Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[NH:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:36])[C:21]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]([C:24]([NH:26][NH2:27])=[O:25])[N:23]=[C:12]21)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53](Cl)=[O:54])=[CH:48][CH:47]=1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:37])[NH:10][C:11]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[CH2:14][N:13]1[C:20](=[O:36])[C:21]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:22]([C:24]([NH:26][NH:27][C:53](=[O:54])[CH2:52][C:49]3[CH:50]=[CH:51][C:46]([F:45])=[CH:47][CH:48]=3)=[O:25])[N:23]=[C:12]21)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)NNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.78 %

Procedure:
To a solution of benzyl(3-(benzyloxy)-2-(hydrazinylcarbonyl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate, Intermediate 9 (400 mg, 0.794 mmol) in CH2Cl2 (15 mL) at 0° C. was added triethylamine (0.221 mL, 1.589 mmol) followed by 2-(4-fluorophenyl)acetyl chloride (0.098 mL, 0.715 mmol) and the resulting mixture stirred for 1 h. The mixture was allowed to warm to room temp and stirred for 3 h. The mixture was then concentrated and purified by preparative HPLC to afford the title compound (70 mg, 0.109 mmol, 13.78% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.00 (1H, br. s.), 8.35 (1H, br. s.), 7.48-7.53 (2H, m), 7.27-7.38 (10H, m), 7.00-7.07 (2H, m), 6.55 (1H, br. s.), 5.39 (2H, s), 5.05 (2H, s), 4.10 (2H, d, J=3.36 Hz), 3.60 (2H, s), 2.56-2.70 (2H, m), 2.47 (1H, br. s.), 1.88-2.04 (4H, m), 1.59-1.71 (2H, m). LCMS (M+H)=640.35.
Reaction SMILES: C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.[CH2:21]([C:23]([S:42]([CH3:45])(=[O:44])=[O:43])([CH2:27][CH2:28][N:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][C:30]1=[O:41])[C:24]([OH:26])=O)[CH3:22].[O:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[O:52][NH2:53].Cl.CN(C)CCCN=C=NCC>ClCCl.O>[CH2:21]([C:23]([S:42]([CH3:45])(=[O:43])=[O:44])([CH2:27][CH2:28][N:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][C:30]1=[O:41])[C:24]([NH:53][O:52][CH:47]1[CH2:48][CH2:49][CH2:50][CH2:51][O:46]1)=[O:26])[CH3:22]
Reactant: CCC(CCn1ccc(-c2ccccc2)cc1=O)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCC(CCn1ccc(-c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 108.1 %

Procedure:
Diisopropylethylamine (35 uL, 0.2 mmol, 2.1 equiv) and 1-hydroxyl benzotriazole monohydrate (27 mg, 0.18 mmol, 1.9 equiv) were added sequentially to a solution of 2-ethyl-2-(methylsulfonyl)-4-(2-oxo-4-phenylpyridin-1(2H)-yl)butanoic acid (34 mg, 0.09 mmol, 1.0 equiv) in dichloromethane (2 mL) at room temperature. After 30 min, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (15 mg, 0.12 mmol, 1.3 equiv) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (26 mg, 0.13 mmol, 1.4 equiv) were added, and the reaction was allowed to stir overnight. Water (2 mL) was added, the organic phase was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude material was purified by flash chromatography (1:1-0:1 heptane/ethyl acetate) to provide a colorless oil (45 mg, 100%). MS (LCMS) m/z 461.8 (M−1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li+].CCC[CH2-].[C:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[CH2:16][CH2:15]1)(=[O:13])[CH3:12].CCOC(C)=O>C1COCC1.O>[OH:13][C:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[CH2:16][CH2:15]1)([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Reactant: c1cscn1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2nccs2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Thiazole (100 mg, 1.175 mmol) was dissolved in THF (11 mL) and cooled to a temperature of −78° C. N-butyllithium (2 M in hexanes, 0.587 mL, 1.175 mmol) was added and the mixture was allowed to stir for 30 minutes at −78° C. A solution of trans-butyl 4-acetylcyclohexanecarboxylate (319 mg, 1.410 mmol) in THF (1 mL) was then added to the mixture, and the combined solution was allowed to stir for 1 hour at −78° C. The reaction was diluted with water, warmed to 23° C., and transferred to a separatory funnel containing EtOAc. The layers were separated and the organic layer was washed with water, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel to afford butyl trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate. MS ESI calc'd. for C16H26NO3S [M+H]+ 312. found 312.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.Cl.O.[NH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH:5]1([CH2:4][N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1CCN(CC2CC2)CC1
Temperature: 85 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
To a suspension of bromomethyl cyclopropane (4 mmol) and 4-piperidone hydrate hydrochloride (4 mmol) in acetonitrile (30 mL) was added sodium carbonate (11 mmol). The reaction mixture was stirred 16 h at 85° C. The resulting suspension was filtered and the solid was washed with acetonitrile. The filtrate was concentrated in vacuo and purified by column chromatography on silica eluting with DCM/2N NH3 in methanol 97:3 to yield 339 mg of the title compound as yellow oil. MS (m/e): 154.2 (MH+, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:31])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([O:29]C)=O)[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[CH3:32][NH2:33]>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:31])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:33][CH3:32])=[O:29])[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: COC(=O)c1cccc(-n2cc(-c3ccccn3)cc(-c3ccccc3C#N)c2=O)c1
Reactant: CN
Product: CNC(=O)c1cccc(-n2cc(-c3ccccn3)cc(-c3ccccc3C#N)c2=O)c1
Temperature: 25 °C

Procedure:
3-(2-Cyanophenyl)-5-(2-pyridyl)-1-(3-methoxycarbonylphenyl)-1,2-dihydropyridin-2-one (10 mg) was added to 6 ml of a 40% methanolic solution of methylamine followed by stirring at room temperature for one night. The reaction solution was concentrated in vacuo to give 10 mg of the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc2ccccc2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1ccc2ccccc2c1Br

Procedure:
A stirred solution of 2-methoxynaphthalene (5g.) in acetic acid (100 ml.) is treated dropwise with a solution of 1.1 molar equivalents of bromine in acetic acid (50 ml.). Upon disappearance of the bromine color, wtaer is added. The solid which forms is collected by filtration, washed with water until neutral, recrystallized, rewashed, and dried to yield 1-bromo-2-methoxynaphthalene.
Reaction SMILES: B1C2CCCC1CCC2.[CH3:10][O:11][C:12](=[O:26])[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([F:22])[C:14]=1[CH2:23][CH:24]=[CH2:25].[OH-:27].[Na+].OO>C1COCC1>[CH3:10][O:11][C:12](=[O:26])[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([F:22])[C:14]=1[CH2:23][CH2:24][CH2:25][OH:27]
Reactant: C=CCc1c(F)ccc([N+](=O)[O-])c1C(=O)OC
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])ccc(F)c1CCCO
Temperature: 0 °C
Reaction time: 5 h

Procedure:
In a 2 L, three necked, round-bottomed flask were charged 892 mL (0.45 mol) of 9-BBN (0.5M) and 100 mL of THF. After cooling to 0° C., 71 g (0.3 mol) of 2-allyl-3-fluoro-6-nitrobenzoic acid methyl ester in 150 mL of THF was added over 30 minutes and the mixture was stirred at room temperature for 5 hours. After cooling to 0° C., 700 mL of 1M NaOH aq was added into the reaction mixture, which was stirred for 30 minutes. To the mixture, 200 mL of hydrogen peroxide (35%) was added over 30 minutes then stirred at room temperature for 1 hours. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water, a solution of sodium thiosulfate and brine, and was dried over sodium sulfate. The solvent was removed under reduced pressure to give 104 g of 3-fluoro-2-(3-hydroxy-propyl)-6-nitro-benzoic acid methyl ester as orange oil. The crude product was used for the next reaction.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]2[S:21][CH:20]=[CH:19][C:10]=2[N:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1)=[O:7].[OH-].[Na+].Cl>CO.O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]2[S:21][CH:20]=[CH:19][C:10]=2[N:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1)=[O:7]
Reactant: CCOC(=O)c1nc(C(=O)c2cccs2)c2sccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
A solution of ethyl 4-(2-thienylcarbonyl)thieno[3,2-d]pyrimidine-2-carboxylate (80 mg, 0.25 mmol) in MeOH (3 mL) was treated with 2M-NaOH (1 mL), stirred at room temperature for 20 min, acidified with 1M-HCl, diluted with water and filtered to give the title compound (36 mg, 50%) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]1=[O:13].[Se](=O)=[O:15]>O1CCOCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:12]=[O:15])[C:3]1=[O:13]
Reactant: O=[Se]=O
Reactant: Cc1nc2ccccc2n(C)c1=O
Solvent: C1COCCO1
Product: Cn1c(=O)c(C=O)nc2ccccc21

Procedure:
A mixture of 1,3-dimethyl-1H-quinoxalin-2-one (1 g) and selenium dioxide (1.33 g, 2.1 eq) in dry dioxane (60 mL) was stirred at reflux under nitrogen for 30 min. After cooling, the dark-brown mixture was concentrated under reduced pressure and the residue was purified by FC (AcOEt) to give the title compound as a yellow solid.
Reaction SMILES: P[C-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C-:7]1(P)[CH:11]=[CH:10][CH:9]=[CH:8]1.[Fe+2:13].[Li]CCCC.CO>C1COCC1.CCCCCC>[CH-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[Fe+2:13]
Reactant: P[c-]1cccc1
Agent: [Fe+2]
Agent: [Li]CCCC
Solvent: CO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1cc[cH-]c1
Temperature: -30 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,1'-bis(phosphino)ferrocene (0.2 g, 0.8 mmol) in THF (30 mL) was added dropwise via syringe n-BuLi (1.0 mL of a 1.6M solution in hexane, 2.0 equiv. ). The orange solution was allowed to stir for 1.5 h during which it became slightly cloudy. To the resulting mixture was then added a THF solution (10 mL) of (3S, 6S)-3, 6-octanediol cyclic sulfate (0.338 g, 1.6 mmol). After stirring for 1 h, n-BuLi (1.15 mL of a 1.6M hexane solution, 2.2 equiv.) was again added dropwise via syringe. The mixture was allowed to stir for 1.5 h, after which MeOH (3 mL) was added to quench any excess n-BuLi remaining. The resulting orange mixture was concentrated to produce a gelatinous residue which was extracted with pentane (150 mL) and filtered. Concentration of the filtrate to 5 mL and cooling to -30° C. for 10 h afforded the product as an orange crystalline solid which was filtered, washed with cold MeOH and dried (0.29 g, 77%). The crude product was essentially pure and may be used without any further purification. 1H NMR (C6D6) δ0.88 (m, 6H, CH3), 0.9-1.20 (m, 4H, CH2), 1.11 (t, JHH =7.3 Hz, 6H, CH3), 1.20-1.40 (m, 4H, CH2), 1.45-1.70 (m, 4H, CH2), 1.70-1.90 (m, 4H, CH), 2.10 (m (br), 2H, CH2), 2.40 (m, 2H, CH), 3.90 (m, 1H, CpH), 4.25 (m, 2H, CpH), 4.35 (m, 1H, CpH); 31P NMR (C6D6) δ-9.4; 13C NMR (C6D6) 5 14.27 (d, JPC =16.1 Hz), 14.82 (d, JPC =7.9 Hz), 23.76, 30.07, 30.49, 34.03, 34.34 (d, JPC =4.4 Hz), 42.42 (d, JCP =9.9 Hz), 44.44 (d, JCP =11.9 Hz), 70.88 (d, JCP =6.2 Hz), 71.24, 71.96 (d, JCP =7.7 Hz), 77.33 (d, JCP =32.8 Hz); HRMS (EI, direct insert): m/z 470.1976 (M+, exact mass calcd for C26H40P2Fe: 470.1955), 359.0485 (M-C8H15) , 328.1046 (M-C8H15 P).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([OH:11])[C:5]([O:12][CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])=[C:4]([O:24][CH2:25][CH2:26][Cl:27])[C:3]=1[C:28](=[O:30])[CH3:29].O.O.Cl[Sn]Cl.[CH3:36][CH2:37]O>>[C:28]([C:3]1[C:4]([O:24][CH2:25][CH2:26][Cl:27])=[C:5]([O:12][CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])[C:6]2[O:11][C:36]([CH3:37])=[N:8][C:7]=2[C:2]=1[Cl:1])(=[O:30])[CH3:29]
Reactant: CC(=O)c1c(Cl)c([N+](=O)[O-])c(O)c(OCCC(C)c2ccc(F)cc2)c1OCCCl
Reactant: CCO
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(=O)c1c(OCCCl)c(OCCC(C)c2ccc(F)cc2)c2oc(C)nc2c1Cl
Temperature: 50 °C
Yield: 64 %

Procedure:
To a stirred solution 38f) (242 mg, 0.52 mmol) in dry EtOH (10 mL) under nitrogen was added SnCl2.2H2O (1.11 g, 4.92 mmol). The solution was heated at reflux for 4 h. The solution was concentrated in vacuo and the residue was dissolved in EtOAc (10 mL) and treated with sodium potassium tartrate (1M, 10 mL). The mixture was warmed at 50° C. until the layers visibly separated. The organic layer was separated and the aqueous further extracted with EtOAc (2×5 mL). The organics were pooled, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was taken up in dry DMF (5 mL) and to this was added triethyl orthoacetate (5 mL, excess). The solution was stirred at reflux for 1 h. The solution was concentrated in vacuo and the residue was taken in CH2Cl2 (5 mL) and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, ethyl acetate/petroleum spirit 2:8) to give the title compound (151 mg, 64%). 1H NMR (300 MHz, CDCl3) δ 7.21-7.16 (m, 2H), 7.02-6.96 (m, 2H), 4.36-4.19 (m, 4H), 3.74-3.71 (m, 2H), 3.30-3.11 (m, 1H), 2.62 (s, 3H), 2.58 (s, 3H) 2.16-1.97 (m, 2H), 1.34-1.31 (d, J=7.0 Hz, 3H), ESIMS m/z [M+H]+ 454.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1.N1C=CC=CC=1.[CH:42]1([C:45](Cl)=[O:46])[CH2:44][CH2:43]1>ClCCl>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:18]=[C:13]([C:10]([CH3:12])([CH3:11])[C:9]([N:8]([CH3:28])[C:5]2[C:4]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[CH:3][C:2]([NH:1][C:45]([CH:42]3[CH2:44][CH2:43]3)=[O:46])=[N:7][CH:6]=2)=[O:27])[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=1
Reactant: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(NC(=O)C2CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.1 %

Procedure:
To a solution of 100 mg (0.20 mmol) N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 3 ml dichloromethane were added 2 ml pyridine and 23 mg (0.22 mmol) cyclopropanecarboxylic acid chloride at 0° C. After stirring for 2 days at room temperature, the solvent was removed in vacuo and the residue was purified by flash-chromatography to give 61 mg (54%) of the title compound as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.C(N(CC)CC)C.Cl.Cl.[NH:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39]1[NH:43][N:42]=[C:41]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[N:40]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][N:47]4[CH2:48][CH2:49][CH:44]([C:41]5[NH:40][C:39]([C:35]6[NH:34][CH:38]=[CH:37][CH:36]=6)=[N:43][N:42]=5)[CH2:45][CH2:46]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1
Reactant: c1c[nH]c(-c2nc(C3CCNCC3)n[nH]2)c1
Reactant: Cc1ccc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)n2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ccc[nH]6)[nH]5)CC4)cc3)c(-c3ccccc3)n2n1
Reaction time: 0.08 h

Procedure:
To a solution of 0.150 g (0.479 mM) of 4-(6-methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)benzaldehyde in 6 mL of THF is added triethylamine (2 eq). The reaction mixture is stirred for 5 minutes. To this solution is added 4-[5-(1H-pyrrol-2-yl)-1H-1,2,4-triazol-3-yl]piperidine dihydrochloride (Intermediate J) (1.5 eq) followed by acetic acid (2.5 eq). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH(OAc)3 (6 eq) over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained is taken up in chloroform and washed with water, dried and concentrated. The crude is purified on a flash column chromatography to obtain the desired compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].[C:18]([CH:21]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:22](OCC)=[O:23])(=O)[CH3:19].O(Cl)Cl>>[OH:10][C:9]1[CH:11]=[C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])[CH:6]=[C:7]2[C:8]=1[C:18]([CH3:19])=[C:21]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:22](=[O:23])[O:12]2
Reactant: CCOC(=O)CCC(C(C)=O)C(=O)OCC
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Agent: ClOCl
Product: CCCCCC(C)C(C)c1cc(O)c2c(C)c(CCC(=O)OCC)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 288 h

Procedure:
A mixture of 262 g. (1.109 mole) of 5-(3-methyl-2-octyl)resorcinol, 283 g. (1.23 mole) of diethyl α-acetylglutarate, and 170 g. (1.11 mole) of phorphorus oxychloride protected from atmospheric mositure is stirred at room temperature for 12 days. The mixture is taken up in benzene-ether and the solution is washed several times with water, aqueous sodium bicarbonate, water and dried over anhydrous magnesium sulfate. After removal of the solvent, 441 g. of an oil is obtained, which solidifies on standing.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:12][Si:13]([CH3:40])([CH3:39])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[CH:25][C:26]([C:27]3[CH:28]=[N:29][N:30]([C:32]4([CH2:36][C:37]#[N:38])[CH2:35][NH:34][CH2:33]4)[CH:31]=3)=[C:21]2[CH:20]=[CH:19]1.Cl[C:42]1[N:43]=[CH:44][C:45]([C:48]([O:50][CH3:51])=[O:49])=[N:46][CH:47]=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[C:37]([CH2:36][C:32]1([N:30]2[CH:31]=[C:27]([C:26]3[CH:25]=[CH:24][N:23]=[C:22]4[N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:39])([CH3:12])[CH3:40])[CH:19]=[CH:20][C:21]=34)[CH:28]=[N:29]2)[CH2:33][N:34]([C:42]2[N:43]=[CH:44][C:45]([C:48]([O:50][CH3:51])=[O:49])=[N:46][CH:47]=2)[CH2:35]1)#[N:38]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ccnc21
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1
Temperature: 120 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
N,N-Diisopropylethylamine (1.0 mL, 6.0 mmol) was added to a mixture of {3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (0.96 g, 2.0 mmol) and methyl 5-chloropyrazine-2-carboxylate (0.34 g, 2.0 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at 120° C. overnight. The mixture was worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-60%) to afford the desired product (0.13 g, 12%). LCMS (M+H)+: m/z=545.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][Cl:12])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: ClCc1ccc(Cl)nc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 108.6 %

Procedure:
6-Chloronicotinic acid (23.36 g, 0.18 mol), phosphorus pentachloride (41.65 g, 0.20 mol) and phosphorus oxychloride (20.50 ml, 0.22 mol) were stirred vigorously together at ambient temperature (20° C.). The resulting mixture was heated with stirring to 120° C. and kept at that temperature for a further 3 hours. The mixture was then allowed to cool to ambient temperature (20° C.) and excess phosphorus oxychloride was evaporated off under reduced pressure to yield 6-chloronicotinyl chloride as a brown oil 31.68 g, 100%), which was used directly in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:61][N:62]1[CH2:66][CH2:65][CH2:64][C@H:63]1[CH:67]=O>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])/[CH:29]=[CH:67]/[C@@H:63]4[CH2:64][CH2:65][CH2:66][N:62]4[CH3:61])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN1CCC[C@H]1C=O
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/[C@@H]1CCCN1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 53.6 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (50 mg, 0.08 mmol) was dissolved in 2 mL of tetrahydrofuran at −78° C., followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (80 μL, 0.08 mmol). After the mixture was stirred for 45 minutes, (2S)-1-methylpyrrolidine-2-carbaldehyde 1b (20 mg, 0.17 mmol) was added. After stirring for another 1 hour, the reaction mixture was warmed up to room temperature and stirred for 12 hours. The reaction mixture was added with 1 mL of water and 1 mL of methanol, then the organic extracts were extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enamide 1 (25 mg, yield 53.5%) as a yellow solid.