Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:41])[C:10]([NH:12][CH:13]2[C:39](=[O:40])[N:15]3[C:16]([C:23]([O:25]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:24])=[C:17]([CH2:20][S:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]>C(Cl)Cl.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:41])[C:10]([NH:12][CH:13]2[C:39](=[O:40])[N:15]3[C:16]([C:23]([OH:25])=[O:24])=[C:17]([CH2:20][S:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=O)c3csc(NC=O)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(NC=O)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
Benzhydryl 7-[(2-formamidothiazol-4-yl)glyoxylamido]-3-methylthiomethyl-3-cephem-4-carboxylate (7.0 g) was dissolved in a solution of methylene chloride (70 ml), anisole (7 ml) and trifluoroacetic acid (14 ml), and the mixture was stirred at ambient temperature for an hour After the solvent was removed by distillation under reduced pressure, the residue was dissolved in water, adjusted to pH 2.0 with conc. hydrochloric acid and then extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride and dried over magnesium sulfate, followed by evaporation. The residue was pulverized with diisopropyl ether to obtain 7-[(2-formamidothiazol-4-yl)glyoxylamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid (3.3 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](S(O)(=O)=O)=[CH:6][CH:7]=1.[OH2:12].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH2:1]([CH:16]([CH2:15][CH2:14][CH2:13][OH:20])[C:17]([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)C(CCCO)Cc1ccccc1
Yield: 71 %

Procedure:
The methyl ester (4 g, 18 mmol) from the above reaction was dissolved in 10 ml of benzyl alcohol and 50 ml of Benzene. After adding TsOH.H2O (0.5 g, 2.63 mmol), the contents were heated under reflux for 2 h. Once the required amount of H2O had been collected, the solution was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, Hexane-AcOEt, 3:1) which gave 3.8 g (71%) of the title compound: 7.40-7.10 (m,10H), 5.03 (s,2H), 3.57 (t,J=6Hz,2H), 3.00-2.60 (m,≈4H), and 1.80-1.40 (m,4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43]CO)[CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH2:43][CH2:42][N:39]2[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CN1CCN(CCCO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCN4CCN(C)CC4)cc3)c2cc1OC
Yield: 11.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-(4-methylpiperazino)-1-propanol (41 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (9 mg, yield 9%).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=O)=[C:5]([F:19])[CH:4]=1)[CH3:2]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]2[O:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[C:5]([F:19])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)Nc2ccccc2O)c(F)c1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2nc3ccccc3o2)c(F)c1

Procedure:
4-Ethyl-2-fluoro-2'-hydroxybenzanilide (29.0 gm.) is heated for 40 minutes in a Wood's metal bath at 240°C. The reaction mixture is then cooled, taken up in chloroform and the chloroform solution treated with carbon, dried over magnesium sulfate and concentrated in vacuo to give 2-(4-ethyl-2-fluorophenyl)benzoxazole.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)=[O:6].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>O(CCCC)CCCC>[CH3:23][O:22][C:20]([C:17]1[CH:18]=[CH:19][C:14]([N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:12][CH:11]=2)[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[CH:15][CH:16]=1)=[O:21]
Reactant: COC(=O)c1ccc(Nc2ccc(C(=O)OC)cc2)cc1
Reactant: O=C(Cl)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: COC(=O)c1ccc(N(C(=O)CCCCCBr)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil; 77.1 mg, 1.93 mmol) in anhydrous n-Bu2O (5 ml) 15a (500 mg, 1.75 mmol) is added batch wise, and the mixture is stirred for an additional two hours at RT. Then, 6-bromohexanoic acid chloride (0.314 ml, 2.10 mmol) is added, and the reaction is heated for 4 h under reflux. The mixture is allowed to cool to RT, poured into ice-water, and extracted with CH2Cl2. The organic phases are unified, washed with a saturated solution of NaHCO3 (2×) and saturated NaCl, and dried over MgSO4. Finally, the solvent is distilled off, and the crude product is crystallized from methanol. 713 mg (88%) of the desired compound 19a are obtained as a colorless solid. Melting point. 133-135° C.; IR (KBr) 2920, 1700, 1645, 1580 cm−1; 1H-NMR (CDCl3) δ 8.06 (d, 8.6 Hz, 4H), 7.30 (d, 8.6 Hz, 4H), 3.92 (s, 6H), 3.38 (t, 6.7 Hz, 2H), 2.29 (t, 7.4 Hz, 2H), 1.88-1.77 (m, 2H), 1.76-1.64 (m, 2H), 1.49-1.35 (m, 2H); MS (FD) m/z 464 (M++1 for Br81), 462 (M++1 for Br79).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH3:16])\[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH2:4][OH:5].[C:17]1(C)C=[CH:21][C:20](S(O)(=O)=O)=[CH:19][CH:18]=1.[OH2:28]>O1C=CCCC1>[CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH3:16])\[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH2:4][O:5][CH:21]1[CH2:20][CH2:19][CH2:18][CH2:17][O:28]1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)=CCC/C(C)=C\CC/C(C)=C/CO
Agent: C1=COCCC1
Product: CC(C)=CCC/C(C)=C\CC/C(C)=C/COC1CCCCO1
Reaction time: 2 h

Procedure:
A solution of 1 g (0.0045 mol) of (2E,6Z)-3,7,11-trimethyl-2,6,10-dodecatrien-1-ol in 32 ml of 3,4-dihydro-2H-pyran is treated at 0° with 91 mg of p-toluenesulfonic acid. The solution is stirred at the same temperature for 2 hours under argon. After the addition of 100 ml of water the mixture is extracted with ether. The organic phase is washed with sodium carbonate solution. After drying and removing the solvent the residue is chromatographed on silica gel with ether-hexane 1:1. There is obtained tetrahyro-2-[[(2E,6Z)-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran which has the following bands in the IR spectrum: 1669 cm-1, 1448 cm-1, 1377 cm-1, 1115 cm-1, 1078 cm-1, 1019 cm-1.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][Cl:20])=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[C:2]#[CH:3].C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:38][CH2:39][NH2:40])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]>CO>[ClH:20].[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][NH:40][CH2:39][CH2:38][C:32]2[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:30]([O:29][CH3:28])[CH:31]=2)=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[C:2]#[CH:3]
Reactant: COc1ccc(CCN)cc1OC
Reactant: C#CCOc1ccc(OCC(O)CCl)c2c1NC(=O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCOc1ccc(OCC(O)CNCCc2ccc(OC)c(OC)c2)c2c1NC(=O)CC2
Product: Cl
Yield: 69.4 %

Procedure:
1.0 g of 8-(2-propynyloxy)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril was dissolved in 20 ml of methanol. 0.5 g of anhydrous potassium carbonate and 1.6 g of 2-(3,4-dimethoxyphenyl)ethylamine were added thereto, and the resulting mixture was stirred while refluxing for 2.5 hours. After completion of the reaction, the methanol was evaporated under reduced pressure, and the residue was dissolved in chloroform and then washed with water. The chloroform layer was dried over anhydrous sodium sulfate, and the chloroform evaporated under reduced pressure. The residue was recrystallized from methanol-diethyl ether to obtain 1.1 g of 8-(2-propynyloxy)-5-{3-[2-(3,4-dimethoxyphenyl)ethylamino]-2-hydroxypropoxy}-3,4-dihydrocarbostyril hydrochloride having a melting point of 160°-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[C:5]([Cl:10])=[CH:4][C:3]=1[O-:11].[K+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[CH:17]=[C:16]([CH3:21])[N:15]=1.O>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:11][C:3]2[CH:4]=[C:5]([Cl:10])[C:6]([S:8][CH3:9])=[CH:7][C:2]=2[Cl:1])[CH:17]=[C:16]([CH3:21])[N:15]=1
Reactant: CSc1cc(Cl)c([O-])cc1Cl
Reactant: Cc1cc(Cl)cc(Cl)n1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(Cl)c(Oc2cc(C)nc(Cl)c2)cc1Cl

Procedure:
A solution of 25.5 gm (0.1 mol) of potassium 2,5-dichloro-4-methylmercapto-phenolate and 16.2 gm (0.1 mol) of 2,4-dichloro-6-methyl-pyridine in 100 ml of dimethylformamide was heated under reflux for 5 hours. It was then cooled and poured into 300 ml of water. The precipitate which separated out was recovered by suction filtration, washed with water, and recrystallized from isopropanol.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][C:3]1=O.[C:17]1(C)C=CC=CC=1.[NH2:24][NH2:25]>CO>[CH3:1][CH:2]1[C:7]2[C:6](=[CH:17][NH:24][N:25]=2)[CH:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccccc1
Reactant: C[C@@H]1CC[C@H](c2ccc(C#N)cc2)CC1=O
Reactant: NN
Solvent: CO
Product: CC1CCC(c2ccc(C#N)cc2)c2c[nH]nc21
Temperature: 120 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
(cis)-4-(4-Methyl-3-oxo-cyclohexyl)benzonitrile (0.55 g, 2.58 mmol) is added to toluene (10.0 mL) and tert-butoxybis(dimtheylamino)methane (0.67 mL, 3.22 mmol) and stirred at 120° C. for 16 hours. The mixture is cooled to room temperature and concentrated in vacuo. The residue is added to MeOH (10.0 mL) and hydrazine (0.07 mL, 2.32 mmol) and stirred at 80° C. for 1.0 hour. The mixture is cooled to room temperature and concentrated in vacuo. The residue is purified by silica gel chromatography (35%-55% EtOAc/hexanes) to give (+/−)-(cis/trans)-4-[7-methyl-4,5,6,7-tetrahydro-2H-indazol-4-yl]benzonitrile (0.360 g, 58%). ES/MS m/z 238 (M+H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.C(Cl)Cl.C(Cl)Cl.C[OH:26]>>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:26])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O)cc1
Reaction time: 72 h

Procedure:
(2-tert-Butoxycarbonylamino-ethyl-2-{[tert-butoxycarbonyl-(2-tert-butoxycarbonylaminoethyl)amino]-methyl}-8-hydroxyoctyl)-carbonic acid tert-butyl ester (2.52 g, 3.82 mmol),p-toluenesulfonyl chloride (1.0 g, 5.2 mmol), triethylamine (1.3 g, 12.8 mmol) and CH2Cl2 (30 ml) were stirred at room temperature with the slow evaporation of solvent. The reaction was monitored by carbon NMR and after 3 days little starting material remained. The reaction volume was made up to 30 ml with CH2Cl2, extracted with water (50 ml×3), dried (MgSO4), filtered and the solvent evaporated to leave a brown residue. This residue was subjected to chromatography on silica gel using CH2Cl2/MeOH (100:5) as eluent. The first compound to elute was unreacted tosyl chloride with an rf=0.95. The title compound eluted with an rf=0.2 and was isolated as a pale yellow viscous oil. Yield (1.20 g, 39%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]=[O:5].Cl[CH:7]([Cl:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCOCC.O>O1CCCC1>[Cl:15][C:7]1([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH:4]([CH2:3][O:2][CH3:1])[O:5]1
Reactant: COCC=O
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COCC1OC1(Cl)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2.106 g of methoxyacetaldehyde, 3.8 ml of tertbutyl dichloroacetate and 25 ml of tetrahydrofuran was cooled to -20° C. and over 15 minutes, 29 ml of potassium tertbutylate in tetrahydrofuran (0.9M) were introduced. The mixture stood for 20 minutes and 25 ml of ether and 25 ml of water were added. The mixture was extracted with ether and the organic phase was washed with water saturated with sodium chloride, then dried and concentrated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with methylene chloride to obtain 1.44 g of 1,1-dimethylethyl 2-chloro-3-methoxymethyloxirane-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])/[C:5]/2=[CH:16]/OC.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])[C:5]2=[CH:16][NH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:31][CH:30]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2cc(OC)c(Br)cc21
Reactant: Nc1ccc(CN2CCCCC2)cc1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)C(=CNc1ccc(CN3CCCCC3)cc1)C(=O)NC2=O
Temperature: 110 °C
Yield: 57 %

Procedure:
A mixture of (4E)-6-bromo-7-methoxy-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (156 mg, 0.50 mmole), N,N-dimethylformamide (1 mL) and 4-piperidin-1-ylmethyl-phenylamine (95 mg, 0.50 mmole) is stirred and heated at 110° C. for one hour, cooled in the refrigerator. The reaction mixture is evaporated to dryness, taken up in 5% methanol in chloroform and passed through a short pad of Florisil eluting with 5% methanol in chloroform. The eluate is evaporated in vacuo, treated with acetonitrile, filtered and dried to give a dull yellow solid 134 mg (57%), mp 264-7° C.; MS (ESI): m/z 470.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[CH3:13].CO[C:16](OC)([N:18]([CH3:20])[CH3:19])[CH3:17].N1CCC[CH2:24]1>CN(C=O)C>[Br:1][C:2]1[C:3](/[CH:13]=[CH:19]/[N:18]2[CH2:20][CH2:24][CH2:17][CH2:16]2)=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)c(C)c1[N+](=O)[O-]
Reactant: C1CCNC1
Reactant: COC(C)(OC)N(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(/C=C/N2CCCC2)c1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To a solution of 1-bromo-4-methoxy-2-methyl-3-nitrobenzene (1.400 g, 5.68 mmol) and 1,1-dimethoxy-N,N-dimethylethanamine (0.884 mL, 6.657 mmol) in DMF (10.0 mL) was added pyrrolidine (0.555 mL, 6.656 mmol) and the mixture was heated to at 110° C. for 4 h. The DMF was removed and the residue was recrystallized from DCM:methanol (1:6) mixture to afford 1-[(E)-2-(6-bromo-3-methoxy-2-nitrophenyl)vinyl]pyrrolidine.
Reaction SMILES: [CH3:1][P:2]1(=[O:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[N:37]([CH3:58])[C:38]3[C:47]4[C:46](=[O:48])[NH:45][C:44]([CH:49](OC(=O)C)[CH:50]=[CH2:51])=[C:43]([CH3:56])[C:42]=4[CH:41]=[CH:40][C:39]=3[N:57]=2)=[C:31]([CH3:59])[CH:30]=1.C([O-])(=O)C>C1COCC1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[N:37]([CH3:58])[C:38]3[C:47]4[C:46](=[O:48])[NH:45][C:44]([CH:49]=[CH:50][CH2:51][N:5]5[CH2:6][CH2:7][P:2]([CH3:1])(=[O:8])[CH2:3][CH2:4]5)=[C:43]([CH3:56])[C:42]=4[CH:41]=[CH:40][C:39]=3[N:57]=2)=[C:31]([CH3:59])[CH:30]=1
Reactant: C=CC(OC(C)=O)c1[nH]c(=O)c2c(ccc3nc(Nc4ccc(F)cc4C)n(C)c32)c1C
Reactant: CP1(=O)CCNCC1
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=CCN4CCP(C)(=O)CC4)[nH]c(=O)c3c2n1C
Reaction time: 0.33 h
Yield: 10.2 %

Procedure:
To a glass scintillation vial was added 4-methyl-[1,4]azaphosphinane 4-oxide (100 mg, 0.75 mmol). To a separate glass vial was added tris(dibenzylacetone)dipalladium (28 mg, 0.031 mmol), triphenylphosphine (30 mg, 0.12 mmol), and THF (2.5 mL). The resulting solution was stirred for 20 minutes, then acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (0.270 g, 0.621 mmol) was added as a solution in THF (7.0 mL), followed by TEA (0.90 mL, 12.2 mmol). Of the resulting solution, 2.4 mL (0.15 mmol total allylic acetate) was transferred to the vial containing 4-methyl-[1,4]azaphosphinane 4-oxide. The solution was stirred at room temperature for 20 h. The solvent was removed in vacuo and the resulting solid redissolved in MeCN (2 mL) and DMSO (2 mL). The solution was filtered, then purified directly by preparative reverse-phase HPLC (0% to 100% MeCN:H2O+0.1% formic acid) to give 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ5[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (32 mg, 42%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.33 (br s, 1H), 10.68 (br s, 1H), 7.79 (d, 1H, J=8.6 Hz), 7.72 (d, 1H, J=8.6 Hz), 7.56 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.35 (dd, 1H, J1=3.9 Hz, J2=9.8 Hz), 7.25 (td, 1H, J1=3.1 Hz, J2=8.6 Hz), 7.19-7.15 (m, 2H), 6.54-6.48 (m, 1H), 4.18 (s, 3H), 4.10-4.00 (br s, 2H), 3.80-3.30 (br m, 4H), 3.16 (s, 3H), 2.36 (s, 3H), 3.31 (s, 3H), 2.30-2.10 (br m, 4H), 1.7-1.6 (br m, 3H); ESMS (m/z): found, 508.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62](Cl)(=[O:64])=[O:63]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:62]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[CH3:55])(=[O:64])=[O:63])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1S(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 18 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-methylbenzenesulfonyl chloride as starting materials in 18% yield. LCMS for C31H33ClN7O3S (M+H)+: m/z=618.2.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br/[CH:19]=[CH:20]\[CH3:21].II.[Mg]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])(/[CH:19]=[CH:20]\[CH3:21])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: C/C=C\Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C/C=C\C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (510 mg) in THF (5 mL) at 0° C. was added Grignard reagent, which was freshly prepared from cis-1-bromo-1-propene (1.07 mL), a small iodine flake, and magnesium powder (306 mg) in THF (5 mL). The resulting mixture was then stirred at room temperature for 3 hr. The reaction was quenched with NH4Cl (sat. aq), filtered through a pad of Celite®, rinsed with EtOAc, the layers were separated, the aqueous layer extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:8](=O)[O:7][C:5](=[O:6])[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.C(N(CC)C(C)C)(C)C.[CH2:23]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:37]=1[NH:43][C:44]([C:46]1[CH:55]=C(O)[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]=1[OH:57])=[O:45])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CCCCCC.O1CCCC1>[CH3:1][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][C:8]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([OH:57])=[C:46]([C:44](=[O:45])[NH:43][C:37]2[CH:38]=[C:39]([CH3:42])[CH:40]=[CH:41][C:36]=2[O:35][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:55]=1)=[O:6]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: CCCCCCCCCCCCOc1ccc(C)cc1NC(=O)c1cc(O)c2ccccc2c1O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(C)cc1NC(=O)c1cc(OC(=O)c2ccccc2NC)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
N-Methylisatoic anhydride (18.00 g, 90% technical grade containing mineral oil) was suspended in hexane (300 ml) and stirred for 0.75 hr at room temperature. The solid was filtered under suction, washed with petroleum ether (40–60° C.) and dried briefly before use. 1,4-Dihydroxy-naphthalene-2-carboxylic acid (2-dodecyloxy-5-methyl-phenyl)-amide was recrystallised from a mixture of petroleum ether (60–80° C.) and toluene before use. N,N-Diisopropylethylamine (16.20 g, 0.125 mol) was added to a stirred suspension of 1,4-dihydroxy-naphthalene-2-carboxylic acid (2-dodecyloxy-5-methyl-phenyl)-amide (29.14 g, 0.061 mol) and N-methylisatoic anhydride (12.00 g {of 90%}, 0.061 mol) in tetrahydrofuran (150 ml, dried over 4 Å molecular sieves) under an atmosphere of argon. The reaction was heated to reflux overnight. An aliquot was removed, added to dilute hydrochloric acid and extracted with ethyl acetate. Thin layer chromatography indicated the presence of a small amount of residual starting naphthol. A further quantity of N-methylisatoic anhydride (1.1 g) was added and the reflux continued for a further 18 hr. The reaction was allowed to cool and then the solvent was removed under reduced pressure. The residue was taken-up in a mixture of dilute aqueous (2 M) hydrochloric acid (500 ml) and warm ethyl acetate (1000 ml). Some material failed to dissolve and collected at the interface. The buff solid was filtered, washed with ethyl acetate and dried in vacuo (27.3 g). The organic solution was separated and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Methanol (100 ml) was added and the mixture stirred and boiled under reflux for 15 min and then allowed to cool. A further quantity of a solid precipitated which was filtered and dried in vacuo (3.8 g). The solids were analysed and the results were consistent with the desired 2-methylamino-benzoic acid 3-(2-dodecyloxy-5-methylphenylcarbamoyl)-4-hydroxy-naphthalen-1-yl ester. The total yield of product was 31.1 g (83%).