Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:6]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16](Cl)=[O:17])[O:9][CH2:8][CH2:7]1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[O:6]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17])[O:9][CH2:8][CH2:7]1
Reactant: C1CCNC1
Reactant: O=C(Cl)C1CCCCC12OCCO2
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C1CCCCC12OCCO2)N1CCCC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Pyrrolidine (0.21 mL, 2.5 mmol) was added at 0° C. to a 1 M solution of 1,4-dioxa-spiro[4.5]decane-6-carbonyl chloride in toluene (1 mL, 1 mmol). The mixture was stirred at 20° C. for 1 h, then diluted with ethyl acetate (40 mL), and washed successively with water (10 mL), saturated aquous sodium carbonate solution (10 mL), 1 N hydrochloric acid, and with brine (10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the title compound (97 mg, 41%) as a white solid. MS ISP (m/e): 240.3 (100) [(M+H)+].
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)[CH3:2].[CH2:10](N(CC)CC)C.C([Li])CCC.CI>CCCCCC.O1CCCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[N:4]=1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCc1cccc(C)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCc1cccc(CC)n1
Temperature: -40 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
In a 250-ml 3-neck jacketed reactor flask, 4.3 g (40.2 mmol) of 2,6-dimethylpyridine and 4.06 g (40.2 mmol) of triethylamine were dissolved by addition of 50 ml of anhydrous tetrahydrofuran, and the solution was cooled to −40° C., after which 28.7 ml (46 mmol) of 1.6 M butyllithium in hexane was added dropwise thereto. At the same time, the solution changed to deep red. Next, the solution was stirred for 1 hour, and then warmed to 0° C., after which 5.7 g (40.2 mmol) of methyl iodide was added dropwise thereto, followed by stirring for 1 hour. Then, the reaction product was concentrated, and the concentrate was dissolved in ethyl acetate, washed with water and saline, dried with anhydrous magnesium sulfate, and then concentrated again, thereby obtaining crude 2-ethyl-6-methylpyridine. Subsequently, 3.2 g of the obtained 2-ethyl-6-methylpyridine was placed in a 250-ml 3-neck jacketed reactor flask and dissolved by addition of 4.06 g (40.2 mmol) of triethylamine and 50 ml of anhydrous tetrahydrofuran. The solution was cooled to −40° C., and 28.7 ml (46 mmol) of 1.6 M n-butyllithium in hexane was added dropwise. At this time, the solution changed to deep red. Next, the solution was stirred for 1 hour, and then cooled to 0° C., after which 6.0 g (42 mmol) of methyl iodide was added thereto dropwise. Then, the cooling bath was removed, and the solution was stirred at room temperature for 1 hour, and then concentrated. The concentrate was dissolved in ethyl acetate, washed with water and saline, dried with anhydrous magnesium sulfate, and then concentrated again. The concentrate was purified by column chromatography (stationary phase: silicagel; eluent: n-hexane/ethyl acetate (6/1), thereby obtaining 2 g of 2,6-diethyl pyridine as liquid. The obtained 2,6-diethyl pyridine was analyzed by NMR.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:29])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][CH:24]([CH2:27][F:28])[CH2:25][F:26])[CH:22]=3)[C:17](O)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[NH2:36][C:37]1[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][N:38]=1>C(Cl)Cl>[N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:29])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][CH:24]([CH2:25][F:26])[CH2:27][F:28])[CH:22]=3)[C:17]([NH:36][C:37]3[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][N:38]=3)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc(N)cn1
Reactant: O=C(O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(OC(CF)CF)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(OC(CF)CF)c2)cn1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 57.9 %

Procedure:
1-Chloro-N,N-2-trimethylpropenylamine (0.08 mL, 0.60 mmol) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzoic acid (215 mg, 0.5 mmol) in DCM (5 mL) and the reaction stirred at RT for 30-40 minutes. Pyridine (0.08 mL, 1.0 mmol) and 2-amino-5-methylpyrazine (108 mg, 1.0 mmol) were added and the reaction stirred for 16 hours before being concentrated in vacuo and water (20 mL) added. The mixture was extracted with ethyl acetate (3×20 mL), washed with 1N hydrochloric acid (20 mL), a saturated solution of sodium hydrogen carbonate (20 mL), brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed on silica, eluting with a gradient of 0-10% methanol in DCM, to give the desired compound as a white solid (150 mg). 1H NMR δ (CDCl3): 2.40 (quintet, 2H), 2.56 (s, 3H), 4.22-4.31 (m, 2H), 4.32-4.40 (m, 2H), 4.62-4.82 (m, 5H), 7.06 (t, 1H), 7.38 (t, 1H), 7.47 (t, 1H), 8.15 (s, 1H), 8.17 (s, 1H), 8.25 (d, 1H), 8.46 (s, 1H), 9.55 (s, 1H); m/z 518 (M+H)+, 516 (M−H)−
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[C:14]([C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1)#[CH:15].CCN(CC)CC>C1COCC1>[C:14]([C:16]1[CH:17]=[C:18]([NH:22][C:7]([C:3]2[O:4][CH:5]=[CH:6][C:2]=2[CH3:1])=[O:9])[CH:19]=[CH:20][CH:21]=1)#[CH:15]
Reactant: Cc1ccoc1C(=O)O
Reactant: C#Cc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: C#Cc1cccc(NC(=O)c2occc2C)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A dry 25 mL flask was charged with 3-methylfuran-2-carboxylic acid (0.500 g, 3.46 mmol) and thionyl chloride (10 mL). The reaction was heated to 50° C. and allowed to react for 2 h. The reaction was then cooled to room temperature and concentrated affording the crude acid chloride. The acid chloride was then dissolved in THF (5 mL) and 3-ethynyl-phenylamine (0.41 g, 3.47 mmol) was added followed by NEt3 (0.95 mL, 7 mmol). The mixture was allowed to stir at 55° C. for 3 hours and the cooled to room temperature. The reaction was then partitioned between EtOAc and water. The organic layer was then washed once with 1M HCl (5 mL) and then once with saturated aqueous NaHCO3 (5 mL). The organic extracts were then concentrated to give the title compound as a light brown solid (631 mg, 2.80 mmol, 81%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[CH2:4][C:5]([CH3:8])([CH3:7])[CH:6]=1.[N+]([CH3:13])([O-])=O.[OH-:14].C([N+](C)(C)C)C1C=CC=CC=1>CO.CCOCC>[CH:13]([CH:6]1[C:5]([CH3:8])([CH3:7])[CH2:4][C:3](=[O:9])[CH:2]1[CH3:1])=[O:14]
Reactant: [OH-]
Reactant: CC1=CC(C)(C)CC1=O
Reactant: C[N+](=O)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: CC1C(=O)CC(C)(C)C1C=O
Reaction time: 0.5 h

Procedure:
124 g. of 2,4,4-trimethyl-cyclopent-2-en1-one are introduced into 67 g. of nitromethane and, after the addition of 10 ml. of a 40% solution of benzyltrimethylammonium hydroxide in methanol, stirred at 70°C. for 3 days. The mixture is then taken up in ether The ether solution is washed with 10% sulfuric acid, dried over sodium sulfate and evaporated under reduced presssure. The remaining 2,4,4-trimethyl-3-nitromethyl-cyclopentanone boils after rectification in a high vacuum at 97°-100°C/0.2 mmHg. 83 g. of the 2,4,4-trimethyl-3-nitromethyl-cyclopentanone are treated with 36 g. of sodium hydroxide in 600 ml. of water. After the addition of 300 ml. of a saturated aqueous magnesium sulfate solution, the mixture is stirred for 30 minutes, then treated dropwise at 0°C. within 1 hour with a solution of 49.7 g. of potassium permanganate in 800 ml. of water and subsequently filtered. The filtrate is extracted with methylene chloride. The extract is dried over sodium sulfate and evaporated under reduced pressure. There is obtained 1-formyl-3-oxo-2,5,5-trimethyl-cyclopentane, whose 2,4-dinitrophenylhydrazone has a melting point of 174°-177°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[C:24]5[CH:36]=[CH:35][CH:34]=[N:33][C:25]=5[NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:22]4=[N:21][C:20]=3[CH2:37][C:38]([OH:40])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>ClCCl>[O:40]=[C:38]([NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:37][C:20]1[N:21]=[C:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]3[N:33]=[CH:34][CH:35]=[CH:36][C:24]=3[N:23]2[C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:11][CH2:12]2)=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CC(=O)O)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CC(=O)Nc4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.3 %

Procedure:
To a solution of 2-(3-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetic acid (0.04 g, 1 eq.) in dichloromethane (2 mL) was added successively aniline (0.027 g, 4 eq.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (0.029 g, 2 eq.) and diisopropylethylamine (70 μL, 5 eq.). The reaction was stirred at room temperature for 20 hours. The reaction mixture was diluted with dichloromethane (10 mL), washed with water (2×10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative HPLC (YMC PACK ODS-AM; AM12S05-1020WT; 100×20 mm ID; CAN/0.1% TFA, 30 mL/min) gave tert-butyl (1-(4-(2-(2-oxo-2-(phenylamino)ethyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.022 g, 48%). LCMS: 613 [M+H].
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6][CH2:7][C:8](Br)=[O:9].[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]([CH3:36])([CH3:35])[CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:14])([CH3:13])[CH3:12].C(OCC)(=O)C>O>[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]([CH3:36])([CH3:35])[CH2:19][N:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:8](=[O:9])[CH2:7][Br:6])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(CNc1ccccc1OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CN(C(=O)CBr)c1ccccc1OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
1.08 g of sodium bicarbonate (12.9 mmol) and 1.0 ml of bromoacetyl bromide (11.3 mmol) were added to a solution of 4.00 g of [2-(2-benzyloxyphenylamino)-1,1-dimethylethyl]carbamic acid t-butyl ester obtained in Example (10a) (10.7 mmol) in a mixed solvent of ethyl acetate (50 ml) and water (50 ml) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. After extraction with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=2/1) to obtain 4.86 g of the title compound (yield: 92%).
Reaction SMILES: C([N:8]([CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])C1C=CC=CC=1>C(O)C.C(O)(=O)C.[Pd]>[CH2:22]([O:21][P:16]([CH2:15][NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:18][CH2:19][CH3:20])=[O:17])[CH3:23]
Reactant: CCOC(=O)CN(Cc1ccccc1)CP(=O)(OCC)OCC
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CNCP(=O)(OCC)OCC
Temperature: 50 °C
Reaction time: 32 h

Procedure:
A 250-mL pressure tank reactor was purged, flushed and maintained with a hydrogen atmosphere, then, was added a solution of ethyl 2-(benzyl((diethoxyphosphoryl)methyl)amino)acetate (8.0 g, 23.32 mmol, 1.00 equiv) in ethanol (180 mL), acetic acid (10 mL), Pd/C (0.9 g). The resulting solution was stirred at 20 atm for 32 h at 50° C. The solids were filtered out, and the resulting mixture was concentrated under vacuum. This resulted in 6.0 g (82%) of the acetic acid salt of ethyl 2-((diethoxyphosphoryl)methylamino)acetate as a brown oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.Br[CH2:24][C:25]1[N:30]=[C:29]2[O:31][CH2:32][CH2:33][O:34][C:28]2=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:34]1[C:28]2[C:29](=[N:30][C:25]([CH2:24][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:22])[CH2:6][CH2:7]3)=[CH:26][CH:27]=2)[O:31][CH2:32][CH2:33]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: BrCc1ccc2c(n1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.5 %

Procedure:
To 5 mL of an N,N-dimethylformamide solution containing 170 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 130 mg of 6-bromomethyl-2,3-dihydro-1,4-dioxino[2,3-b]pyridine, 230 mg of potassium carbonate was added, and stirred at room temperature for 3 days. The solvent was removed under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel N, eluent; chloroform:methanol=5:1] to give 95.1 mg of 1-(2-(4-((2,3-dihydro-1,4-dioxino[2,3-b]pyridin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a yellow oil.
Reaction SMILES: C(O[B:4]([O:8]CC)[O:5]CC)C.Br[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.C([Li])CCC.Cl.CCOC(C)=O.CCCC(C)C>C1COCC1>[F:19][C:18]([F:21])([F:20])[C:16]1[CH:17]=[C:12]([B:4]([OH:5])[OH:8])[CH:13]=[N:14][CH:15]=1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: CCOB(OCC)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCC(C)C
Product: OB(O)c1cncc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Triethylborate (24 ml, 139 mmol) is added to a solution of 3-bromo-5-trifluoromethyl-pyridine (30 g, 133 mmol) in THF (300 ml) and the resulting pale yellow solution is cooled to −78° C. A solution of 1.6 M n-butyl lithium in hexanes (97 ml, 139 mmol) is added via cannula dropwise over 40 minutes, keeping the temperature below −65° C. Once addition is complete, the reaction mixture is allowed to warm slowly to room temperature and stirred for 1 hour. 1M HCl (200 ml) is added and the reaction mixture stirred for 15 minutes. The layers are separated and the organic layer is washed with 1M HCl (200 ml). The aqueous layers are combined and washed with EtOAc (2×250 ml). The pH of the aqueous phase is adjusted by the addition of 2M NaOH, and extracted with EtOAc (2×250 ml). Concentration in vacuo affords a solid, which is recyrstallised from EtOAc/iso-hexane to yield the title compound as a yellow solid [M+H]+ 192.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:28]=3)[C:23](O)=[O:24])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.C(Cl)CCl.[CH2:39]([NH2:41])[CH3:40].C1COCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:39]([NH:41][C:23](=[O:24])[C:22]1[CH:26]=[C:27]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[CH:28]=[C:20]([NH:19][C:6]2[C:5]3[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:7]=2[CH3:18])[CH:21]=1)[CH3:40]
Reactant: CCN
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(C(=O)O)cc(N2CCOCC2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCNC(=O)c1cc(Nc2c(C)c(-c3ccccn3)nc3cc(F)ccc23)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure U by stirring 3-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinobenzoic acid (0.025 g, 0.055 mmol), DMAP (0.013 g, 0.109 mmol), EDC (0.021 g, 0.109 mmol), 2M ethanamine THF (0.035 mL, 0.071 mmol), and DCM (0.6 mL) at 23° C. for 1 hour. Purification by reverse-phase HPLC afforded N-ethyl-3-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)benzamide as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67-8.71 (1H, m), 8.61 (1H, s), 8.27 (1H, m), 8.09 (1H, dd, J=9.3, 6.2 Hz), 7.97-8.02 (1H, m), 7.84-7.91 (1H, m), 7.71-7.77 (1H, m), 7.45-7.52 (2H, m), 6.86-6.89 (1H, m), 6.59-6.62 (1H, m), 6.44-6.48 (1H, m), 3.69-3.75 (4H, m), 3.17-3.25 (2H, m), 3.05-3.11 (4H, m), 2.16-2.20 (3H, m), 1.04-1.10 (3H, m). Mass Spectrum (ESI) m/e=486.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([CH3:8])[CH3:7])=[O:4].C(N(CC)C(C)C)(C)C.[F:18][C:19]1[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH:27]=1)[C:24](Cl)=[O:25]>ClCCl>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH:27]=1)[C:24]([NH:1][CH2:2][C:3]([NH:5][CH:6]([CH3:8])[CH3:7])=[O:4])=[O:25]
Reactant: CC(C)NC(=O)CN
Reactant: O=C(Cl)c1cc(F)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A solution of 2-amino-N-isopropylacetamide (11.3 g, 97.0 mmol) and N,N-diisopropylethylamine (20.1 g, 162 mmol) in dichloromethane (200 mL) was cooled using an ice water bath. A solution of 5-fluoro-2-nitrobenzoyl chloride (16.5 g, 81.0 mmol) in dichloromethane (200 mL) was added dropwise over 15 minutes. The resulting solution was stirred overnight. The reaction mixture was washed with 2N HCl solution (2×250 mL), brine (250 mL) and then dried over magnesium sulphate. The solution was filtered before concentrating under reduced pressure to afford 5-fluoro-N-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzamide (18.5 g, 65.0 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH:8]=[CH:7]2.Cl[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:21]=2[N:20]=1>>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:19]3[NH:23][C:22]4[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:21]=4[N:20]=3)[CH2:14][CH2:13]1)[CH:8]=[CH:7]2
Reactant: Oc1cccc2ccc(N3CCNCC3)nc12
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Product: Oc1cccc2ccc(N3CCN(c4nc5ccc(C(F)(F)F)cc5[nH]4)CC3)nc12

Procedure:
The piperazine from step (b) above (0.329 g, 1.67 mmol) and 2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.370 g, 1.67 mmol, Example 1c) reacted under the conditions of Example 3c to give the title compound. M.p. 191-193° C. MS (ESI, pos. ion) m/z: 414 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][C:9]([CH3:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23]([O:30][C:31](=[O:34])[CH2:32]Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:32][C:31]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:34])[C:12]2[C:7](=[CH:8][C:9]([CH3:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)c2ccc(C)cc2n1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCC(=O)OCc2ccccc2)c2ccc(C)cc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5.00 g 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid methyl ester in 35 ml of DMF, 8.25 g of cesium carbonate and 5.80 g of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 12 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step. Yield: 10.00 g.
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)(=[O:10])[CH3:9].[CH3:17][C:18]1([CH3:32])[O:22][C@H:21]([C:23]2[C:24]([F:31])=[C:25]([CH:28]=[CH:29][CH:30]=2)[CH:26]=[O:27])[CH2:20][O:19]1.Cl>C1COCC1>[CH3:17][C:18]1([CH3:32])[O:22][C@H:21]([C:23]2[C:24]([F:31])=[C:25]([CH:26]([OH:27])[CH2:9][C:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:10])[CH:28]=[CH:29][CH:30]=2)[CH2:20][O:19]1
Reactant: CC1(C)OC[C@@H](c2cccc(C=O)c2F)O1
Reactant: CC(=O)c1cccnc1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](c2cccc(C(O)CC(=O)c3cccnc3)c2F)O1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
In a stream of argon, anhydrous THF solution containing 0.72 ml of N,N-diisopropylamine was cooled to about −70° C., 3.3 ml of 1.54 M n-butyl lithium-hexane solution was added dropwise thereto, and then the reaction liquid was risen to about −15° C. The reaction liquid was again cooled to about −70° C., mixed with 0.54 ml of 3-acetylpyridine and then stirred at the same temperature for about 30 minutes, and subsequently, 5 ml of anhydrous THF solution containing 1.1 g of 3-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluorobenzaldehyde was gradually added dropwise thereto. After stirring at −70° C. for about 20 minutes and then at about −30° C. for about 3 hours, this was mixed with an appropriate amount of 0.2 M hydrochloric acid aqueous solution and subjected to several times of extraction operation with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate, and then the solvent was evaporated and the thus formed residue was isolated and purified by a silica gel column chromatography to obtain 0.77 g (45%) of 3-[3-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluorophenyl]-3-hydroxy-1-pyridin-3-yl-propan-1-one as a colorless oil from an ethyl acetate-hexane (7:3) eluate. FA: 346
Reaction SMILES: C([O:3][C:4](=[O:39])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:38])[NH:14][C:15]2[CH:20]=[CH:19][C:18]3=[N:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:25]=4)=[CH:23][N:17]3[N:16]=2)[CH:8]=1)C.[OH-].[Na+]>C1COCC1.CO>[CH3:34][C:33]([CH3:36])([CH3:35])[C:32]([NH:31][C:26]1[CH:25]=[C:24]([C:22]2[N:21]=[C:18]3[N:17]([CH:23]=2)[N:16]=[C:15]([NH:14][C:13]([C:9]2[CH:8]=[C:7]([CH:6]=[CH:5][C:4]([OH:39])=[O:3])[CH:12]=[CH:11][CH:10]=2)=[O:38])[CH:20]=[CH:19]3)[CH:29]=[CH:28][C:27]=1[CH3:30])=[O:37]
Reactant: CCOC(=O)C=Cc1cccc(C(=O)Nc2ccc3nc(-c4ccc(C)c(NC(=O)C(C)(C)C)c4)cn3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2cn3nc(NC(=O)c4cccc(C=CC(=O)O)c4)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A 20-mL vial is charged with ethyl-3-[3-[[2-[3-(2,2-dimethylpropanoylamino)-4-methyl-phenyl]imidazo[2,1-f]pyridazin-6-yl]carbamoyl]phenyl]prop-2-enoate (0.042 g, 0.08 mmol) and a solution of THF-MeOH (1 mL, 1:1). To this mixture is added aqueous NaOH (1 mL, 1 M), then stirred at 50° C. for 1 hour. The mixture is concentrated to remove the organics and extracted with EtOAc once. Aqueous HCl (1M) is added to lower the pH to 2 and the resulting solids are filtered to give the title compound (0.025 g), which is used without further purification. LCMS (m/z)=498.5 [M+H]+, tR=2.47 min.