Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([Cl:19])=[N:14][CH:13]=[C:12]2[OH:20])C1C=CC=CC=1.C(Cl)Cl.C(O)(=O)C.[S:28]([Cl:32])(Cl)(=[O:30])=[O:29]>O>[Cl:19][C:15]1[C:16]2[C:11](=[CH:10][C:9]([S:28]([Cl:32])(=[O:30])=[O:29])=[CH:18][CH:17]=2)[C:12]([OH:20])=[CH:13][N:14]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1cnc(Cl)c2ccc(SCc3ccccc3)cc12
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc2c(Cl)ncc(O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A round-bottom flask was charged with 6-(benzylthio)-1-chloroisoquinolin-4-ol (0.280 g, 0.928 mmol), DCM (8.84 ml), acetic acid (0.221 ml), and water (0.221 ml) to give a thin suspension. The flask was cooled in an ice-bath for 10 min, then sulfuryl chloride (0.226 ml, 2.78 mmol) was added in one portion, leading to a solution. The reaction was stirred for 30 minutes, then warmed to room temperature and stirred for one hour. The reaction was concentrated and purified via column chromatography (40 g silica gel column, gradient elution 0 to 100% EtOAc:Heptane) to afford 1-chloro-4-hydroxyisoquinoline-6-sulfonyl chloride (as a light pink solid. (ESI) 280.1 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[C:5]1=[O:12].[CH:13]#[C:14][CH:15]([OH:19])[CH2:16][CH2:17][CH3:18]>C(OCC)C>[OH:12][C:5]1([C:13]#[C:14][CH:15]([OH:19])[CH2:16][CH2:17][CH3:18])[C:6]([CH3:11])([CH3:10])[CH2:7][CH2:8][CH2:9][CH:4]1[CH3:3]
Reactant: CC1CCCC(C)(C)C1=O
Reactant: C#CC(O)CCC
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCC(O)C#CC1(O)C(C)CCCC1(C)C
Reaction time: 24 h

Procedure:
In a three-necked vessel of 250 ml equipped with a thermometer, a condenser and a dropping funnel, there were placed 23.9 g (0.427M) of finely ground KOH and 50 ml of anhydrous diethyl ether. 14 G (0.1M) of 2,6,6-trimethylcyclohexanone and 13.5 g (0.138M) of hex-1-yn-3-ol were then added dropwise to the obtained suspension. The addition is slightly exothermic. After standing for 24 h, the mixture was poured onto ice and extracted with ether while the combined extracts were washed with a 10% HCl solution, with brine until neutrality and finally dried over Na2SO4 and concentrated. A fractional distillation of the obtained residue gave 12 g of 1-(1-hydroxy-2,6,6-trimethylcyclohexyl)-hex-1-yn-3-ol having b.p. 100°-125°/13.3 Pa.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[CH2:20]([C:22]1([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21].C(=O)([O-])[O-].[Ca+2]>CN(C)C(=O)C>[CH2:20]([C:22]1([CH3:28])[CH2:27][CH2:26][N:25]([C:2]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:5])[CH2:24][CH2:23]1)[CH3:21]
Reactant: O=C(c1ccc(Cl)cc1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCC1(C)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)N(C)C
Product: CCC1(C)CCN(c2ccc([N+](=O)[O-])cc2C(=O)c2ccc(Cl)cc2)CC1
Yield: 57.4 %

Procedure:
Proceeding as indicated in example 2 with 0.0734 mole (21.7 g) of 2,4'-dichloro-5-nitro-benzophenone, 0.11 mole (18 g) of 4-ethyl4-methylpiperidine and 0.22 mole (30.4 g) of calcium carbonate in 100 cm3 of N,N-dimethyl acetamide, 16.3 g (Yield: 57%) of the expected product are obtained after re-crystallization in isopropyl ether. M.P.: 105° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[CH3:16])=[CH:12]/[C:13]([OH:15])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[NH:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8](/[C:11](/[CH3:16])=[CH:12]/[C:13]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:15])=[CH:9][CH:10]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: C1CCN(C[C@@H]2CCCN2)CC1
Reactant: C/C(=C\C(=O)O)c1ccc(CC(C)C)cc1
Product: C/C(=C\C(=O)N1CCC[C@H]1CN1CCCCC1)c1ccc(CC(C)C)cc1

Procedure:
130 mg of the title compound were synthesized as described for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(Isobutyl)phenyl)but-2-enoic acid instead of (E)-4-bromocinnamic acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.Cl.[F:10][C:11]1[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.O>[F:10][C:11]1[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=1[O:13][CH2:14][CH:15]1[CH2:16][CH2:17][N:18]([CH2:2][C:3]2[NH:4][C:5](=[O:8])[NH:6][N:7]=2)[CH2:19][CH2:20]1
Reactant: O=c1[nH]nc(CCl)[nH]1
Reactant: Fc1ccccc1OCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: O=c1[nH]nc(CN2CCC(COc3ccccc3F)CC2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
After adding 150 mg of 5-chloromethyl-2,4-dihydro-[1,2,4]triazol-3-one, 331 mg of 4-(2-fluorophenoxymethyl)piperidine hydrochloride and 180 mg of anhydrous potassium carbonate to acetonitrile, the mixture was stirred overnight at room temperature. Water and ethyl acetate were added to the reaction mixture and the insoluble portion was filtered out to obtain the title compound (70 mg, 21% yield).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][N:13]([CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:14]1[CH:27]=[CH:26][C:17]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:16][CH:15]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:38](Br)[CH:39]=[CH2:40].O>CN(C=O)C>[CH2:40]([N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:17]1[CH:16]=[CH:15][C:14]([N:13]([CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:12][CH2:11][O:10][Si:3]([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4])=[CH:27][CH:26]=1)[CH:39]=[CH2:38]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)c1ccc(N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.265 g) was added to a stirred solution of 4-[bis(2-tert-butyldimethylsilyloxyethyl)amino]-N-(tert-butoxycarbonyl)aniline (3.15 g) in DMF (20 ml) which had been cooled to 0° C. The resultant mixture was stirred at ambient temperature for 1 hour. Allyl bromide (0.625 ml) was added and the mixture was stirred at ambient temperature for 12 hours. Water (5 ml) was added and the mixture was partitioned between diethyl ether and water. The organic phase was dried (MgSO4) and evaporated to give N-allyl-4-[bis(2-tert-butyldimethylsilyloxyethyl)amino]-N-(tert-butoxycarbonyl)aniline (3.5g); NMR Spectrum: (CDCl3) 0.0 (s, 12H), 0.81 (s, 9H), 0.82 (s, 9H), 1.4 (s, 9H), 3.43 (t, 4H), 3.71 (t, 4H), 4.11 (d, 2H), 5.07 (m, 2H), 5.87 (m, 1H), 6.58 (d, 2H), 6.93 (d, 2H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([NH:21][C:22]3[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=3)[CH:12]=[C:13]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:14]=2)O1.Br[C:34]1[S:38][C:37]([C:39]2([OH:43])[CH2:42][CH2:41][CH2:40]2)=[N:36][CH:35]=1.N#N.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.ClCCl>[F:20][C:17]([F:19])([F:18])[CH2:16][NH:15][C:13]1[CH:14]=[C:9]([C:34]2[S:38][C:37]([C:39]3([OH:43])[CH2:42][CH2:41][CH2:40]3)=[N:36][CH:35]=2)[CH:10]=[C:11]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][N:23]=2)[CH:12]=1
Reactant: OC1(c2ncc(Br)s2)CCC1
Reactant: CC1(C)OB(c2cc(NCC(F)(F)F)cc(Nc3nccc(C(F)(F)F)n3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: ClCCl
Solvent: C1COCCO1
Product: OC1(c2ncc(-c3cc(NCC(F)(F)F)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CCC1
Temperature: 85 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
A mixture of the product of Step 4 (50 mg, 0.108 mmol), PdCl2(dppf) (as the dichloromethane adduct; 4.42 mg, 5.41 μmol) and Intermediate 1 (27.9 mg, 0.119 mmol) was degassed (alternating vacuum-N2 cycles). Dioxane (0.3 mL) and Na2CO3 (2.0 M, 162 μL, 0.325 mmol) were added. The mixture was degassed again and stirred at 85° C. for 2 hrs. The mixture was cooled to room temperature, diluted with ethyl acetate and gravity filtered on celite. After in vacuo concentration, the residue was purified by Chromatography on silica gel (0-100% ethyl acetate in hexanes) then briefly triturated in hexanes to give the 1-[5-(3-[(2,2,2-trifluoroethyl)amino]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutanol (36.4 mg, 0.074 mmol, 69% yield) as a white solid. MS ESI: [M+H]+ m/z 490.0. 1H NMR (500 MHz, CD3OD) δ 8.73 (d, J=4.9, 1H), 7.92 (s, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 7.15 (d, J=4.9, 1H), 6.69 (s, 1H), 3.88 (q, 9.2, 2H), 2.79-2.67 (m, 2H), 2.67-2.36 (m, 2H), 2.12-1.92 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:28][O:27][C:19]1[CH:18]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1ccc(O)cc1OC
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1OC
Temperature: 0 °C

Procedure:
Trifluoromethanesulfonic anhydride (2.24 mL) was added to an ice-cooled mixture of methyl 4-hydroxy-2-methoxybenzoate (2.02 g) and pyridine (0.135 mL) in methylene chloride (15 mL) with stirring. The mixture was stirred at room temperature for 30 minutes, and poured into a mixture of hydrochloric acid and ethyl acetate. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford methyl 2-methoxy-4-trifluoromethanesulfonyloxybenzoate (3.49 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][C:11](=[O:13])[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][O:27][CH3:28])[C:20]=2[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.ClCCl.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][C:11](=[O:13])[N:10]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][O:27][CH3:28])[C:20]=3[CH:29]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCN1C(=O)COc2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CNC(=O)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COCN1C(=O)COc2ccc(N3C[C@@H](NC(=O)OC(C)(C)C)CC3=O)cc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
A mixture of [(3R)-5-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester (synthesized with reference to WO2004/22536; 1.5 g, 7.49 mmol), 6-bromo-4-(methoxymethyl)-2H-1,4-benzoxazin-3(4H)-one (Reference Examples 36; 2.04 g 7.49 mmol), potassium carbonate (3.11 g, 22.5 mmol), copper (I) iodide (1.43 g, 7.49 mmol), N,N′-dimethylethylenediamine (0.80 ml, 7.49 mmol) and toluene (95 ml) was stirred overnight at 100° C. under a stream of nitrogen gas. After cooling, dichloromethane was added to the reaction solution to remove insoluble material by filtration and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 1.79 g (61%) of the title compound in the form of a colorless foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](I)[C:25]=1[F:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:23][C:24]1[C:25]([F:31])=[C:26]([C:21]#[C:20][C:17]2[CH:18]=[CH:19][C:14]([N:12]3[C:11](=[O:22])[NH:10][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:13]3)=[CH:15][CH:16]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Fc1c(Cl)cccc1I
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2cccc(Cl)c2F)cc1
Yield: 28.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 1-chloro-2-fluoro-3-iodobenzene (0.123 g, 0.470 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.040 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.29 (t, J=7.8 Hz, 1H), 7.50 (t, J=8.7 Hz, 1H), 7.57-7.72 (m, 6H), 8.04 (d, J=9.0 Hz, 2H), 12.74 (br s, 1H). MS (m/z): 442.35 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11](O)=[O:12])=[C:9]([CH3:14])[N:8]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:6]=2[N:7]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:52][CH2:53][C:54]1[C:55]([OH:62])=[N:56][C:57]([CH3:61])=[CH:58][C:59]=1[CH3:60]>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:52][CH2:53][C:54]3[C:55]([OH:62])=[N:56][C:57]([CH3:61])=[CH:58][C:59]=3[CH3:60])=[O:12])=[C:9]([CH3:14])[N:8]([C@@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[C:6]=2[N:7]=1
Reactant: Cc1c(C(=O)O)c2cnc(Cl)nc2n1[C@H](C)c1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a solution of (R)-2-chloro-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (100 mg 0.32 mmol) in dichloromethane (10 mL) was added with 1-hydroxybenzotriazole (65 mg, 0.48 mmol), (3-dimethylaminopropyl)ethyl-carbodiimid hydrochloride (92 mg, 0.48 mmol) and triethylamine (97 mg, 0.96 mmol). After stirred for 30 minutes, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (49 mg, 0.32 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours. The solution was concentrated, diluted with water (20 mL), extracted with ethyl acetate (20 mL). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (100 mg, 70%). LRMS (M+H+) m/z: calcd 449.16; found 449.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:8][CH2:9][CH2:10][C:11](=[O:13])[C:6]=2[CH:7]=1
Reactant: O=C(O)CCSc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: O=C1CCSc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
200 mL of concentrated sulfuric acid was added to 27.7 g (0.106 mol) of the title compound of Step A. The mixture was stirred at room temperature under nitrogen overnight, and was then poured over crushed ice. The mixture was filtered, and the solid was dissolved in methylene chloride. The resulting solution was dried (MgSO4), filtered, and evaporated to dryness to yield 14.77 g of the title compound of Step B as a solid melting at 50° C. (dec). 1H NMR (CDCl3): δ3.0 (m,2H), 3.2 (m,2H), 7.16-8.2 (3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:17][O:18][C:19](=[O:38])[C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[C:22]([N+:35]([O-:37])=[O:36])[CH:21]=1>COCCOC.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>[CH3:17][O:18][C:19](=[O:38])[C:20]1[CH:21]=[C:22]([N+:35]([O-:37])=[O:36])[CH:23]=[C:24]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:25]=1
Reactant: Cc1ccc(Br)nc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc([N+](=O)[O-])c1
Yield: 39.6 %

Procedure:
To a solution of 2-bromo-5-methylpyridine (1.24 g, 7 mmol), Pd(PPh3)4 (226 mg, 0.2 mmol) and K3PO4 (2.76 g, 13 mmol) in DME/H2O (5 ml/1 ml) was added 3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.00 g, 6.5 mmol) under N2 atmosphere. The mixture was subjected to microwave radiation at 130° C. for 0.5 hours. The reaction mixture was cooled and solvent was evaporated under reduced pressure. The residue was purified by flash-chromatography (CH2Cl2/MeOH) to give 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (700 mg, 40%).
Reaction SMILES: C(SC=C)=C.C1C(I)=[C:10]([OH:13])C(I)=C2OC3C(C4(OC(=O)C5C(Cl)=C(Cl)C(Cl)=C(Cl)C4=5)C=12)=CC(I)=C(O)C=3I.O=O.FC1C=CC(S[C:49]2([C:62]3[CH:67]=[CH:66][CH:65]=[C:64]([O:68][C:69](=[O:74])[C:70]([CH3:73])([CH3:72])[CH3:71])[CH:63]=3)[C:52]3([CH:59]4[CH2:60][CH:55]5[CH2:56][CH:57]([CH2:61][CH:53]3[CH2:54]5)[CH2:58]4)[O:51][O:50]2)=CC=1.O1CCO1>CO>[CH3:10][O:13][C:49]1([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([O:68][C:69](=[O:74])[C:70]([CH3:73])([CH3:71])[CH3:72])[CH:63]=2)[C:52]2([CH:53]3[CH2:54][CH:55]4[CH2:56][CH:57]([CH2:58][CH:59]2[CH2:60]4)[CH2:61]3)[O:51][O:50]1
Reactant: O=C1OC2(c3cc(I)c(O)c(I)c3Oc3c2cc(I)c(O)c3I)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CC(C)(C)C(=O)Oc1cccc(C2(Sc3ccc(F)cc3)OOC23C2CC4CC(C2)CC3C4)c1
Agent: C1COO1
Agent: C=CSC=C
Agent: O=O
Solvent: CO
Product: COC1(c2cccc(OC(=O)C(C)(C)C)c2)OOC12C1CC3CC(C1)CC2C3
Temperature: 25 °C

Procedure:
The vinyl sulfide of Example 4(a) (0.051 g) was irradiated in 20 mL of CH3OH containing ca. 1 mg of Rose Bengal with continuous oxygen bubbling at -78° C. using a 1000 W Na lamp. When the alkene was shown by TLC to be completely consumed, iodine (0.096 g) and 1 mL of 30% H2O2 were added and the mixture warmed to room temperature. Progress of the reaction was monitored by the disappearance of dioxetane 4 by TLC (20% ethyl acetate in hexane) and the appearance of new bands which emitted blue light when the plate was heated and by observing the color of chemiluminescence from an aliquot of the reaction solution reacted with 0.1 M TBAF in DMSO. The yellow emission of dioxetane 4 was gradually replaced by the blue emission of dioxetane 20 over a period of two hours. The solution was concentrated to 1-2 mL and separated on preparative TLC with 5% ethyl acetate in hexane. The band containing dioxetane 20 was collected and desorbed and evaporated to yield the product as a slightly yellow oil: 1H NMR (CDCl3) δ1.02 (m, 1H), 1.28 (m, 1H), 1.375 (s, 9H), 1.45-1.94 (m, 10H), 2.17 (br s, 1H), 3.04 (br s, 1H), 3.232 (s, 3H), 7.07-7.49 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([C:11]([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[C:12]([C:16]([O:18]CC)=[O:17])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.[OH-].[Li+]>O1CCCC1.O>[C:23]([CH2:22][CH2:21][C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13][C:12]=1[C:16]([OH:18])=[O:17])([OH:25])=[O:24]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(-c3ccccc3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1c(C(=O)O)[nH]c2cc(-c3ccccc3)ccc12
Temperature: 25 °C
Yield: 95 %

Procedure:
Ethyl 6-phenyl-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (3.65 g, 10 mmol) was dissolved in 25 ml tetrahydrofurane (THF) with stirring at rt. Then a solution of 1.26 g of lithium hydroxide trihydrate (3 equiv.) in 25 ml water was added and the resulting mixture was let to stir at rt for 24 h. After completion of the reaction THF was removed under reduced pressure and the pH was adjusted to 4-5, and the product was extracted with diethyl ether (3×25 ml). The organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to yield a light-beige-colored solid in 95-100% yield. mp. 238-239° C. 1H-NMR (DMSO-d6) δ 2.54 (m, 2H, 2′-H); 3.28 (m, 2H, 1′-H); 7.35 (m, 2H, 4-H, 5-H); 7.46 (m, 2H, 2″-H, 6″-H); 7.60 (dd, 1H, 4″-H); 7.63 (m, 2H, 3″-H, 5″-H); 7.75 (dd, 1H, 7-H); 11.55 (s, 1H, NH); 12.50 (b, 2H, 2CO2H). 13C-NMR (DMSO-d6) δ 20.1 (C2′); 35.3 (C1′); 110.2 (C-7); 119.2 (C-5), 121.1 (C-4); 121.4 (C-3); 124.8 (C-3a); 126.6 (C-2); 127.0 (C-3″, C-5″); 127.2 (C-4″); 129.1 (C-3″, C-6″); 136.8 (C-7a); 137.2 (C-6); 141.3 (C-1″); 163.1 (2′-CO2H); 174.1 (2-CO2H). LC-MS (m/z): 310 [M]+, 308 [M]−. Purity (LC-MS): 98%.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.[C:30]1([CH2:36][C:37]([N:39]=[C:40]=[O:41])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.CCCCCC>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:27]=[CH:28][C:2]([NH:1][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:41])=[CH:3][C:4]=3[F:29])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyridine (87.4 mg) in tetrahydrofuran (4.5 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 2.2 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (82 mg, 67%) as white powder.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC.O.C(O)C>[F:12][C:4]1[CH:3]=[C:2]([C:21]2[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH:24]=[CH:23][CH:22]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2cccn2C(=O)OC(C)(C)C)cc1F

Procedure:
A mixture of EXAMPLE 50A (4 g), 1-(tert-butoxycarbonyl)pyrrole-2-boronic acid (5.44 g), and dichlorobis(triphenylphosphine)palladium(II) (1.2 g) in 7:3:2 DME/water/ethanol (300 mL) and 2M aqueous Na2CO3 (17.2 mL) at 80° C. was stirred for 140 minutes, cooled and concentrated. The concentrate was dissolved in ethyl acetate, washed with brine and concentrated. The concentrate was flash chromatographed on silica gel with 1:4 ethyl acetate/hexane.