Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H:3]([S:7]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.[CH3:33][NH2:34]>>[OH:26][C:22]1[CH:21]=[C:20]([C:19]#[C:18][C:16]2[CH:15]=[N:14][CH:13]=[C:12]([CH:17]=2)[C:10]([N:9]=[S:7]([CH2:3][C:4]([NH:34][CH3:33])=[O:6])(=[O:8])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:11])[CH:25]=[CH:24][CH:23]=1
Reactant: CN
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Product: CNC(=O)CS(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Yield: 90.2 %

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (50 mg, 0.11 mmol) and methylamine (2.0 M solution in MeOH, 0.5 mL, 1.0 mmol) were reacted to give the title compound as colorless oil (43 mg, 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[CH2:14]([OH:20])[CH2:15][CH2:16][CH2:17][C:18]#[CH:19]>>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=[O:20]
Reactant: COc1ccc2nccc(Br)c2n1
Reactant: C#CCCCCO
Product: COc1ccc2nccc(CCCCCC=O)c2n1
Yield: 42 %

Procedure:
The title intermediate was obtained starting from 8-bromo-2-methoxy-[1,5]naphthyridine (4 g, 16.7 mmol) and hex-5-yn-1-ol (2.7 g, 1.65 eq.) and following the procedures of Example 29, step 29.i and Example 33, steps 33.i and 33.ii. The title aldehyde was isolated as a yellowish liquid (1.2 g, 42% yield over 3 steps).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]1([CH:15]=[CH:14][C:12]([OH:13])=[CH:11][CH:10]=1)[OH:9].[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]2[CH2:33][CH2:32][C:29]3([CH2:31][O:30]3)[CH2:28][CH2:27]2)=[CH:20][CH:19]=1)#[N:17]>O>[C:16]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][N:26]2[CH2:33][CH2:32][C:29]([CH2:31][O:9][C:8]3[CH:15]=[CH:14][C:12]([OH:13])=[CH:11][CH:10]=3)([OH:30])[CH2:28][CH2:27]2)=[CH:22][CH:23]=1)#[N:17]
Reactant: N#Cc1ccc(CCN2CCC3(CC2)CO3)cc1
Reactant: Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCN2CCC(O)(COc3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Yield: 9 %

Procedure:
60% sodium hydride (46 mg) was added to an anhydrous dimethylformamide solution (4 mL) of hydroquinone (0.18 g) under cooling with ice-water and the mixture was stirred at room temperature for fourty minutes under nitrogen atmosphere. The compound (0.40 g) obtained in Step 3 was added to the mixture, and the reaction mixture was stirred at 80° C. for four hours under nitrogen atmosphere. Water (40 mL) was added to the mixture under cooling with ice-water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, dried over anhydrous sodium sulfate and then, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=49:1 to 19:1) and the obtained fractions were concentrated and washed with ether-ethyl acetate to obtain the titled compound (52 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[C@@H:20]([CH2:21][F:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@H:16]3[C@@H:20]([CH2:21][F:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CF
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnn2cc(Br)cc2c1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CF
Yield: 80.1 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 740 mg, 2.70 mmol), (3S,4S)-benzyl 3-amino-4-(fluoromethyl)pyrrolidine-1-carboxylate (Intermediate 10, 714 mg, 2.83 mmol) and DIPEA (0.989 mL, 5.66 mmol) in DMF (8 mL) was heated to 80° C. for 16 hrs. The reaction mixture was concentrated and purified on silica gel column with Hexanes/EtOAc (1/1) to give the title compound (1.06 g, 80% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.94 (br. s., 1H), 7.42-7.27 (m, 5H), 7.15 (s, 1H), 5.16-4.94 (m, 3H), 4.70-4.54 (m, 2H), 3.90-3.41 (m, 4H), 3.02-2.84 (m, 1H), MS (ES+) m/z: 490.1, 492.1 (M+H); LC retention time: 3.261 min (analytical HPLC Method H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16](O)=[O:17])=[CH:13][CH:14]=3)[C:9]([CH3:19])=[C:8]2[CH3:20])=[CH:4][C:3]=1[O:23][C@@H:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].Cl.[CH:31]([C:34]1[CH:35]=[C:36]([C@@H:40]([NH2:42])[CH3:41])[CH:37]=[CH:38][CH:39]=1)([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCN(C(C)C)C(C)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16](=[O:17])[NH:42][C@H:40]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([CH:31]([CH3:33])[CH3:32])[CH:35]=4)[CH3:41])=[CH:13][CH:14]=3)[C:9]([CH3:19])=[C:8]2[CH3:20])=[CH:4][C:3]=1[O:23][C@@H:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)ccc1Cl
Reaction time: 15 h

Procedure:
The (S)-1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (55 mg, 0.13 mmol), the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride (37 mg, 0.19 mmol) and HATU (61 mg, 0.16 mmol) were dissolved in DMF (3 mL) and DIEA (0.1 mL). It was stirred for 15 h. The solution was filtered and purified by preparative HPLC.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22]>CN(C=O)C.CC#N.CC#N.Cl[Pd]Cl>[CH:21]([C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])=[CH2:22]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 2-iodoadenosine (1.585 g, 4.03 mmol) and bis(acetonitrile)palladium chloride (0.053 g, 0.20 mmol) in DMF (20 ml) was added vinyltributyltin (1.24 ml, 4.23 mmol), and the mixture stirred at 100° C. for 1 h. The reaction mixture was cooled and filtered. The solvent was evaporated and the residue was purified through silica gel with chloroform and 10% methanol/chloroform to give 1.099 g (92%) of 2-vinyladenosine: 1H NMR (Me2SO-d6) δ3.66 (m, 2H), 3.98 (m, 1H), 4.16 (m, 1H), 4.65 (m, 1H), 5.18 (d, 1H), 5.38-5.62 (m, 3H), 5.89 (d, 1H), 6.41 (dd, 1H), 6.59 (dd, 1H), 7.27 (br.s, 2H), 8.32 (s, 1H); UV (EtOH) λmax 293 nm, 271 nm, 265 nm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:23]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([F:32])[CH:31]=1)#[N:25]>>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:7]1([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[C:6]2[CH:23]=[C:2]([C:28]3[CH:27]=[C:26]([CH:31]=[C:30]([F:32])[CH:29]=3)[C:24]#[N:25])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: O=C1COC(c2ccco2)(c2ccco2)c2cc(Br)ccc2N1
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Product: N#Cc1cc(F)cc(-c2ccc3c(c2)C(c2ccco2)(c2ccco2)OCC(=O)N3)c1

Procedure:
Prepared from 7-bromo-5,5-di(2-furyl)-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-cyano-5-fluorobenzeneboronic acid generally according to the coupling procedure of example 1. 1H NMR (DMSO-d6): δ 10.34 (s, 1H), 7.73-7.87 (m, 5H), 7.59 (dt, J=10.25, 1.95 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 6.98 (d, J=1.95 Hz, 1H), 1H, 6.52 (dd, J=3.42, 1.95 Hz, 2H), 6.29 (dd, J=3.42, 0.98 Hz, 2H), 4.16 (s, 2H); MS (ESI) m/z 415 ([M+H]+); MS (ESI) m/z 413 ([M−H]−); Anal. calcd for C24H15FN2O4: C, 69.56; H, 3.65; N, 6.76. Found: C, 67.60; H, 3.77; N, 5.81.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]2[O:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][O:11][C:6]=2[CH:5]=1)(=O)[CH3:2]>C(O)(=O)C.[Pd]>[CH2:1]([C:4]1[CH:18]=[CH:17][C:7]2[O:8][CH:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][O:11][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)C1=COc2cc(C(C)=O)ccc2O1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C1COc2cc(CC)ccc2O1
Yield: 70 %

Procedure:
Hydrogenate a solution of 3 g of ethyl 6-acetyl-1,4-benzodioxin-2-carboxylate in 15 cm3 of acetic acid under hydrogen pressure (50 psi) in the presence of 0.750 g of 5% palladium on carbon. The crude product obtained by concentrating to dryness is purified by chromatography on a silica column (eluant: petroleum ether/diethyl ether, 70:30). Ethyl 6-ethyl-2,3-dihydro-1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 70%. ##STR31##
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][OH:8].[H-].[Na+].I[CH3:12]>O1CCCC1>[CH3:12][O:8][CH2:7][C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1]
Reactant: Cc1ccsc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1sccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.3 g (3-methyl-thiophen-2-yl)-methanol in 65 ml tetrahydrofuran was added 2.73 g sodium hydride 55% in oil and the mixture was stirred at room temperature for 1 h. To ethe resulting mixture was added 4.3 ml iodomethane and the mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between aqueous potassium hydrogensulfate and ethyl acetate. The phases were separated and the organic phase was washed with water and brine dried over magnesium sulfate dehydrate and purified by distillation (13 mBar 160° C.) to yield 6.5 g of the title compound as light brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[C@@H:5]([O:43][CH2:44][CH3:45])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[C:16](/[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:42])=[CH:31][CH2:32][O:33]C[Si](C(C)(C)C)(C)C)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)\[CH3:17])=[CH:9][CH:8]=1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:46])[C@@H:5]([O:43][CH2:44][CH3:45])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14]/[CH:15]=[C:16](/[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27](/[C:30](/[CH3:42])=[CH:31]/[CH2:32][OH:33])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)\[CH3:17])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(C(C)=CCOC[Si](C)(C)C(C)(C)C)cc3)cc2)cc1)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(/C(C)=C/CO)cc3)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A solution of E)(E)(S) 3-{4-[3-(4′-{3-[(tert-butyidimethylsilanyl)-methoxy]-1-methylpropenyl}-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid ethyl ester (1.18 g, 1.84 mmol) in dry THF was cooled on ice and slowly added a 1.1M solution of tetrabutylammonium fluoride in THF (1.93 mL, 1.93 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water and ethyl acetate, the aqueous layer collected and further extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to give 0.94 g of (E)(E)(S) 2-ethoxy-3-(4-{3-[4′-{3-hydroxy-1-methyl-propenyl)-biphenyl-4-yl]-but-2-enyloxy}-phenyl)-propionic acid ethyl ester.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][S:25]([NH:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:27])=[O:26].[OH-].[Na+]>CN(C=O)C.CO>[CH3:24][S:25]([NH:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:31][CH:30]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-methylsulphonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C@@H:9]1[C:17](=[O:18])[O:16][C@@H:15]([CH3:19])[C@H:14]([O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[C@@H:13]([CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:12][O:11][CH2:10]1)=O)(C)(C)C.[ClH:44].O1CCOCC1>C(Cl)Cl>[Cl-:44].[C:21]([O:20][C@H:14]1[C@H:15]([CH3:19])[O:16][C:17](=[O:18])[C@@H:9]([NH3+:8])[CH2:10][O:11][CH2:12][C@@H:13]1[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:25])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)C(=O)O[C@@H]1[C@@H](Cc2cccc3ccccc23)COC[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Reactant: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)C(=O)O[C@@H]1[C@@H](Cc2cccc3ccccc23)COC[C@H]([NH3+])C(=O)O[C@H]1C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of [(3S,6S,7R,8S)-3-[bis(tert-butoxycarbonyl)amino]-6-methyl-8-(1-naphthylmethyl)-4-oxo-1,5-dioxonan-7-yl]2-methylpropanoate (260 mg, 0.434 mmol) in CH2Cl2 (1 mL) was added 4 M HCl in dioxane (2.17 mL, 8.67 mmol) slowly (gas evolution) and the resulting solution was stirred at room temperature for 2.5 h. The solvent was evaporated under a stream of N2 to give (3S,7S,8R,9S)-8-(isobutyryloxy)-9-methyl-7-(naphthalen-1-ylmethyl)-2-oxo-1,5-dioxonan-3-aminium chloride as a white powder. The powder was dried under high vacuum for 20 h to remove residual HCl and was used without further purification for the amide picolinamide formation: ESIMS m/z 400 ([M+H]+).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[C:12](P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13].[OH-].[Na+].[CH2:38]1COCC1>O>[CH2:15]([O:14][C:12](/[CH:38]=[CH:1]/[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a stirred solution of 4-formyl-benzoic acid (10.0 g, 66.7 mmol) in THF (140 ml) was added carboethoxytriphenylphosphorane (25.0 g, 71.8 mmol). To this solution was added NaOH (2.50 g, 66.7 mmol) as a solution in water (20 ml). The reaction was stirred at rt overnight. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3×50 ml). The combined extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 5% MeOH/CH2Cl2) to give the desired compound as a white solid (11.68 g, 53.1 mmol, 80% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=2)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:7]=1.O.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>CCO.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>[C:35]([CH2:34][CH2:33][C:21]1[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:4]2[CH:3]=[C:2]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=2)=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])([OH:37])=[O:36]
Reactant: OB(O)c1cccc(F)c1
Reactant: CN(C)C(=O)c1cc(Br)cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
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: [K+]
Solvent: O
Solvent: CCO
Product: CN(C)C(=O)c1cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cccc(F)c2)c1
Temperature: 78 °C

Procedure:
To a solution of 4-[3-[7-(3-bromo-5-dimethylcarbamoyl-phenyl)-hept-6-ynyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (80 mg, 0.14 mmol) in EtOH (4 mL)/H2O (1 mL) were added 3-fluorophenylboronic acid (39 mg, 0.28 mmol), potassium carbonate (77 mg, 0.56 mmol) and Pd(PPh3)4 (3 mg, 0.0028 mmol). The mixture was heated at 78° C. for 5 h and then cooled to room temperature. The reaction mixture was filtered using a syringe filter 0.45 μm and the filtrate was concentrated under reduced pressure. The crude oil was then purified by preparative HPLC using acetonitrile/water gradient.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][N:2]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:21]/[CH:22]=[O:23])=[CH:3][N:2]=1
Reactant: O=Cc1cncc2ccccc12
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1cncc2ccccc12

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-isoquinolinecarboxaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)N(C2CC2)CCC3(C)C)=[CH:7][CH:6]=1)[CH3:2].C(O)(=O)C1C=CC=CC=1.[CH2:38]([O:40][C:41](=O)[C:42]1[CH:47]=CC(I)=CC=1)C>C(N(CC)CC)C.[Cu]I.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>[CH3:38][O:40][C:41]1([C:20]2[CH:15]=[CH:14][C:13]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:28])=[CH:6][CH:7]=3)=[CH:22][CH:21]=2)[CH2:42][CH2:47]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCN3C2CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-methoxycyclopropyl)-benzene (Intermediate 61, 100.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 141.0 mg, 0.51 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (109 mg, 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 135.0 mg (90%) of the title compound as an orange solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][C:42](I)=[CH:41][CH:40]=3)=[C:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].CC1(C)C(C)(C)OB([C:62]2[CH:63]=[N:64][NH:65][CH:66]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.O>[NH:64]1[CH:63]=[C:62]([C:42]2[CH:43]=[CH:44][C:39]([O:38][CH2:37][CH2:36][CH2:35][C:25]3[S:24][C:23]([N:20]4[CH2:19][CH2:18][C:17]5[C:22](=[C:13]([C:11](=[O:12])[N:10]([C:2]6[S:1][C:5]7[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=7[N:3]=6)[CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:52])([CH3:51])[CH3:53])[CH:14]=[CH:15][CH:16]=5)[CH2:21]4)=[N:27][C:26]=3[C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:40][CH:41]=2)[CH:66]=[N:65]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCOc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCOc1ccc(-c2cn[nH]c2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of compound 41A (90 mg, 0.102 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (29.7 mg, 0.153 mmol), Na2CO3 (108 μl, 0.102 mmol) (1M) and (Ph3P)2Cl2Pd (7.15 mg, 10.19 μmol) in EtOH-DME-H2O (7:3:2, 4 ml) was in a Smith microwave synthesizer at 120° C. for 30 min and then concentrated. The residue was purified by flash chromatography to give the compound 73A. LCMS (APCI) m/e 824 (M+H).
Reaction SMILES: C([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([CH:26]([F:28])[F:27])=[CH:21][C:20]=3[O:29][CH3:30])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CC(O)=O.[OH2:35].[Cl:36]N1C(C)(C)C(=O)N(Cl)C1=O.[OH2:47]>C(Cl)Cl>[F:27][CH:26]([F:28])[C:22]1[C:23]([F:25])=[CH:24][C:19]([C:13]2[C:12]3[C:17](=[CH:18][C:9]([S:8]([Cl:36])(=[O:47])=[O:35])=[CH:10][CH:11]=3)[N:16]=[CH:15][N:14]=2)=[C:20]([O:29][CH3:30])[CH:21]=1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: COc1cc(C(F)F)c(F)cc1-c1ncnc2cc(SCc3ccccc3)ccc12
Reactant: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(F)F)c(F)cc1-c1ncnc2cc(S(=O)(=O)Cl)ccc12
Reaction time: 0.25 h
Yield: 69.5 %

Procedure:
A solution of 7-(benzylthio)-4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)quinazoline (0.966 g, 2.265 mmol) in 22 mL DCM and 0.44 mL (3:2 HOAc/water) solution was cooled to 0° C. and was treated with 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.893 g, 4.53 mmol). After stirring for 15 minutes, LC/MS showed mostly product, so the reaction mixture was diluted with water. The layers were separated, and the organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography gave 4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)quinazoline-7-sulfonyl chloride (0.634 g, 1.574 mmol, 69.5% yield) as a white solid. (M+H)+=402.9.
Reaction SMILES: [ClH:1].[S:2]1[C:6]2[CH:7]=[C:8]([N:11]3[CH2:15][CH2:14][N:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:21]=4[NH:22]C(=O)C)[C:12]3=[O:26])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.CO>C(O)C.C(Cl)(Cl)Cl>[ClH:1].[NH2:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:13]1[CH2:14][CH2:15][N:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:4]=[CH:3][S:2][C:6]=3[CH:7]=2)[C:12]1=[O:26]
Reactant: CC(=O)Nc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCO
Product: Nc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Temperature: 65 °C
Yield: 29.02 %

Procedure:
6N HCl (3 mL) was added to a solution of N-[3-(3-benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridin-4-yl]-acetamide (150A: 70 mg, 0.198 mmol) in ethanol (3 mL) and the resulting mixture was refluxed at 65° C. overnight. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was concentrated and the concentrate was washed with diethyl ether and dried to afford 20 mg of the product (29.02% yield).