Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27]C(=O)OCC1C=CC=CC=1>O1CCCC1.[C].[Pd]>[NH2:27][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:17])[N:18]([CH3:26])[CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)[CH:10]=2)=[CH:7][C:2]=1[F:1]
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)OCc4ccccc4)c(F)c3)ccn2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of benzyl (2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamate (110 mg) in tetrahydrofuran (10 ml) was 10% palladium carbon (46.2 mg), followed by stirring under a hydrogen atmosphere at room temperature for 18 hrs. The reaction mixture was filtered to remove the catalyst, which was then washed with tetrahydrofuran. The filtrate was dried over anhydrous sodium sulfate, and concentrated to a volume of 40 ml to give a solution of the target compound in tetrahydrofuran (40 ml) as a pale yellow solution. Assuming that the reaction preceded quantitatively, the solution was used for a next reaction.
Reaction SMILES: [O:1]=[C:2]1[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4][CH2:3]1.[OH-].[Na+]>CO>[O:1]=[C:2]1[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[CH2:4][CH2:3]1
Reactant: CCOC(=O)CCCCCCN1C(=O)CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)C(=O)CC3)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 7-(6-oxo-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) (2.0 g, 4.12 mmol) in MeOH (40 ml) was treated with 1M sodium hydroxide (12.36 ml, 12.36 mmol) and the resulting solution was stirred at 50° C. for 1 hour. The solution was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with water, acidified (pH ˜2 with 1N HCl) and the resulting suspension was extracted with DCM (×3). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to afford the titled compound as a white solid;
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[OH:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[O:28][CH2:2][CH2:3][NH:4][C:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
8.0 g (35.7 mmol) of t-butyl (2-bromoethyl)carbamate was dissolved in 20 ml of DMF. 4.0 g (17.7 mmol) of 4-benzyloxy-3-hydroxybenzonitrile and 7.4 g (41.3 mmol) of potassium carbonate were added to the obtained solution, and they were stirred at 100° C. for 3 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the solvent was evaporated, and the obtained residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[C:5]([N+:14]([O-])=O)[CH:4]=1.CCO>[Fe].O>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([NH2:14])=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=1
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OC
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: COc1cc(N)c([N+](=O)[O-])cc1OC
Temperature: 70 °C
Yield: 119.3 %

Procedure:
4.50 g (20.0 mmol) 4,5-dimethoxy-1,2-dinitrobenzene was taken into 50.0 mL EtOH/8.4 mL AcOH mixture. To this was added 4.00 g powdered iron (O). The reaction was heated to an oil bath temperature of 70° C. overnight. The reaction was allowed to cool to room temperature and was poured into 400 mL H2O. Aqueous layer was extracted several times with diethyl ether. Organic layers were dried over magnesium sulfate and evaporated under reduced pressure to give 4.73 g orange solid as a mixture of starting material and product. This solid was purified over silica gel (30% DCM in hexanes) to give the title compound 86A as an orange solid (1.15 g, 5.80 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:31])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:30])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[CH:23]=[CH:24]/[CH:25]=[C:26](/[CH:28]=O)\[CH3:27])\[CH3:22].[CH3:32][O-:33].[Na+].S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(C)C>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:31])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:30])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[CH:23]=[CH:24]/[CH:25]=[C:26](/[CH:28]=[CH:1]/[CH:2]=[C:3](/[CH:32]=[O:33])\[CH3:4])\[CH3:27])\[CH3:22]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(\C)C=O)C(C)(C)CCC1
Reactant: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C=C(\C)C=O)C(C)(C)CCC1
Temperature: 70 °C

Procedure:
For the performance of the Wittig reaction, 75 g (0.18 mol) of β-apo-8'-carotenal were placed in a 2.5 l sulphonation flask equipped with a stirrer, condenser, thermometer, automatic dosage device (Dosimat) and argon gasification. The β-apo-8'-carotenal was then suspended in 900 ml of dry isopropanol and the resulting red, not very thick suspension was heated to 70° C. The freshly prepared alkaline acetal solution from the previously process step was then added and rinsed in with 100 ml of dry isopropanol. 38.99 ml of sodium methylate solution (containing 0.2080 mol of base) were subsequently dosed in within 30 minutes using the Dosimat. Subsequently, the mixture was stirred at 70° for a further hour and thereafter 342.3 mol of 0.5N sulphuric acid (0.0858 mol of acid) were dosed in at 70° C. within one hour using the Dosimat. Then the oil bath was replaced by a water bath, 342.3 ml of 0.5N sodium hydroxide solution (0.1711 mol of base) were added within 15 minutes using the Dosimat and thereby the reaction mixture was cooled to 25° C. The red-brown crystal slurry was stirred for a further 60 minutes, thereafter filtered over a slotted glass suction filter having a paper filter and the filter cake was washed in sequence twice with 340 ml each time of isopropanol and three times with 340 ml each time of deionized water. The thus-obtained wine-red crystals were subsequently dried for 2 days at 50° C. in a vacuum drying oven at 20-30 mbar (2-3 kPa). There were obtained 82.7 g of a cystallizate of the desired product, β-apo-4'-carotenal. The weight yield was 95.2% based on β-apo-8'-carotenal used. The composition of the product according to HPLC or, respectively, Karl-Fischer titration was as follows:
Reaction SMILES: [C:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6](=[O:25])[C:5]=1O)(=O)[CH3:2].[NH:27]([C:29]1[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=1)[NH2:28]>CCO.C1(C)C=CC=CC=1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]2[C:4]3[C:1]([CH3:2])=[N:28][N:27]([C:29]4[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=4)[C:5]=3[C:6](=[O:25])[N:7]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:10][CH:11]=1
Reactant: Cn1nccc1NN
Reactant: COc1ccc(CN2C(=O)C(O)=C(C(C)=O)C2c2ccc(Cl)cc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(CN2C(=O)c3c(c(C)nn3-c3ccnn3C)C2c2ccc(Cl)cc2)cc1
Temperature: 115 °C
Reaction time: 20 h
Yield: 85.4 %

Procedure:
To a stirred solution of 4-acetyl-5-(4-chlorophenyl)-3-hydroxy-1-(4-methoxybenzyl)-1H-pyrrol-2(5H)-one (Step 71.2) (3 g, 8.07 mmol) in EtOH (50 mL) and toluene (50 mL) was added 5-hydrazinyl-1-methyl-1H-pyrazole (Step 74.2) (1.941 g, 10.49 mmol) and the resulting mixture was heated up and stirred at 115° C. for 20 hr. The reaction was quenched with a saturated aq. NaHCO3 solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc 40-50%) to afford the title product (3.15 g, 6.89 mmol, 85% yield) as yellow solid. tR: 5.60 min (HPLC 1); tR: 1.24 min (LC-MS 2); ESI-MS: 448 [M+H]+ (LC-MS 2); Rf=0.41 (hexane/EtOAc 1:1).
Reaction SMILES: C(Cl)Cl.[CH3:4][S:5][C:6]1[CH:16]=[C:15]2[C:10](=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]([O:14]2)=[O:13])[CH:9]=[CH:8][CH:7]=1.C[OH:24]>>[CH3:4][S:5][C:6]1[CH:16]=[C:15]2[C:10](=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([OH:24])=[CH:19][CH:18]=3)[C:12]([O:14]2)=[O:13])[CH:9]=[CH:8][CH:7]=1
Reactant: CO
Reactant: CSc1cccc2c(-c3ccccc3)c(=O)oc-2c1
Solvent: ClCCl
Product: CSc1cccc2c(-c3ccc(O)cc3)c(=O)oc-2c1

Procedure:
TLC(CH2Cl2:MeOH, 92:8 v/v): Rf=0.55; UV/vis λmax 262 nm, 432 nm; HRMS (m/z): [M]+ calculated for C16H12O3S, 285.0585. found 285.0578. See Table 2 for NMR data. Roseobacticide B. TLC(CH2Cl2:MeOH, 92:8 v/v): Rf=0.58; UV/vis λmax 262 nm, 316 nm, 430 nm; HRMS (m/z): [M]+calculated for C16H12O2S, 269.0637. found 269.0635. See Table 3 for NMR data.
Reaction SMILES: ClC(OC(Cl)C)=O.[CH3:8][N:9](C)[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][S:15][C:14]2[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:13]1=2>ClCCCl>[CH3:8][NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][S:15][C:14]2[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:13]1=2
Reactant: CN(C)CCN1CCSc2cc([N+](=O)[O-])ccc21
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CNCCN1CCSc2cc([N+](=O)[O-])ccc21
Reaction time: 3 h

Procedure:
1-Chloroethyl chloroformate (0.612 mL, 5.61 mmol) was added to a solution of N,N-dimethyl-2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanamine (1.0 g, 3.74 mmol) in 1,2-dichloroethane (20 mL) at 0° C. in an argon atmosphere. The solution was brought to room temperature and refluxed under vigorous stirring for 3 hours. The solution was concentrated and then refluxed in MeOH (20 mL). The solution was concentrated to give dark brown viscous oil (1.05 g, quantitative). 1H NMR (CDCl3) δ 7.96 (d, J=2.4 Hz, 1H), 7.86 (dd, J=2.7, 9.3 Hz, 1H), 6.67 (d, J=9.3 Hz, 1H), 3.85-3.82 (m, 2H), 3.55 (t, J=6.9 Hz, 2H), 3.03-3.00 (m, 2H), 2.86 (t, J=6.9 Hz, 2H), 2.48 (s, 3H); ESI-MS (m/z, %): 256, 254 (MH+, 100).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38]([OH:40])=O)[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[C:64]1([C:110]2[CH:115]=[CH:114][CH:113]=[CH:112][CH:111]=2)[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[NH:70][C:71](=[O:109])[O:72][CH:73]1[CH2:78][CH2:77][N:76]([CH2:79][CH2:80][N:81]([CH3:108])[C:82](=[O:107])[CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][NH:88][C:89]2[S:90][C:91]3[CH:97]=[C:96]([C:98](=[O:106])[N:99]([CH3:105])[CH2:100][CH2:101][CH2:102][NH:103][CH3:104])[CH:95]=[CH:94][C:92]=3[N:93]=2)[CH2:75][CH2:74]1>>[C:64]1([C:110]2[CH:115]=[CH:114][CH:113]=[CH:112][CH:111]=2)[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[NH:70][C:71](=[O:109])[O:72][CH:73]1[CH2:74][CH2:75][N:76]([CH2:79][CH2:80][N:81]([C:82](=[O:107])[CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][NH:88][C:89]2[S:90][C:91]3[CH:97]=[C:96]([C:98](=[O:106])[N:99]([CH2:100][CH2:101][CH2:102][N:103]([C:38](=[O:40])[CH2:37][O:36][C@@H:28]4[C:25]5([CH2:24][CH2:23][N:22]([CH2:21][CH2:20][C@:11]6([C:13]7[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=7)[O:10][CH2:9][N:8]([C:6](=[O:7])[C:5]7[CH:41]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:43]=[C:3]([C:2]([F:1])([F:49])[F:48])[CH:4]=7)[CH2:12]6)[CH2:27][CH2:26]5)[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH2:29]4)[CH3:104])[CH3:105])[CH:95]=[CH:94][C:92]=3[N:93]=2)[CH3:108])[CH2:77][CH2:78]1
Reactant: CNCCCN(C)C(=O)c1ccc2nc(NCCCCCC(=O)N(C)CCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)sc2c1
Reactant: O=C(O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1nc2ccc(C(=O)N(C)CCCN(C)C(=O)CO[C@H]3Cc4ccccc4C34CCN(CC[C@@]3(c5ccc(F)cc5)CN(C(=O)c5cc(C(F)(F)F)cc(C(F)(F)F)c5)CO3)CC4)cc2s1
Yield: 24.1 %

Procedure:
The compound (101 mg, 0.146 mmol) obtained in Example 1j, triethylamine (23 μL, 0.167 mmol), pivaloyl chloride (18 μL, 0.144 mmol) and the compound (101 mg, 0.139 mmol) obtained in Example 93d were used to give the title compound (47 mg; yield, 24%) as a white solid according to the method described in Example 92c.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5ccc(Cl)cc5s4)cc3CC[C@@H]12
Yield: 52.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2,6-dichloro-benzothiazole (155 mg, 0.76 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 86 mg (53%) of the title compound as an amorphous solid. mp 156°-162°. FDMS: m/e =429. α[D]589 =+63.53 (c=0.66, chloroform).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:21])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[F:20])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>CCOCC>[CH:22]1([NH:25][CH:4]=[C:5]([C:11](=[O:21])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[F:20])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:24][CH2:23]1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1F
Reactant: NC1CC1
Solvent: CCOCC
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)cc1F
Temperature: 10.5 °C
Reaction time: 0.17 h

Procedure:
A solution of 9.67 g of α-(ethoxymethylene)-2,4,5-trifluoro-β-oxobenzenepropanoic acid, ethyl ester in 70 ml of dry ether was cooled in an ice bath to 10° C. A 2.44 ml portion of cyclopropylamine was added dropwise, maintaining the reaction temperature at 10 to 11° C. When addition was complete the ice bath was removed, the mixture stirred at room temperature for 10 minutes and then evaporated, giving 10.02 g of α-[(cyclopropylamino)methylene]2,4,5-trifluoro-β-oxobenzenepropanoic acid, ethyl ester as an oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([CH3:35])[CH:27]=1)#[N:25].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH:3]=2)=[C:28]([CH3:35])[CH:27]=1)#[N:25]
Reactant: Cc1cc(I)cc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Reactant: Cc1cc(C#N)ccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(C#N)cc2C)cc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1,3-bis(1,1-dimethylethyl) 2-(3-iodo-5-methylphenyl)propanedioate (the product of Step A, 320 mg, 0.74 mmol), 4-cyano-2-methylphenylboronic acid (178 mg, 1.11 mmol), sodium carbonate (78 mg, 0.74 mmol), bis(triphenylphosphine)palladium(II) dichloride (52 mg, 0.074 mmol), dioxane (5 mL), and water (1 mL) was heated to 80° C. and stirred for 20 minutes. The reaction mixture was then cooled to room temperature, and filtered through a plug of silica gel eluting with 20% ethyl acetate in hexanes. Concentration of the eluant under reduced pressure provided a brown oil (430 mg) containing the crude product, which was used in the next step without further purification.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)C>C1C=CC=CC=1>[C:13]1([C:10]2[CH:9]=[CH:8][C:7]3[O:6][CH:5]=[CH:4][C:12]=3[CH:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(COc1ccc(-c2ccccc2)cc1)OCC
Solvent: c1ccccc1
Product: c1ccc(-c2ccc3occc3c2)cc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A mixture of 1-(2,2-diethoxyethoxy)-4-phenylbenzene (3.52 g, 12.3 mmol) and polyphosphoric acid (2.95 g, 29.4 mmol) in benzene (60 mL) was stirred at reflux for 2 h. The reaction mixture was cooled to room temperature, decanted from the PPA and filtered through a plug of silica gel, which was washed with hexanes. The filtrate and the wash were combined and concentrated under reduced pressure to yield 2.00 g of the crude benzofuran: 1H NMR (400 MHz, CD3OD) δ 7.79 (dd, 1H), 7.66 (d, 1H), 7.63-7.60 (m, 2H), 7.58-7.51 (m, 2H), 7.45 (t, 2H), 7.36-7.33 (m, 1H), 6.82 (dd, 1H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]([C:23]1[CH:24]=[C:25]([CH2:29][CH:30](O)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[CH:27][CH:28]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C(C)=CC=CC=1>[C:15]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[CH:27][CH:28]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CC(O)Cc1cccc(C(=O)c2ccccc2)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: CCOC(=O)CC=Cc1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C

Procedure:
315 mg of phosphoric anhydride were added to a solution of 1.12 g of ethyl 4-(m-benzoyl-phenyl)-3-hydroxybutyrate in 20 ml of xylene and the mixture was refluxed for 2 hours and then cooled to room temperature. The organic phase was washed with water, then with an aqueous saturated sodium bicarbonate solution and then water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with methylene chloride which was evaporated to dryness to obtain ethyl 4-(m-benzoylphenyl)-3-butenoate whose ultraviolet spectrum was in accord with the structure.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3]([NH:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:8]([CH2:20][CH2:21]O)[CH:7]=1)=[O:4].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>ClCCl.O>[C:16]([O:15][C:13](=[O:14])[CH2:12][C:9]1[CH:10]=[N:11][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:24])([CH3:23])[CH3:1])=[CH:7][C:8]=1[CH2:20][CH2:21][Br:50])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)Cc1cnc(NC(=O)C(C)(C)C)cc1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Cc1cnc(NC(=O)C(C)(C)C)cc1CCBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl {6-[(2,2-dimethylpropanoyl)amino]-4-(2-hydroxyethyl)pyridin-3-yl}acetate (2.30 g, 6.84 mmol) with imidazole (0.558 g, 8.20 mmol) in dichloromethane (50 mL) was treated with triphenylphosphine (1.79 g, 6.84 mmol) and carbon tetrabromide (2.72 g, 8.20 mmol). The reaction mixture was allowed to stir at room temperature for 2 h, then was diluted with water and the layers separated. The organic layer was washed successively with 5% hydrochloric acid, saturated sodium bicarbonate solution, and brine, then dried (Na2SO4), filtered and concentrated. The residue was filtered through a short silica plug (20% EtOAc:hexanes eluent) to afford the title compound which was used immediately in the next step: LC/MS (M+1)+=398.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2C)=[CH:5][N:4]=1.IC1C=CC([F:27])=CC=1>>[F:27][C:16]1[CH:17]=[CH:18][C:13]([C:12]#[C:11][C:6]2[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[N:4][CH:5]=2)=[CH:14][CH:15]=1
Reactant: COc1cc(C#Cc2ccccc2C)cnc1OC
Reactant: Fc1ccc(I)cc1
Product: COc1cc(C#Cc2ccc(F)cc2)cnc1OC

Procedure:
Prepared as described for 2,3-dimethoxy-5-[(2-methylphenyl)ethynyl]pyridine (Intermediate 33) but using 1-iodo-4-fluorobenzene instead of 1-iodo-2-methylbenzene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29]([OH:31])=O)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[CH2:35][NH:36][CH3:37]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](=[O:31])[N:36]([CH2:35][C:34]4[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=4[F:32])[CH3:37])=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CNCc1ccccc1F
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)N(C)Cc4ccccc4F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-fluoro-N-methylbenzylamine.