Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1.C1C2NC3C(=CC=CC=3)C=2C(OC(C)(C)C(O)=O)=CC=1.Cl[CH2:43][C:44]1[CH:62]=[CH:61][C:47]([O:48][CH2:49][C:50]2[N:51]=[C:52]([C:56]3[S:57][CH:58]=[CH:59][CH:60]=3)[O:53][C:54]=2[CH3:55])=[C:46]([O:63][CH3:64])[CH:45]=1.ClCC1C=CC(OCC2N=C(C3C=CC=CC=3)OC=2C)=C(OC)C=1>>[CH3:64][O:63][C:46]1[CH:45]=[C:44]([CH:62]=[CH:61][C:47]=1[O:48][CH2:49][C:50]1[N:51]=[C:52]([C:56]2[S:57][CH:58]=[CH:59][CH:60]=2)[O:53][C:54]=1[CH3:55])[CH2:43][N:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[C:4]([O:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])[C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2cccs2)oc1C
Reactant: CC(C)(COc1cccc2[nH]c3ccccc3c12)C(=O)O
Agent: CC(C)(Oc1cccc2[nH]c3ccccc3c12)C(=O)O
Agent: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Product: COc1cc(Cn2c3ccccc3c3c(OCC(C)(C)C(=O)O)cccc32)ccc1OCc1nc(-c2cccs2)oc1C

Procedure:
The subject compound was prepared by performing the same operation as that of the example 3 by using 3-(9H-carbazole-4-yloxy)-2,2-dimethylpropionic acid prepared by the reference 30 instead of 2-(9H-carbazole-4-yloxy)-2-methylpropionic acid used in the example 3, and using 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-2-(thiophene-2-yl)-5-methyloxazole prepared by the reference 3 instead of 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-5-methyl-2-phenyloxazole.
Reaction SMILES: [O-]Cl.[Na+].[C:4]([C:7]1[S:11][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=1)(=[O:6])C.[O-:17]S(S([O-])=O)=O.[Na+].[Na+]>>[C:4]([C:7]1[S:11][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=1)([OH:6])=[O:17]
Reactant: CC(=O)c1ccc(-c2cccs2)s1
Reactant: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1ccc(-c2cccs2)s1
Reaction time: 2 h

Procedure:
35 ml of NaOCl solution was heated to 55° C. and 5-acetyl-2,2'-bithiophene was then added and stirred at 60°-70° C. for 2 hours. Then the reaction solution was cooled by ice bath and aqueous Na2S2O4 solution was added for removing the residual NaOCl. The reaction mixture was acidified by HCl(aq) and filtered to obtain golden product. The product was further recrystallized with 95% ethanol. The melting point of the product was 183-184%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:17](Br)[CH:18]([CH3:20])[CH3:19].Cl>>[CH2:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)[CH2:12][CH2:13]1)[CH:18]([CH3:20])[CH3:19]
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Reactant: CC(C)CBr
Agent: Cl
Product: CC(C)CN1CCC(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)piperidine and i-butylbromide; m.p. 212° C. (HCl); MS m/z (rel. intensity, 70 eV) 295 (M+, 1), 252 (80), 129 (40), 115 (50), 70 (bp)
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([F:21])=[C:6]([O:13]CC2C=CC=CC=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)#N.[C:22]([CH2:24][C:25]1[C:26]([N+:40]([O-])=O)=[CH:27][C:28]([F:39])=[C:29]([O:31]CC2C=CC=CC=2)[CH:30]=1)#N.[H][H]>C(O)C.C(O)(=O)C.[Pd]>[F:21][C:5]1[C:6]([OH:13])=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:1][NH:10]2.[F:39][C:28]1[CH:27]=[C:26]2[C:25]([CH:24]=[CH:22][NH:40]2)=[CH:30][C:29]=1[OH:31]
Reactant: N#CCc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Reactant: N#CCc1cc(OCc2ccccc2)c(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Oc1cc2cc[nH]c2cc1F
Product: Oc1ccc2[nH]ccc2c1F

Procedure:
A solution of a mixture of 3-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene and 5-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene (23 g, 80.4 mmol) in ethanol (220 ml) and acetic acid (30 ml) containing 10% palladium on charcoal (600 mg) was hydrogenated under 3 atmospheres pressure until hydrogen uptake ceased. The mixture was filtered and the filtrate was evaporated under vacuum. The residue was purified on column chromatography using a Prochrom® equipment eluting with methylene chloride/petroleum ether (20/80) to give 4-fluoro-5-hydroxyindole (2.48 g) and 6-fluoro-5-hydroxyindole (3.5 g).
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[CH3:13][N:14]1[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15]1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[CH:30]([NH:32][C:33]1[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH2:43])[CH:39]=3)[N:34]=1)[CH2:29][CH2:28][CH2:27]2>>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[CH:30]([NH:32][C:33]1[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH:43][C:1]([NH:19][C@@H:16]4[CH2:17][CH2:18][N:14]([CH3:13])[CH2:15]4)=[O:2])[CH:39]=3)[N:34]=1)[CH2:29][CH2:28][CH2:27]2
Reactant: CN1CC[C@@H](N)C1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)N[C@@H]4CCN(C)C4)ccc3n1)CCC2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, (3R)-1-methyl-3-pyrrolidinamine (CAS no: 457097-75-5) and rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine; MS: m/e=446.4 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:10](=[O:26])[N:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][N:15]=[C:14](Cl)[N:13]=1.[CH3:27][N:28]([CH3:39])[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.FC(F)(F)C(O)=O>C(O)(C)C>[CH3:27][N:28]([CH3:39])[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:14]2[N:13]=[C:12]([N:11]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:10](=[O:26])[O:9][C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=3[CH3:8])[CH:17]=[CH:16][N:15]=2)=[CH:34][CH:33]=1
Reactant: Cc1cccc(C)c1OC(=O)N(Cc1ccccc1)c1ccnc(Cl)n1
Reactant: CN(C)CCOc1ccc(N)cc1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C)c1OC(=O)N(Cc1ccccc1)c1ccnc(Nc2ccc(OCCN(C)C)cc2)n1
Temperature: 100 °C

Procedure:
A resealable tube was charged with the benzyl-(2-chloropyrimidin-4-yl)carbamic acid 2,6-dimethylphenyl ester (0.093 g, 0.253 mmol), 4-(2-dimethylaminoethoxy)-phenylamine (0.050 g, 0.278 mmol), and isopropanol (4 mL). Trifluoroacetic acid (0.072 g, 0.049 mL, 0.633 mmol) was added and the system was flushed with argon. The tube was sealed and the mixture was heated at 100° C. for 20 h. The reaction mixture was cooled to room temperature and concentrated to afford a pale purple oil. The oil was purified via column chromatography (gradient elution with 0-100% dichloromethane-(90: 10:1, dichloromethane/methanol/ammonium hydroxide)) to afford 2,6-dimethylphenyl 2-((4-((2-(dimethylamino)ethyl)oxy)phenyl)amino)-4-pyrimidinyl(phenylmethyl)carbamate as a white solid. MS (MH+) 512.3; Calculated 511.62 for C30H33N5O3.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][CH:7]([NH:14][C:15](=[O:26])[CH2:16][CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:17][CH2:16][C:15]([NH:14][CH:7]([CH3:6])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[O:26])=[S:4]
Reactant: CC(C)CCCC(C)NC(=O)CCC(=O)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)CCCC(C)NC(=O)CCC(=NNC(N)=S)c1ccccc1
Yield: 56.1 %

Procedure:
Thiosemicarbazide (1.32 g, 14.5 mmol) was added to a solution of N-(1,5-dimethyl-hexyl)-4-oxo4-phenyl-butyramide (2.54 g, 87.9 mmol), prepared in the previous step, in 30 ml of methanol plus 2.4 ml of 1 N HCl plus 2.4 ml of water and the reaction stirred at room temperature for 48 hours. The reaction was concentrated under reduced pressure to remove the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2.95 g of an off-white solid foam. Purification of this foam by chromatography on silica gel (230-400 mesh) using 3:1 hexane-ethyl acetate and then 3:1 ethyl acetate-methylene chloride as the eluted gave the title compound (2.63 g, 82%) as a white foam, mp 58-65° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH2:17](O)[CH2:18][OH:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[O:19]1[C:2]2([CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH2:3]2)[O:1][CH2:17][CH2:18]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC2(C1)OCCO2
Temperature: 120 °C

Procedure:
A mixture of benzyl 3-oxopyrrolidine-1-carboxylate (2.00 g), ethane-1,2-diol (2.85 mL), p-toluenesulfonic acid monohydrate (10 mg) and toluene (20 mL) was stirred with heating in a Dean-Stark apparatus at 120° C. for 6 hr. The mixture was allowed to cool to room temperature, diluted with ethyl acetate (10 mL), washed successively with water (5 mL×2) and brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.1 g) as a pale-yellow liquid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[CH:38](O)[CH3:39])[C:33]#[N:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:38]([C:37]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=4[Cl:29])[CH3:39])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reactant: CC(O)c1ccc(C#N)cc1Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccc(C#N)cc1Cl

Procedure:
In a similar manner as described for example B31, 1.42 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 0.8 g of 3-chloro-4-(1-hydroxyethyl)benzonitrile, 2.26 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 1.56 g of di-tert-butyl azodicarboxylate in 40 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[N+:11]([C:14]1[O:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:18]([C:17]3[O:20][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc([N+](=O)[O-])o1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 5-nitro-furfuraldehyde in an analogous manner to that described in Example 1 to give 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(5-nitro-2-furyl)-1,8(2H,5H)-acridinedione. Crystallization from ethyl acetate/methanol gave a beige crystalline solid of melting point 248-250° C. (decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[NH:8][C:7]2=O.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:7]1[C:6]2[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([CH3:12])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(O)cccc2c(=O)[nH]1
Product: Cc1nc(Cl)c2cccc(O)c2n1

Procedure:
8-Hydroxy-2-methyl-4(3H)-quinazolinone (0.01 mol) and phosphorus oxychloride (10 mL) were heated under reflux for 30 min. The excess phosphorus oxychloride was removed under reduce pressure and the residue was added to a mixture of ice (50 g) and water (50 ml), and the pH adjusted to 6 (aqueous ammonia). 4-Chloro-8-hydroxy-2-methyl-quinazoline (A2) was isolated via filtration.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([NH:11][C:12](=[O:24])[NH:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18]O)=[CH:16][C:15]=2[O:22][CH3:23])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(N=C=O)C=CC=CC=1.CCCCCCC>ClCCl>[C:5]1([NH:11][C:12](=[O:24])[NH:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18][Cl:3])=[CH:16][C:15]=2[O:22][CH3:23])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COc1cc(CO)ccc1NC(=O)Nc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCCCCCC
Solvent: O=C=Nc1ccccc1
Solvent: ClCCl
Product: COc1cc(CCl)ccc1NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.55 mL (103.4 mmol) of thionyl chloride were added dropwise to a suspension of 14.07 g (51.7 mmol) of 4-(3-phenylureido)-3-methoxybenzyl alcohol (prepared as described in Example 1, phenyl isocyanate being employed instead of 2-methylphenyl isocyanate) in 200 mL of dichloromethane. The mixture then was stirred at room temperature for 2 hours, allowed to stand overnight and poured onto 800 mL of heptane. The heptane was decanted off from the separated oil, the residue was suspended several times in heptane and in each case the heptane was decanted off. The residue was dissolved in 100 mL of dichloromethane and added dropwise to 800 mL of diisopropyl ether. The mixture was stirred for 1 hour with ice cooling, and the product was filtered off with suction, washed with diisopropyl ether and dried in vacuo.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:25][NH2:26].CCN(C(C)C)C(C)C>C(O)C>[CH3:24][NH:23][C:12]1[N:11]=[C:10]([C:8]2[CH:7]=[C:6]3[C:3]([C:4]([NH2:5])=[N:25][NH:26]3)=[CH:2][CH:9]=2)[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[N:13]=1
Reactant: NN
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CCOC[C@H]2C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C)n1
Temperature: 150 °C
Yield: 41.8 %

Procedure:
To a 5-mL microwave vial was added 2-fluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile (270 mg, 0.824 mmol), hydrazine (0.31 mL, 9.9 mmol), Hunig's base (0.576 mL, 3.30 mmol), and ethanol (3 mL). The reaction mixture was heated at 150° C. for 70 minutes in a microwave reactor. LCMS analysis indicated good conversion, so the reaction mixture was concentrated, dissolved in DMSO and purified by RP-HPLC (8-32% CH3CN in water, 0.1% TFA). The product fractions were pooled, then basified with NaHCO3 and extracted with EtOAc. The organic layer was dried and concentrated to afford the title compound (117 mg). LC-MS (ES) m/z=340 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.17-1.23 (m, 3H), 2.84 (d, J=4.0 Hz, 3H), 3.02-3.20 (m, 1H), 3.38-3.51 (m, 1H), 3.56-3.66 (m, 1H), 3.67-3.78 (m, 1H), 3.87-3.98 (m, 1H), 4.07-4.19 (m, 1H), 4.45-4.57 (m, 1H), 5.38 (s, 2H), 6.55 (bs, 2H), 7.61 (s, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.98 (bs, 1H), 11.51 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH:11]([CH3:13])[CH3:12])[C:3]=1[OH:14].I[CH2:16][CH2:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[C:4]([CH:11]([CH3:13])[CH3:12])[C:3]=1[O:14][CH2:16][CH2:17][CH3:18]
Reactant: CCCI
Reactant: CC(C)c1cc(Br)c(O)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1c(Br)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 64 h
Yield: 95.5 %

Procedure:
A mixture of 2-bromo-4,6-diisopropyl-phenol (Intermediate 2, 14.5 g, 56 mmol), 1-iodopropane (16.5 mL, 169 mmol), and K2CO3 (38.6 g, 280 mmol) in acetone (100 mL) was stirred at room temperature for 64 h. The solvent was removed in vacuo, and the residue was taken up in CHCl3 and filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash column chromatography on silica gel (hexanes) to yield the title compound as a colorless oil (16.0 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:36])[O:11][C:12]2[C:17]([C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=1)=[CH:16][CH:15]=[C:14]([OH:34])[C:13]=2I.[C:37]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.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>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:36])[O:11][C:12]2[C:17]([C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=1)=[CH:16][CH:15]=[C:14]([OH:34])[C:13]=2[CH3:37]
Reactant: O=C([O-])[O-]
Reactant: O=c1oc2c(I)c(O)ccc2c(Cc2ccc(OCCN3CCCC3)cc2)c1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c(O)ccc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(Cl)cc3Cl)c(=O)oc12
Temperature: 25 °C

Procedure:
A mixture of 3-(2,4-dichlorophenyl)-7-hydroxy-8-iodo-4-(4-(2-pyrrolidin-1-yl-ethoxy)-benzyl)-chromen-2-one (1.85 g, 2.91 mmol), K2CO3 (1.21 g, 8.75 mmol), trimethylboroxine (427 μL, 3.05 mmol) and Pd(Ph3P)4 (336 mg, 0.29 mmol) in anhydrous dioxane (22 mL) was stirred at reflux temperature for 2.5 h. After cooling the resultant green suspension to room temperature, the solvent was removed in vacuo. The resultant residue was dissolved in CH2Cl2, and the organic layer was washed with H2O and brine, dried (MgSO4) concentrated in vacuo. The resultant residue was purified using flash chromatography (125 g silica gel, 8:0.5:0.5→7:0.5:0.5 CH2Cl2:MeOH:AcOEt→9:1 CH2Cl2:MeOH) to afford a yellow solid that was further purified using reverse phase HPLC (followed by an extraction with CH2Cl2/NaHCO3). The title compound was isolated as a yellow solid (220.4 mg, 14%). 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J=2.0 Hz, 1H), 7.24 (dd, J=2.0, 8.0 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 1H), 6.72 (d, J=8.8 Hz, 2H), 4.23 (t, J=5.0 Hz, 2H), 4.00 (d, J=15.5 Hz, 1H), 3.74 (d, J=15.5 Hz, 1H), 3.24 (t, J=5.0 Hz, 2H), 3.15–3.04 (m, 4H), 2.20 (s, 3H), 2.05–1.93 (m, 4H); MS (ESI) m/z 523.8 (M)+; HPLC tR 4.74 min.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CO>[N:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][NH:24][C:2]3[C:3]([C:4]([O-:6])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=3)[CH2:21][CH2:22]2)=[CH:13][CH:12]=1.[NH4+:10]
Reactant: O=C(O)c1cccnc1Cl
Reactant: NCC1CCN(c2ccncc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C([O-])c1cccnc1NCC1CCN(c2ccncc2)CC1
Product: [NH4+]
Yield: 96.7 %

Procedure:
A mixture of 2-chloronicotinic acid (10.74 g, 67.5 mmol), 1-(4-pyridyl)piperidine-4-methylamine (8.60 g, 45.0 mmol), and potassium carbonate 15.5 g. 112.6 mmol) in dimethylformamide (90 mL) was heated at reflux. After 16 h. the mixture was diluted with methanol, filtered, and concentrated. The residue was dissolved in methanol, acidified with 1 N HCl in ether, heated at reflux for 0.25 h, cooled, and the solid removed by filtration. The filtrate was then treated with 2 M NH3 in methanol until slightly basic, triturated with THF and the resulting solid collected by filtration yielding 10.75 g of the title compound which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)nc4)nc23)CC1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.054 mMol 6-chloro-3-pyridinecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8](=[O:12])[O:7][CH2:6]1
Reactant: O=C1OCCc2cc(Br)ccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OCC(Br)c2cc(Br)ccc21

Procedure:
6-Bromo-3,4-dihydro-1H-isochromen-1-one (3.00 g, 13.2 mmol) was dissolved in CCl4 (150 mL) then added N-bromosuccinimide (2.352 g, 13.21 mmol) followed by benzoyl peroxide (0.0960 g, 0.396 mmol) and refluxed for 3 hrs. Filtered and concentrated then chromatographed through a 120 g ISCO Redi-sep. column and eluted with 0-25% ETOAc/Hexane to yield 4,6-dibromo-3,4-dihydro-1H-isochromen-1-one. LC-MS (IE, m/z): 306.9 [M+1]+; 1H-NMR (500 MHz, CDCL3) δ ppm 8.03 (d, J=8.9 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.68 (s, 1H), 5.32 (t, J=3 Hz, 1H), 4.72-4.81 (q, 1H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[C:16]([CH2:20][C:21](Cl)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH:24]1([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[CH:33]=[CH:32][C:30]([N:31]3[CH2:13][CH2:12][C:6]4([CH2:7][CH2:8][N:9]([C:21](=[O:22])[CH2:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11]4)[C:4]3=[O:5])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1
Reactant: Nc1ccc(C2CC2)cc1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CC(C)(C)CC(=O)N1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O

Procedure:
Light yellow solid. MS (ESI): 369.25 (MH+). This example was prepared in analogy to example 7 step A) to B) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), tert-butyl acetyl chloride and 4-cyclopropyl-aniline.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]1(=O)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]1.O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH:10][C:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(N)cc1OC1CCCC1
Reactant: O=C1CCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(NC2=CC(=O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
1.04 g (5.02 mole) of 3-cyclopentyloxy-4-methoxyaniline, 0.51 g (5.02 mmole) of 1,3-cyclopentanedione, and 0.03 g of p-toluenesulfonic acid were dissolved in 30 ml of benzene and the solution was heated reflux in an apparatus fitted with a water separation tube for 3 hours, while azeotropically separating the water produced. After the reaction, the solution was cooled to room temperature, a yellow crystal was precipitated. The precipitated yellow crystal was collected by suction filtration, and the crystal was washed with diethyl ether, then dried to obtain the title compound 1.16 g (yield 80.4%) as a pale yellow crystal.