solid. LCMS Method C: rt 6.19 min; m/z 587.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[C:20]([O:24][C:25](=[O:35])[CH2:26][NH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)([CH3:23])([CH3:22])[CH3:21].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:20]([O:24][C:25](=[O:35])[CH2:26][N:27]([C:11](=[O:13])[CH:10]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH2:28][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)CNCC1CCCCC1
Reactant: N#Cc1ccc(CC(C(=O)O)C2CCCCC2)cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN(CC1CCCCC1)C(=O)C(Cc1ccc(C#N)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.3 %

Procedure:
To 3-(4-cyano-phenyl)-2-(R,S)-cyclohexyl-propionic acid (5 g, 19.43 mmol) and (cyclohexylmethyl-amino)-acetic acid tert-butyl ester (4.42 g, 19.43 mmol) in dimethylformamide (50 ml) were added TOTU (7.01 g, 21.37 mmol) and diisopropylethyl amine (2.51 g, 19.43 mmol) at −15° C. The mixture was stirred for 1 hour and then allowed to warm to room temperature. After evaporation, the residue was treated with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was evaporated to yield 10 g of crude material which was used in the next step without further purification, MS m/z: 467.4 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].I[CH2:10][CH:11]([CH3:13])[CH3:12].CC1(C)CCCCC1=O>>[CH2:10]([C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CI
Reactant: CC1CCCCC1=O
Agent: CC1(C)CCCCC1=O
Product: CC(C)CC1(C)CCCCC1=O

Procedure:
The alkylation of 2-methylcyclohexanone with 1-iodo-2-methyl-propane takes place in a manner similar to that described above for the preparation of 2,2-dimethyl-cyclohexanone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27]([N:34]1[CH:38]=[C:37]([C:39]2[C:40](Cl)=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:36]=[N:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)(C(F)(F)F)=O>CCOC(C)=O.O>[CH2:27]([N:34]1[CH:38]=[C:37]([C:39]2[C:40]([O:1][C:2]3[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=3[CH3:20])[C:5]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=3)=[O:6])=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:36]=[N:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1O
Reactant: Clc1ncccc1-c1cnn(Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1Oc1ncccc1-c1cnn(Cc2ccccc2)c1
Temperature: 130 °C

Procedure:
3-Hydroxy-N-(3-isopropylphenyl)-4-methylbenzamide (100 mg, 0.371 mmol), cesium carbonate (220 mg, 0.676 mmol) and 3-(1-benzyl-1H-pyrazol-4-yl)-2-chloropyridine (91.0 mg, 0.338 mmol) were combined in an argon-purged sealed tube. DMSO (1.5 mL) was added and the mixture was heated to 130° C. for 23 hours. The cooled reaction was diluted with EtOAc and water and then neutralized with TFA (pH˜7). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified first by silica gel chromatography (1:1 MTBE/benzene) followed by trituration of the resulting solid with 20:1 hexanes/EtOAc to yield 3-(3-(1-benzyl-1H-pyrazol-4-yl)pyridin-2-yloxy)-N-(3-isopropylphenyl)-4-methylbenzamide as an off-white solid. MS m/z=503 [M+1]+. Calc'd for C32H30N4O2: 502.62.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[N:8]([CH3:17])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[N:8]([CH3:17])[C:9]2[C:14]([C:15]=1[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2ccccc2n(C)c1=O
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCN(C)CC2)c2ccccc2n(C)c1=O

Procedure:
A stirred mixture of 9.5 g. of 4-chloro-1,2-dihydro-1-methyl-2-oxo-3-quinolinecarboxylic acid ethyl ester, 3.6 g. of N-methylpiperazine and 3.8 g. of sodium carbonate in 50 ml. of ethanol was heated under reflux for 3 hours and filtered. The filtrate was taken to dryness on a rotary evaporator leaving a thick, tarry oily residue. On triturating the oil with diethyl ether, there was obtained 9.4 g. of impure title compound, m.p. 144°-148° C. Recrystallization from ethanol gave 5.5 g. of the title compound, m.p. 154°-156° C.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].B(F)(F)F.[CH3:34]COCC>CO>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:34])=[O:26])=[CH:28][CH:29]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1
Temperature: 0 °C

Procedure:
A solution of 50.5 g. of 4-(15-carbomethoxypentadecylamino)benzoic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of methanol is stirred under reflux for 4 hours, allowed to cool, and is poured into 1.20 liters of ice cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield methyl 4-(15-carbomethoxypentadecylamino)benzoate, m.p. 92°-93° C.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:51]=[C:52]([Cl:54])[CH:53]=1)[O:31][C:32]1[C:33]([CH2:49][CH3:50])=[N:34][N:35]([CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:36]=1[CH2:37]O>ClCCl>[Br:1][CH2:37][C:36]1[N:35]([CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[N:34]=[C:33]([CH2:49][CH3:50])[C:32]=1[O:31][C:30]1[CH:29]=[C:28]([Cl:27])[CH:53]=[C:52]([Cl:54])[CH:51]=1
Reactant: BrBr
Reactant: CCc1nn(CCNC(=O)OC(C)(C)C)c(CO)c1Oc1cc(Cl)cc(Cl)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1nn(CCNC(=O)OC(C)(C)C)c(CBr)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
Bromine (160 μl, 3.12 mmol) was added dropwise to a stirred solution of triphenylphosphine (820 mg, 3.12 mmol) and imidazole (213 mg, 3.12 mmol) in dichloromethane (15 ml) at room temperature under nitrogen. A solution of the alcohol of Example 135 (1.12 g, 2.60 mmol) in dichloromethane (5 ml) was then added to the reaction. The reaction was stirred at room temperature for 2 hours, diluted with dichloromethane (50 ml), washed with brine (20 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) to provide the title compound (969 mg) as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[N:34]([CH3:35])[N:33]=[C:32]([C:36]([CH3:42])([CH3:41])[C:37]([F:40])([F:39])[F:38])[CH:31]=3)=[O:28])=[C:22]([F:43])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10]CC1C=CC(OC)=CC=1)[CH3:2].C(Cl)[Cl:45]>C(O)(C(F)(F)F)=O>[ClH:45].[CH2:1]([O:3][C:4]1[C:9](=[O:10])[NH:8][CH:7]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[N:34]([CH3:35])[N:33]=[C:32]([C:36]([CH3:42])([CH3:41])[C:37]([F:39])([F:40])[F:38])[CH:31]=3)=[O:28])=[C:22]([F:43])[CH:21]=2)[CH:5]=1)[CH3:2]
Reactant: ClCCl
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3cc(C(C)(C)C(F)(F)F)nn3C)c(F)c2)cnc1OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(C(C)(C)C(F)(F)F)nn3C)c(F)c2)c[nH]c1=O
Product: Cl
Yield: 63.9 %

Procedure:
A mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamide (150 mg, 0.250 mmol) in TFA.DCM (solvate) (10 mL, 10%) was stirred for 0.5 h at 25° C. Then the mixture was concentrated to give the residue which purified by preparative HPLC (column: ASB C18 150*25 mm/Mobile phase A: Water (Water+0.1% HCl)/Mobile phaseB: Acetonitrile/Gradient: 37-67(B %)/Flowrate: 25 mL/min/Run time: 15 min) to yield 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamide hydrochloride (83.1 mg, 0.160 mmol, 63.9% yield): 1H NMR (400 MHz, CD3OD) δ 7.48-7.41 (m, 1H), 7.39 (s, 1H), 7.37 (d, J=3.5 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 6.29 (s, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.86 (s, 2H), 3.73 (s, 3H), 1.51 (s, 6H), 1.50-1.45 (m, 3H). ES-LCMS m/z 481 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH3:8].F[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1>CC(N(C)C)=O>[CH3:8][CH:3]1[N:2]([CH3:1])[CH2:7][CH2:6][N:5]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=2)[CH2:4]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CC1CNCCN1C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N2CCN(C)C(C)C2)cc1
Temperature: 150 °C
Yield: 36.2 %

Procedure:
1,2-Dimethyl-piperazine (0.914 g, 8.00 mmol) and ethyl 4-fluorobenzoate (0.587 mL, 4 mmol) were dissolved in DMA (6 mL) and sealed into a microwave tube. The reaction was heated to 150° C. for 90 mins in the microwave reactor and cooled to room temperature. The reaction mixture was evaporated and the crude product was purified by silica column chromatography, eluting with 5% MeOH in DCM (containing 0.1% 0.880 ammonia). Pure fractions were evaporated to dryness to afford ethyl 4-(3,4-dimethylpiperazin-1-yl)benzoate (0.380 g, 36.2%) as a colourless waxy solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Cl[C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1.[F:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH2:23][N:24]2[CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH2:23][N:24]2[CH:27]2[CH2:32][CH2:31][N:30]([C:10]3[N:11]=[N:12][C:13]([N:6]4[CH:5]=[C:4]([CH2:3][CH2:2][OH:1])[CH:8]=[N:7]4)=[CH:14][CH:15]=3)[CH2:29][CH2:28]2)=[CH:20][CH:19]=1
Reactant: OCCc1cn[nH]c1
Reactant: Clc1ccc(Cl)nn1
Reactant: Fc1ccc2c(c1)N(C1CCNCC1)CC2
Product: OCCc1cnn(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)c1

Procedure:
The title compound was prepared following the procedure as described in Example 14, reacting 4-(2-hydroxyethyl)pyrazole, 3,6-dichloropyridazine, and 6-fluoro-1-(piperidin-4-yl)indoline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]>C(O)CCC>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCCCCl
Reactant: Nc1ccccc1
Solvent: CCCCO
Product: OCCCCCCN(CCCCCCO)c1ccccc1
Yield: 70 %

Procedure:
Using a modified literature method (Moon, K.-J.; Shim, H.-K.; Lee, K.-S.; Zieba, J.; Prasad, P. N. Macromolcules 1996, 29, 861), the reaction of aniline with 6-chloro-1-hexanol in butanol provided N,N-bis(6-hydroxyhexyl)-aniline in 70% yield. A 100 mL two-necked flask containing 15 mL of dry DMF was cooled down to 0° C. with an ice bath. To this solution, 4.7 g (30.7 mmol) of phosphorous oxychloride was added dropwise and the mixture was stirred for 30 min at 0° C. 3 g (10.2 mmol) of N,N-bis(6-hydroxyhexyl)-aniline in dry DMF (15 mL) was added to the above solution and heated to 90° C. for 2 hrs. The reaction solution was cooled down to room temperature, poured into ice water and neutralized to pH 6-8 with saturated sodium hydroxide aqueous solution. The resulting solution was extracted with methylene chloride and then dried over magnesium sulfate. The crude compound was purified by silica gel column chromatography (ethyl acetate/hexane=1:5) to yield 2.3 g (63%) of pure light brown oil, (9). 1H-NMR (200 MHz, CDCl3): δ 9.71 (s, 1H, —CHO), 7.71 (d, 2H, J=9.0 Hz), 664 (d 2H, J=9.0 Hz), 3.55 (t, 4H, —CH2Cl, J=6.6 Hz), 3.35 (t, 4H, —NCH2—, J=7.6 Hz), 1.80 (m, 4H), 1.68-1.37 (m, 12H). 13C-NMR (100 MHz, CDCl3): δ 190.2, 152.7, 132.5, 124.9, 110.9, 51.1, 45.2, 32.7, 27.2, 26.9, 26.5. HRMS (EI): m/z=357.1617 (M+), Δ=2.6 ppm.
Reaction SMILES: CO[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]([O:9]C)=O.[CH3:15][N:16]([CH3:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>CN(C=O)C>[CH3:15][N:16]([CH3:24])[C:17]1[CH:23]=[CH:22][C:20]([N:21]2[C:7](=[O:9])[CH:6]=[CH:5][C:4]([C:11]([O:13][CH3:14])=[O:12])=[CH:3]2)=[CH:19][CH:18]=1
Reactant: COC=C(C=CC(=O)OC)C(=O)OC
Reactant: CN(C)c1ccc(N)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(=O)n(-c2ccc(N(C)C)cc2)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
After 1.24 g (6.1 mmol) of dimethyl 4-(methoxymethylene)2-pentenedioate obtained in Example 1-1 was dissolved in 10 mL of DMF, 830 g (6.1 mmol) of 4-dimethylaminoaniline was added to the solution. Afterward, the resulting reaction solution was stirred under reflex at about 50° C. for about 3 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo and was then washed using brine, followed by drying using magnesium sulfate and filtration. After distillation under reduced pressure, the resulting product was purified using column chromatography (hexane:ethyl acetate=1:1) to obtain a target compound (Actual yield: 357 mg, Yield ratio: 21%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.C1COCC1.OS(O)(=O)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC(c2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A solution of the intermediate from step B (8.6 g, 36.5 mmol) in toluene (40 mL), THF (20 mL) and 10% H2SO4 in water (25 mL) was stirred at reflux overnight. After cooling to room temperature, the organic layer was separated, washed with brine, dried over MgSO4 and concentrated. Flash chromatography on silica gel eluting with 5% and then 10% EtOAc in hexanes provided the title compound (6.0 g, 86%) as an oil. MS calculated (M+H)+ 193, found 193.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[O:22][CH2:23][CH2:24][NH2:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C@@H:11]1[CH2:16][CH2:15][C@H:14]([NH:25][CH2:24][CH2:23][O:22][C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[O:19][CH3:18])[CH2:13][CH2:12]1
Reactant: COc1ccccc1OCCN
Reactant: O=C1CCC(c2c[nH]c3ccc(F)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccccc1OCCN[C@H]1CC[C@@H](c2c[nH]c3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-(5-fluoro-1H-indol-3-yl)-cyclohexanone (0.38 g, 1.6 mmol), [2-(2-methoxy-phenoxy)-ethyl]-amine (0.27 g, 1.6 mmol), sodium triacetoxyborohydride (0.5 g, 2.2 mmol) and acetic acid (0.06 ml, 1.8 mmol) in 1,2-dichloroethane (8 ml) was allowed to stir at room temperature for 4 hours. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×60 ml) and washed with brine (3×60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.43 g (71%) of product as a white solid.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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(O)C>[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Brc1ccc(CN2CCNCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCNCC2)cc1
Temperature: 120 °C

Procedure:
This compound could be made in the following manner: 1-(4-Bromo-benzyl)-piperazine would be combined with 1 equ of 2-(Trifluoromethyl)phenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 2M sodium carbonate solution, toluene and ethanol. The reaction mixture would be heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture would then be filtered through Celite and concentrated in vacuo. The residue would then be purified by flash chromatography.