Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([OH:6])[CH2:3][C:4]#[CH:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>CN(C=O)C.CCN(CC)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:7][C:8]1[C:9]([C:5]#[C:4][CH2:3][C@@H:2]([OH:6])[CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC[C@H](C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC[C@H](C)O)c21

Procedure:
Using Method C above, (S)-pent-4-yn-2-ol (68 mg, 0.82 mmol) (see Example 81 below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (100 mg, 0.27 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (31 mg, 0.03 mmol) and Cul (6 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was concentrated and the residue was chromatographed on a silica gel column with neat CH3CN then THF and finally MeOH as elution solvent. The resulting (S)-(Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was triturated with Et2O and then recrystalized from superheated EtOH. (Yield 57 mg, 65%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[C:14]([NH:16][CH3:17])[CH:13]=[CH:12][N:11]=1.C([O-])(=O)C.[K+]>CC(O)=O>[Cl:9][C:10]1[CH:15]=[C:14]([NH:16][CH3:17])[C:13]([Cl:1])=[CH:12][N:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CNc1ccnc(Cl)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CNc1cc(Cl)ncc1Cl
Temperature: 80 °C
Reaction time: 1.25 h
Yield: 18 %

Procedure:
N-Chlorosuccinimide (0.623 g, 4.67 mmol) was added to 2-chloro-N-methyl-pyridin-4-amine (0.50 g, 3.89 mmol) and potassium acetate (0.763 g, 7.78 mmol) in AcOH (25 mL) and the mixture was stirred at 80° C. for 1.25 hours. The mixture was cooled and concentrated in vacuo. The concentrated mixture was diluted with water, neutralised with aqueous NaOH and extracted with EtOAc (x3). The organic extracts were evaporated onto silica gel. Gradient chromatography, eluting with 10-50% EtOAc:c-Hex, gave 2,5-dichloro-N-methylpyridin-4-amine (0.114 g, 0.699 mmol, 18% yield).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:13][C:12]=1[C:17]([F:20])([F:18])[F:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(C(F)(F)F)c(C(=O)NCc2ccccc2)s1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1nc(C(F)(F)F)c(C(=O)NCc2ccccc2)s1)c1ccccc1
Yield: 62 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2-amino-4-trifluoromethylthiazole-5-carboxylic acid benzylamide in place of 2-amino-4-methylthiazole-5-carboxylic acid 4-chlorobenzylamide to react with benzoyl chloride, the title compound was obtained as a white solid in 62% yield; 1H NMR (CDCl3, 300 MHz) δ 13.28 (t, J=6.2 Hz, 1H), 9.30-9.25 (m, 1H), 8.10-8.08 (m, 2H), 7.65-7.50 (m, 3H), 7.35-7.20 (m, 5H), 4.40-4.35 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 166.4, 159.5, 158.7, 139.1, 136.2, 135.7, 133.7, 131.4, 129.2, 128.8, 127.7, 127.5, 122.9, 119.3, 43.4; MS (ES+) m/z 406.1 (M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]([F:17])([F:16])[C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.F[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>CN(C=O)C>[F:7][C:8]([F:16])([F:17])[C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
K2CO3 (23.45 g, 170 mmol) was added to a solution of 3-(trifluoromethyl)phenol (25 g, 154 mmol) and 4-fluorobenzaldehyde (19.14 g, 154 mmol) in DMF (300 mL), and the reaction mixture was stirred at 140° C. for 4 h. After cooling down to room temperature, the reaction mixture was poured into ice water (2500 ml), extracted with ethyl acetate (500 ml×2), and washed with brine (200 mL×2). The organic phase was dried with sodium sulfate, filtered, and concentrated to give the title compound as a brown solid (35 g, 66.9% yield). LCMS: rt=1.62 min, [M+H+]=267
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[CH:7][CH:6]=[CH:5][N:4]=1.Br[C:13]1[CH:41]=[CH:40][C:16]([C:17]([N:19]2[CH2:39][CH2:38][C:22]3([N:27]([CH3:28])[CH2:26][CH2:25][N:24]4[C:29]([C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=[C:23]34)[CH2:21][CH2:20]2)=[O:18])=[CH:15][C:14]=1[CH3:42].C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1.CN(C=O)C.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]>[F:36][C:33]([F:34])([F:35])[C:32]([C:29]1[N:24]2[CH2:25][CH2:26][N:27]([CH3:28])[C:22]3([CH2:38][CH2:39][N:19]([C:17](=[O:18])[C:16]4[CH:40]=[CH:41][C:13]([C:8]5[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=5)=[C:14]([CH3:42])[CH:15]=4)[CH2:20][CH2:21]3)[C:23]2=[CH:31][CH:30]=1)=[O:37]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)c2ccc(C(=O)C(F)(F)F)n2CCN3C)ccc1Br
Reactant: COc1ncccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: COc1ncccc1-c1ccc(C(=O)N2CCC3(CC2)c2ccc(C(=O)C(F)(F)F)n2CCN3C)cc1C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a microtube with Pd(dppf)Cl2 (5.5 mg, 0.075 mmol) was added 2-methoxypyridin-3-ylboronic acid (0.10 mmol) in NMP (0.2 mL), followed by a solution of 1-(1-(4-bromo-3-methylbenzoyl)-2′-methyl-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-6′-yl)-2,2,2-trifluoroethanone (0.75 mmol) in DMF (0.3 mL) and aq. Na2CO3 (2M, 4 mmol). The reaction mixture was shaken at 80° C. for 16 h. Filtration followed by purification using preparatory-HPLC (1-99% ACN in water (HCl modifier)) gave 2,2,2-trifluoro-1-[1′-[4-(2-methoxy-3-pyridyl)-3-methyl-benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone. ESI-MS m/z calc. 526.2, found 527.3 (M+1)+; Retention time: 1.38 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CN1CCNCC1
Reactant: O=C1CCC(C(=O)NCc2nccnc2Cl)CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@H](C(=O)NCc3nccnc3Cl)CC2)CC1

Procedure:
To a stirred solution of N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide (40.7 mmol, 10.9 g) in dichloromethane (145 ml) and acetic acid (1.450 ml) at room temperature was added 1-methylpiperazine (52.9 mmol, 5.87 ml, 5.30 g) and sodium cyanoborohydride (81 mmol, 5.12 g). After 16 hours at room temperature dichloromethane and an aqueous saturated sodium hydrogencarbonate solution (15 mL) were added and the organic layer was separated. This organic layer was washed with brine. The aqueous layers were washed with dichloromethane twice and the combined organic extracts dried (sodium sulfate). Concentration in vacuo gave the crude product (mixture of cis and trans), which was purified using column chromatography (silica gel; dichloromethane/methanol gradient (0 to 20% methanol) to afford the cis isomer (275 mg), the trans isomer (2.5 g) and a mixture of cis and trans isomers (5.5 g).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([NH2:13])[CH:4]=1.C(N(CC)CC)C.C(Cl)Cl.CO>C(O)(=O)C.Br.O.C(OCC)(=O)C>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([NH2:13])[CH:4]=1
Reactant: COc1cc(N)cc2ccccc12
Agent: Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1cc(O)c2ccccc2c1

Procedure:
A solution of 4-methoxy-2-naphthylamine (230 mg, 1.33 mmol) in glacial acetic acid (9.6 mL) and hydrobromic acid in water (16 mL, 48%) was refluxed under N2 for 4 h. A small amount of sample (0.1 mL) was diluted with ethyl acetate (0.5 mL), and then water (0.5 mL) and triethylamine (0.1 mL) were added. TLC (20:1 DCM/methanol) of the organic layer showed no starting material and a new much lower spot (Rf=0.1). The solvent was removed under reduced pressure and the product was dried under vaccum to yield the intermediate 4-hydroxy-2-naphthylamine which was used for the next step without any purification. To a solution of 4-hydroxy-2-naphthylamine in dioxane (10 mL) was added TEA (1 mL) and di-tert-butyl dicarbonate (1.149 g, 5.27 mmol). The reaction mixture was refluxed under N2 for 4 h. TLC (4:1 hexane/ethyl acetate) showed no starting material and a new higher spot (Rf=0.55). The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water. The aqueous layer was extracted with ethyl acetate (2×50 mL) and the organics were combined and washed with brine. The organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield N-(tert-butyloxycarnonyl)-4-O-(tert-butyloxycarbonyl)-2-naphthylamine (2, 80% yield) as oil. To a solution of compound 2 in acetone (10 mL) was added NaOH solution in water (10 mL, 1 M). The reaction mixture was stirred at room temperature for overnight. TLC (4:1 Hexane/Ethyl acetate) showed no starting material and a new lower spot. The reaction mixture was extracted with ethyl acetate (50 mL) and washed with water. The aqueous layer was extracted with ethyl acetate (2×50 mL) and the organics were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified on 10 g silica gel column with 10-20% ethyl acetate in hexane to yield compound 3 (181 mg, 53%) as an oil.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[C:27]([C:29]#[N:30])[C:26]([Br:31])=[CH:25][C:24]=2[O:32][CH3:33])=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C[O-].[Na+]>C(Cl)Cl>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[C:24]([O:32][CH3:33])=[CH:25][C:26]([Br:31])=[C:27]([CH:28]=1)[C:29]#[N:30])[C:17](=[O:19])[CH:16]=[CH:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(C#N)c(Br)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Br)c(C#N)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 80 °C
Yield: 90.9 %

Procedure:
A RBF was charged with (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-cyano-2-methoxyphenyl)amino)phenyl)acrylate (963 mg, 1.840 mmol) and MeOH (9199 μl) to give a thick, yellow suspension. Sodium methoxide (25 wt % in MeOH) (80 μl, 0.368 mmol) was added. A reflux condenser was attached, and the flask was heated to 80° C. overnight. In the morning, the mixture was diluted with DCM and concentrated. The residue was taken up in 2-PrOH, heated briefly to boiling, then sonicated for 20 s. The mixture was cooled then filtered. The collected solid was washed with 2-PrOH, then dried under a stream of N2 (g). The filtration was repeated with the filtrate. The two lots of material were combined to give 5-(6-(benzylthio)-2-oxoquinolin-1(2H)-yl)-2-bromo-4-methoxybenzonitrile (798 mg, 1.672 mmol, 91% yield) as a light-orange solid. m/z (ESI) 477.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([C:2]2[C:22]([O:23][CH3:24])=[CH:21][C:5]3[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[C:14]#[N:15])[C:4]=3[CH:3]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Agent: OB(O)c1ccccc1
Product: COc1cc2c(cc1-c1cccc(Cl)c1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 36 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used m-chlorophenyl boronic acid. The title compound (58 mg) was obtained as a white solid, (yield=36%).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([NH2:10])=[CH:8][N:7]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C1C(C(O)=O)=CN=C(C2C=CC(C(F)(F)F)=CC=2)N=1.[C:44]([O:48][C:49](=[O:64])[C:50]([O:53][C:54]1[CH:59]=[CH:58][C:57]([CH2:60][C:61](O)=[O:62])=[CH:56][CH:55]=1)([CH3:52])[CH3:51])([CH3:47])([CH3:46])[CH3:45]>>[C:44]([O:48][C:49](=[O:64])[C:50]([O:53][C:54]1[CH:59]=[CH:58][C:57]([CH2:60][C:61](=[O:62])[NH:10][C:9]2[C:4]([CH:1]3[CH2:2][CH2:3]3)=[N:5][C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=3)=[N:7][CH:8]=2)=[CH:56][CH:55]=1)([CH3:52])[CH3:51])([CH3:46])([CH3:45])[CH3:47]
Reactant: Nc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CC(=O)O)cc1
Agent: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(F)(F)F
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CC(=O)Nc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1

Procedure:
In analogy to the procedures described in example 26B] and 124C], 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylamine (prepared from 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid, see example 133], in analogy to the procedures described in examples 125B] and 125C]) was reacted with 2-(4-carboxymethyl-phenoxy-2-methyl-propionic acid tert-butyl ester (example 124A]) to give 2-(4-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylcarbamoyl]-methyl}-phenoxy)-2-methyl-propionic acid tert-butyl ester, which was subsequently cleaved with trifluoroacetic acid to yield the title compound as yellow solid.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>C(OCC)(=O)C>[CH2:7]([O:6][C:4]([CH:3]1[CH2:9][CH2:10][CH2:11][N:1]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH2:2]1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C1CCCNC1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
Combine Ethyl nipecotate (9.9 mL, 63.6 mmol), K2CO3 (13.2 g, 95.4 mmol), and DMF (300 mL) at room temperature under a Nitrogen atmosphere. Heat reaction mixture to 70° C. for 30 minutes then add 4-Methoxybenzyl chloride (9.5 mL, 69.9 mmol). Stir the reaction for 5 hours at 70° C. then cool the reaction mixture to room temperature and stir for an additional 12 hours. Add Ethyl acetate to the reaction mixture and extract with water and then brine. Dry the organic layer over Na2SO4. Concentrate under reduced pressure and flash chromatograph using 3:1 Hexanes:Ethyl acetate to give 14.6 g (82% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.2 (3H, t), 1.4-1.6 (2H, m), 1.6-1.7 (1H, m), 1.9-2.1 (2H, m), 2.2 (1H, t), 1.5-1.8 (2H, m), 2.9 (1H, d), 3.5 (2H, q), 3.8 (3H, s), 4.1 (2H, dd), 6.8 (2H, d), 7.2 (2H, d); MS m/z 278 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[N:8]([CH:13]=[CH:14][CH:15]=3)[N:9]([CH3:12])[C:10]=2[CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:35]N1C(=O)CCC1=O.[Al]>C1COCC1>[Cl:35][C:13]1[N:8]2[N:9]([CH3:12])[C:10]3[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:6](=[O:16])[C:7]2=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c2cc(Cl)ccc2c(=O)c2cccn21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Al]
Solvent: C1CCOC1
Product: Cn1c2cc(Cl)ccc2c(=O)c2ccc(Cl)n21
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.6 %

Procedure:
To a solution containing 7-chloro-5-methylpyrrolo[1,2-b]cinnolin-10(5H)-one (3.0 g) and a catalytic amount of dibenzoyl peroxide in 50 ml of THF was added portionwise N-chlorosuccinimide (1.74 g) over 15 min. The flask was covered with aluminum foil and the solution stirred at room temperature for 24 hrs. The solution was then concentrated and the residue purified by HPLC (silica, dichloromethane) to give 2.43 g of a yellow powder. This powder was recrystallized from ethanol to give 2.23 g of pale yellow crystals, mp 129°-131°.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][CH:48]1[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]1=[O:62].Br[C:64]1[CH:65]=[C:66]([CH3:70])[CH:67]=[CH:68][CH:69]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:66]1([CH3:70])[CH:67]=[CH:68][CH:69]=[CH:64][C:65]=1[C:48]1([CH3:47])[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]1=[O:62]
Reactant: CC1CCC(=CN(C)c2ccccc2)C1=O
Reactant: Cc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1C1(C)CCC(=CN(C)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 51.7 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with tris(dibenzylideneacetone)dipalladium (0) (11.5 mg, 0.0125 mmol, 5 mol % Pd), (S)-BINAP (31.4 mg, 0.05 mmol, 10 mol %) and 2-methyl-5-(N-methyl-anilinomethylene)cyclopentanone (108 mg, 0.5 mmol). Toluene (2 mL) was added and the mixture was stirred for 1 min at room temperature. 3-Bromotoluene (171 mg, 1.0 mmol) and sodium t-butoxide (96 mg, 1.0 mmol) were added to the tube. The tube was capped with the septum, purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was heated to 100° C. with stirring until the starting ketone had been completely consumed, as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 79 mg (52%) of the title compound. The ee was determined to be 8% by chiral HPLC analysis.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[N+:21]([O-])=O)[C:4]=1[OH:24].[OH-].[Na+].C(S(O)=O)(N)=N.Cl>C(O)C.O>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]3=[N:21]2)[C:4]=1[OH:24]
Reactant: COc1cc(CO)c(O)c(N=Nc2ccc(OC)cc2[N+](=O)[O-])c1
Agent: Cl
Agent: N=C(N)S(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(CO)c(O)c(-n2nc3ccc(OC)cc3n2)c1
Temperature: 80 °C
Yield: 27 %

Procedure:
In a 500 ml round bottom 3-neck flask equipped with a magnetic stirrer, addition funnel, powder addition funnel, and nitrogen inlet was added 2-(hydroxymethyl)-4-methoxy-6-((4-methoxy-2-nitrophenyl)diazenyl)phenol and 200 ml absolute ethanol (Pharmco Products, Brookfield, Conn.). NaOH pellets, 97% (Aldrich, 16.8 g, 420 mmol) were dissolved in 80 ml deionized water and approximately one-fourth of the solution was added dropwise to the azo mixture. The reaction mixture was heated to 80° C. and 22.6 g (209 mmol) formamidinesulfinic acid (Aldrich) and the remaining NaOH solution were added concurrently to the azo mixture over 0.5 hr. The mixture was heated at 80° C. for 3 hours, poured into 3.5 L water, and acidified to pH 4-5 with conc. HCl (J. T. Baker). The crude product was recrystallizsed from ethanol and then collected and vacuum dried (0.1 mm Hg) at 50° C. for 72 hours to give 7 g (27%) of a light yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[C:23]([OH:25])[C:22]([C:26](=[O:28])[CH3:27])=[CH:21][C:20]=2[CH2:29][CH3:30])=[CH:10][CH:9]=[CH:8][C:7]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]C)=[O:38].O.[OH-].[Li+]>O1CCCC1.O>[C:37]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[C:23]([OH:25])[C:22]([C:26](=[O:28])[CH3:27])=[CH:21][C:20]=2[CH2:29][CH3:30])[C:6]=1[CH2:5][CH2:4][C:3]([OH:41])=[O:2])([OH:39])=[O:38]
Reactant: CCc1cc(C(C)=O)c(O)cc1OCCCCCCc1cccc(OCCCCCC(=O)OC)c1CCC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C(C)=O)c(O)cc1OCCCCCCc1cccc(OCCCCCC(=O)O)c1CCC(=O)O
Reaction time: 18 h
Yield: 99.9 %

Procedure:
2-(6-Methoxy-6-oxohexyloxy)-6-[6-[[4-acetyl-2-ethyl-5-hydroxyphenyl]oxy]hexyl]benzenepropanoic acid methyl ester (25.8 mg, 0.0452 mmol) was dissolved in tetrahydrofuran (5 mL). Lithium hydroxide monohydrate (18.9 mg, 0.452 mmol) was dissolved in water (1 mL) and added to the reaction. The reaction was stirred for 18 h. The reaction was then concentrated, brought up in water, acidified to pH 5 with 1N HCl, and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and evaporated. The resulting oil recrystallized with hexane:ethyl acetate to give 24.5 mg (100%) of product. MS: Calcd. For C31H42O8+H, 543.2958; Found, 543.2946
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl.Cl[CH2:13][CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.C(OCC)C>C(N)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH2:14][C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)=[CH:6][CH:5]=1
Reactant: ClCCc1c[nH]cn1
Reactant: Oc1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: NC=O
Product: Brc1ccc(OCCc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
240 mg (60% in oil; 6 mmol) of sodium hydride are slowly added to a solution of 2.07 g (12 mmol) of 4-bromophenol in 10 ml of formamide and the mixture is stirred at room temperature for 1 hour. 200 mg (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride and tetrabutylammonium iodide (catalyst) are added and the mixture is stirred at 80° C for 3 days. The reaction mixture is cooled and 150 ml of diethyl ether are added. The precipitate is separated by filtration and the filtrate is evaporated under reduced pressure to give a residue which is subjected to column chromatography through silica gel (first eluent ethyl acetate and second eluent 95/5 ethyl acetate/methanol). The title compound is purified by preparative high performance chromatography and then converted to the oxalate which, after crystallization from an ethanol/diethyl ether mixture, melts at 162°-165° C.