Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:9][S:10]([C:13]2[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=2)[C:16]([NH:18][C:19]2[S:20][C:21]3[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=3[C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)=[O:25])=[O:17])(=[O:12])=[O:11])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:52](I)[CH3:53].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([N:9]([CH2:52][CH3:53])[S:10]([C:13]2[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=2)[C:16]([NH:18][C:19]2[S:20][C:21]3[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=3[C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)=[O:25])=[O:17])(=[O:12])=[O:11])[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)C1(NS(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(N(CC)S(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 250 mg of methyl 4-(2-{4-[({2-[(3-{[1-(ethoxycarbonyl)cyclopropyl]sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate, 0.081 mL of ethyl iodide, 142 mg of potassium carbonate, and 2.5 mL of DMF was stirred at 60° C. overnight. To the reaction mixture was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 243 mg of methyl 4-(2-{-4-[({2-[(3-{[1-(ethoxycarbonyl)cyclopropyl](ethyl)sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate as a yellow solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N+:4]([O-:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.B(F)(F)[F:11].CCOCC.[F:19][B-:20]([F:23])([F:22])[F:21].[H+].FF>C(#N)C>[F:19][B-:20]([F:23])([F:22])[F:21].[F:19][B-:20]([F:23])([F:22])[F:21].[OH:9][N+:4]12[CH2:7][CH2:8][N+:1]([F:11])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: FB(F)F
Reactant: [O-][N+]12CCN(CC1)CC2
Agent: FF
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Solvent: CCOCC
Product: O[N+]12CC[N+](F)(CC1)CC2
Yield: 149.2 %

Procedure:
A solution of 1,4-diazabicyclo[2.2.2]octane N-oxide (2.56 g, 20 mmole), boron trifluoride etherate (2.4 mL, 20 mmole), and tetrafluoroboric acid (50% solution, 3.66 g, 20 mmole) in acetonitrile (250 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10% V/V, 52 mmole). The reaction was evaporated, the remaining solid washed with acetone and dried to afford 4.8 grams of 1-hydroxyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (75% yield).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](=[NH:7])[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[O:15][C:10]=3[CH:9]=2)[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:1][C:2]1[S:6]/[C:5](=[N:7]\[S:32]([CH3:31])(=[O:34])=[O:33])/[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[O:15][C:10]=3[CH:9]=2)[CH:3]=1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)c(=N)s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/S(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The imine (Example 26A, 30 mg, 0.09 mmol) was dissolved in dichloromethane (1.5 mL). Diisopropylethylamine (31 μl, 0.18 mmol, 2 equiv.) was added followed by the methanesulfonyl chloride (0.1 mmol, 1.1 equiv.). The reaction was stirred at room temperature for 4 hours. The reaction mixture was passed through a Si-amine cartridge (1 g, 1.6 mmol/g) to remove the excess sulfonyl chloride and washed with additional dichloromethane. The resulting solution was dried, concentrated, and purified by reverse phase HPLC. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.24 (3H), 2.90-2.96 (3H), 7.31 (1H), 7.56 (1H), 7.68 (1H), 7.8 (1H); MS (ESI) m/z 398.9 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].CC(C)([O-])C.[Li+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: BrCc1ccccc1
Reactant: O=C(CN1C(=O)CNC1=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1C(=O)CN(Cc2ccccc2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of phenylmethyl 2-(2,5-dioxoimidazolidinyl)acetate (4.0 g, 16.1 mmol) in DMF (50 ml) at 0° C. were added lithium tert-butoxide (1.6 g, 19.3 mmol) and benzyl bromide (2.1 ml, 17.7 mmol). After stirring the mixture at room temperature overnight, the reaction mixture was poured into water (100 ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with water, 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, n-hexane:ethyl acetate=3:1) to give phenylmethyl 2-(2,5-dioxo-3-benzylimidazolidinyl)acetate (3.42 g).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25](C(=O)C)[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=[C:7]1[CH:31]([OH:33])[CH3:32])[CH2:4][CH3:5])[CH3:2].Cl.[CH3:35]O>O1CCOCC1>[CH2:4]([CH:3]([N:6]1[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[CH:20][CH:21]=3)[N:13]=[CH:14][C:9]=2[CH:8]=[C:7]1[CH:31]([O:33][CH3:35])[CH3:32])[CH2:1][CH3:2])[CH3:5]
Reactant: CCC(CC)n1c(C(C)O)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: CCC(CC)n1c(C(C)OC)cc2cnc(Nc3ccc(N4CCNCC4)cc3)nc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-{4-[7-(1-ethyl-propyl)-6-(1-hydroxy-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone (19 mg, 0.042 mmol) in MeOH (1 mL) is added 4N HCl in dioxane (1 mL). The reaction mixture is stirred at 60° C. for 2 h. The mixture is loaded on Solid Phase Extraction column (Sorbent: benzenesulfonic acid), washed with MeOH, eluted with EtOAc:MeOH:Et3N (1:1:0.05), concentrated in vacuo. The residue is purified by preparative HPLC to give 10 mg of [7-(1-ethyl-propyl)-6-(1-methoxy-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-(4-piperazin-1-yl-phenyl)-amine.
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[O:12][C:13](=O)[CH2:14][CH:15]([C:20](=[O:23])[NH:21][CH3:22])[CH2:16][CH:17]([CH3:19])[CH3:18].[CH2:25]([O:32][C:33](=[O:40])[CH2:34][NH:35][CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([O:32][C:33](=[O:40])[CH2:34][N:35]([CH2:36][CH:37]([CH3:38])[CH3:39])[C:13](=[O:12])[CH2:14][CH:15]([C:20](=[O:23])[NH:21][CH3:22])[CH2:16][CH:17]([CH3:19])[CH3:18])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)CNCC(=O)OCc1ccccc1
Reactant: CNC(=O)C(CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)CC(C)C
Solvent: CN(C)C=O
Product: CNC(=O)C(CC(=O)N(CC(=O)OCc1ccccc1)CC(C)C)CC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To an ice-cooled solution of 5-methyl-3-methylcarbamoyl-hexanoic acid 2,3,4,5,6-pentafluorophenyl ester (350 mg, 0.99 mmol) in DMF (5 ml) was added isobutylamino-acetic acid benzyl ester (110 mg, 0.49 mmol) with stirring. The reaction mixture was allowed to warm to room temperature and stirred for 2 days then for 3 h at 50° C. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and the solution was washed successively with 1M HCl, 1M Na2CO3 and brine. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel, 50→100% ethyl acetate in hexane) to give the title compound as a colorless oil (130 mg, 70%). 1H-NMR; δ (CDCl3, rotamers), 7.33 (5H, m), 6.17 (1H, m), 5.15 (1H, m), 4.21 (1H, m), 3.91 (1H, m), 3.41-2.95 (2H, br m), 2.81 (2H, m), 2.75 (3H, m), 2.32 (1H, m), 1.91-1.40 (3H, br m), 1.28-1.05 (1H, m) and 0.85 (12H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16]CCCCC.[Si](C=[N+]=[N-])(C)(C)C>CO.C1C=CC=CC=1>[CH3:16][O:11][C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of the N-tert-butoxycarbonylproline (6.00 g, 0.0279 mol) in MeOH:benzene (1:4, v/v) was added dropwise 2.0 M-n-hexane solution of TMSCHN2 (16.7 mL, 0.0334 mol) at room temp. After the resulting solution was stirred for 1 hr at room temp, the mixture was evaporated off in vacuo to afford 6.39 g (100%) N-tert-butoxycarbonylproline methyl ester as a yellow syrup. 1H-NMR (CDCl3) δ1.41 (s, 9H), 1.85-1.98 (m, 4H), 2.21-2.28 (m, 2H), 3.72 (s, 3H), 4.29 (m, 1H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([Cl:34])[CH:33]=1)[NH:30][C:29](=[O:35])[CH:28]=[C:27]2[OH:36].Cl>O>[C:1]([C:28]1[C:29](=[O:35])[NH:30][C:31]2[C:26]([C:27]=1[OH:36])=[CH:25][C:24]([Cl:23])=[CH:33][C:32]=2[Cl:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(O)c2cc(Cl)cc(Cl)c2[nH]1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccccc1)c1c(O)c2cc(Cl)cc(Cl)c2[nH]c1=O
Temperature: 25 °C
Yield: 65.6 %

Procedure:
Benzoyl chloride (0.93 gram) is added to a mixture of 1.5 grams of anhydrous aluminum chloride and 10 ml of nitrobenzene, the mixture is stirred at room temperature until it becomes uniform, stirred at 105° to 110° C. for eight hours with 1.26 grams of 6,8-dichloro-4-hydroxy-2-quinolone, decomposed with concentrated hydrochloric acid, small amount of water is added thereto, and crystals separated out therefrom are collected by filtration. The crystals are washed with water and then washed with methanol and ether to give 1.2 grams of 3-benzoyl-6,8-dichloro-4-hydroxy-2-quinolone, pale yellow powder, melting point 258° to 259° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14](=[O:16])[CH3:15])=[C:9]([CH3:17])[CH:8]=1.[Br-:21].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:21][CH2:15][C:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:8][C:9]=1[CH3:17])=[O:16]
Reactant: COc1cccc(Oc2cc(C)c(C(C)=O)c(C)c2)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: COc1cccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of 1-(4-(3-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (5.40 g, 20.0 mmol) in acetonitrile (40.0 mL) was added tetrabutylammoniumtribromide (TBABr3, 10.1 g, 21.0 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-(3-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (7.00 g), which was used directly for the next step without further purification.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].C(N(CC)CC)C.[CH:14](/[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](OS(C(F)(F)F)(=O)=O)[CH:29]=2)[NH:24][N:23]=1)=[CH:15]\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O.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>[CH3:3][O:2][P:1]([C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[C:22]2/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:6])[O:4][CH3:5]
Reactant: COP([O-])OC
Reactant: O=S(=O)(Oc1ccc2[nH]nc(/C=C/c3ccccc3)c2c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COP(=O)(OC)c1ccc2[nH]nc(/C=C/c3ccccc3)c2c1
Temperature: 85 °C
Yield: 6.4 %

Procedure:
40.7 μl (1.09 eq; 0.444 mmol) of dimethyl phosphite, 61.9 μl (1.09 eq; 0.444 mmol) of triethylamine and 18.8 mg (0.04 eq; 0.016 mmol) of tetrakis(triphenylphosphine)palladium(0) are stirred under an argon atmosphere for 15 minutes. 150 mg (1 eq; 0.407 mmol) of trifluoromethanesulfonic acid 3-((E)-styryl)-1H-indazol-5-yl ester in solution in 5 ml of dimethylformamide are added. The medium is heated at 85° C. overnight. 41 μl of dimethylphosphite, 62 μl of triethylamine and 20 mg of tetrakis(triphenylphosphine)palladium(0) are added to the medium, which is heated for a further two hours. 100 μl of dimethylphosphite, 100 μl of triethylamine and 30 mg of tetrakis(triphenylphosphine)palladium(0) are then added to the medium, which is heated overnight at 105° C. After filtration of the catalyst through filter paper, the solvent is evaporated off under reduced pressure in a rotary evaporator. The reaction crude is purified by LC/MS to obtain 8.6 mg of [3-((E)-styryl)-1H-indazol-5-yl]phosphonic acid dimethyl ester, along with 27.2 mg of [3-((E)-styryl)-1H-indazol-5-yl]phosphonic acid monomethyl ester (Example 13).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:70]1[CH:74]=[C:73]([CH2:75][CH2:76][NH2:77])[N:72]=[CH:71]1>CN(C=O)C>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:77][CH2:76][CH2:75][C:73]2[N:72]=[CH:71][NH:70][CH:74]=2)=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: NCCc1c[nH]cn1
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCCc3c[nH]cn3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and [2-(1H-imidazol-4-yl)ethyl]amine (22.2 mg, 0.2 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (26 mg, 85%). LC-MS m/z 615 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[NH:22][N:21]=3)[C:7]=2[CH:27]=1)#[N:2].[C:28](#[N:31])[CH:29]=[CH2:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:12][O:13][CH3:14])([CH2:15][O:16][CH3:17])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:30][CH2:29][C:28]#[N:31])[N:21]=3)[C:7]=2[CH:27]=1)#[N:2]
Reactant: C=CC#N
Reactant: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)[nH]n2)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)n(CCC#N)n2)[C@@H]1O
Yield: 58.2 %

Procedure:
(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-[(1,6-dihydro-6-oxo-3-pyridazinyl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol (150 mg, 0.40 mmol) obtained in Example 8 and acrylonitrile (0.055 ml, 0.806 mmol) were dissolved in dimethylformamide (3 ml). Potassium carbonate (111 mg) was added and the mixture was reacted at 50° C. overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the residue was purified by silica gel column chromatography (methanol:chloroform=1:30) to give 99 mg of the title compound (58%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:29]1([C:35](=[O:41])[CH2:36][C:37](=O)[CH2:38][CH3:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:38](/[C:37](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])=[CH:36]/[C:35](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:39]
Reactant: CCC(=O)CC(=O)c1ccccc1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: CC/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccc(F)cc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 75 mg (0.195 mmol) of Intermediate 46 and 34 mg (0.2 mmol) of Intermediate 16 to yield 32 mg of Example 8: TLC (DCM/MeOH, 4/1): Rf=0.63; 1H NMR (DMSO-d6, 300 MHz) δ11.57 (d, 1H, J=9.6), 7.97 (m, 2H), 7.86 (d, 1H, J=7.2), 7.42 (m, 5H), 7.18 (d, 2H, 8.4), 6.87 (d, 2H, J=8.4), 5.61 (s, 1H), 4.20 (t, 2H, J=6.6), 4.14 (m, 1H), 3.22 (m, 2H), 2.94 (t, 2H, J=6.6), 2.83 (dd, 1H, J=13.8, 9.3); low resolution MS (ES+)m/e 543 (MH+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:9]12[C:15](=O)[O:14][C:12](=[O:13])[C@@H:10]1[CH2:11]2>>[CH2:1]([N:8]1[C:12](=[O:13])[CH:10]2[CH:9]([CH2:11]2)[C:15]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(=O)[C@@H]2C[C@H]12
Reactant: NCc1ccccc1
Product: O=C1C2CC2C(=O)N1Cc1ccccc1
Temperature: 180 °C

Procedure:
63.2 g (0.486 mol) of 1 was added in portions to 150 ml of thionyl chloride. The mixture was refluxed for 1 hour, then was stripped. The residue was distilled to give cis-1,2-cyclopropanedicarboxylic acid anhydride (3A) bp 134° C. (10 Torr.). 2.14 g (0.02 mol) of benzylamine was carefully added to 2.24 g (0.02 mol) of 3A (CAUTION: THE REACTION IS VERY EXOTHERMIC.) The mixture was heated at 180° C. for 2 hours. After cooling, the residue was recrystallized from isopropyl alcohol to give 3-(benzyl)-3-azabicyclo(3.1.0)hexane-2,4-dione, as white needles, mp 90°-91° C. (3B). A cooled (0°) solution of 305 ml (1.09 mol) of 70% sodium bis(2-methoxyethoxy)aluminum hydride in benzene diluted with 600 ml of ether was treated with 48.7 g (0.24 mole) of 3B. The mixture was stirred at 0° for 1/2 hr and refluxed for 3 hrs. After standing at room temperature overnight, excess metal hydride was destroyed by cautiously adding cold water. The mixture was filtered after addition of diatomaceous silica (Celite). The ether layer was removed and the aqueous layer was extracted with ether. The combined organic layers were dried (MgSO4). Ether and 2-methoxyethanol were evaporated under reduced pressure to give 3, as an oil. Distillation gave 3, bp: 79°-80° C. (0.01 Torr.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:10]([NH:16][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN
Reactant: Cc1cc(C)cc(Br)c1
Product: CCCCCCNc1cc(C)cc(C)c1
Yield: 90.1 %

Procedure:
Using the general procedure, 5-bromo-m-xylene (136 μL, 1.0 mmol) was coupled with n-hexylamine (198 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (20:1) as eluent afforded the desired product as a colorless oil (185 mg, 90% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.CCO.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>[F:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=[C:2]2[C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(Cl)c2ccc(C)c(F)c2n1
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: COC(=O)c1cc(-c2ccc(F)cc2)c2ccc(C)c(F)c2n1
Temperature: 75 °C
Yield: 80.9 %

Procedure:
Methyl 4-chloro-8-fluoro-7-methylquinoline-2-carboxylate (7-8, 993 mg, 3.91 mmol), (4-Fluorophenyl)boronic acid (575 mg, 4.11 mmol), and Pd(Ph3P)4 (226 mg, 0.196 mmol) were dissolved in degassed toluene (25 mL). Degasses EtOH (2.7 mL) was added followed by degassed 2M aq. Sodium Carbonate (4.31 mL, 8.61 mmol). The reaction was heated at 75° C. overnight then quenched with water and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was triturated with ether to afford Methyl 8-fluoro-4-(4-fluorophenyl)-7-methylquinoline-2-carboxylate (7-9, 991 mg, 81% yield) as a tan solid, LCMS shows the compound is 89% pure, LRMS m/z (M+H)+ 314.1 found, 314.0 required.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>C(#N)C>[Cl:21][CH2:20][CH2:19][CH2:18][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCCCCl)cc1
Temperature: 25 °C

Procedure:
A solution of 4-Nitrophenol (10 g, 72 mmol) dissolved in acetonitrile (100 ml was charged with potassium carbonate (24.9 g, 180 mmol) and 1-bromo-3-chloropropane (113.2 g, 720 mmol). The mixture was heated and stirred at reflux overnight. The reaction was cooled to room temperature, the solids filtered off and the solvent evaporated under reduced pressure to give the title compound.