Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].[CH2:6]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([S:27](=[O:30])(=[O:29])[NH2:28])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH3:9]>>[CH2:6]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([S:27](=[O:30])(=[O:29])[NH2:28])[C:19]=1[O:20][C:21]1[CH:22]=[CH:23][C:24]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:25][CH:26]=1)[C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH3:9]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C

Procedure:
To chlorosulphuric acid (5 ml), 3-butylamino-4-phenoxy-5-sulphamyl-benzoic acid (1 g) was added in portions, while stirring and keeping the temperature below 45° C. The reaction mixture was stirred to 10 minutes and then poured into ice water (10 g of ice and 20 ml of water). The precipitated 3-butylamino-4-(4-chlorosulphonylphenoxy)-5-sulphamyl-benzoic acid was isolated by filtration and without further purification added to aqueous ammonia (10 ml containing 2.5 g of ammonia). Excess of ammonia was removed by evaporation, and the resulting solution was adjusted to pH 2.5 by addition of 4N hydrochloric acid. The precipitated 3-butylamino-4-(4-sulphamylphenoxy)-5-sulphamyl-benzoic acid was isolated by filtration, recrystallized from aqueous ethanol, and dried. The obtained compound had a melting point of 265° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]1[S:9][C@@H:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[C@H:7]2[NH:17][C:18]([NH:20][C@@H:6]12)=[O:19].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:41]([C:42]3[CH:47]=[CH:46][N:45]=[C:44]([NH:48][CH2:49][CH2:50][CH2:51][CH3:52])[N:43]=3)=[C:31]3[CH:32]=[CH:33][CH:34]=[C:35]([NH:36][CH2:37][CH2:38][CH2:39][CH3:40])[N:30]3[N:29]=2)=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[O:19]=[C:18]1[NH:20][C@H:6]2[CH2:5][S:9][C@@H:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:41]([C:42]5[CH:47]=[CH:46][N:45]=[C:44]([NH:48][CH2:49][CH2:50][CH2:51][CH3:52])[N:43]=5)=[C:31]5[CH:32]=[CH:33][CH:34]=[C:35]([NH:36][CH2:37][CH2:38][CH2:39][CH3:40])[N:30]5[N:29]=4)=[CH:26][CH:27]=3)=[O:16])[C@H:7]2[NH:17]1
Reactant: CCCCNc1nccc(-c2c(-c3ccc(N)cc3)nn3c(NCCCC)cccc23)n1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCNc1nccc(-c2c(-c3ccc(NC(=O)CCCC[C@@H]4SC[C@@H]5NC(=O)N[C@@H]54)cc3)nn3c(NCCCC)cccc23)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
To a cold (0° C.) solution of thionyl chloride (1 mL) was added solid d-(+)-biotin (100 mg, 0.41 mmol). The resulting mixture was warmed to room temperature and stirred for 1 hour. The excess thionyl chloride and other volatiles were removed under vacuum (<0.1 mm Hg) resulting in a solid residue. To this residue at 0° C. was added N,N-dimethylformamide (3 mL) followed by 2-(4-aminophenyl)-N-butyl-3-[2-(butylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine (70 mg, 0.16 mmol) in 2 mL of N,N-dimethylformamide. The resultant solution was stirred at room temperature for 1 hour at which time the reaction appeared to be complete by analytical methods. The solution was stirred an additional 72 hours. Ethyl acetate and saturated aqueous sodium bicarbonate were added and the layers separated. The organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (8% methanol in dichloromethane) provided 5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]-N-(4-{7-(butylamino)-3-[2-(butylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)pentanamide (30 mg, 28%) as a yellow solid. 1H NMR (DMSO-d6): δ 10.00 (s, 1 H), 7.90 (d, 1 H), 7.66 (m, 3 H), 7.46 (d, 2 H), 7.29 (t, 1 H), 6.99–6.94 (m, 2 H), 6.40 (s, 1 H), 6.32 (s, 1 H), 6.11–6.09 (m, 2 H), 6.25 (m, 1 H), 4.09 (m, 1 H), 3.47–3.06 (m, 4 H), 2.77 (m, 1 H), 2.53 (m, 1 H), 2.44 (m, 1 H), 2.97 (m, 2 H), 1.62–1.27 (m, 14 H), 0.89–0.83 (m, 6 H); MS m/z 656 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH2:16][O:17][Si:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20])[CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH:12]=[CH2:13])=[C:7]([CH3:11])[CH:8]=2)[CH:3]1[OH:15].B(C1CCCCC1)C1CCCCC1.C1C[O:41]CC1>>[OH:41][CH2:13][CH2:12][C:6]1[C:5]([CH3:14])=[C:4]2[C:9]([CH2:10][C:2]([CH3:1])([CH2:16][O:17][Si:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:3]2[OH:15])=[CH:8][C:7]=1[CH3:11]
Reactant: C=Cc1c(C)cc2c(c1C)C(O)C(C)(CO[Si](CC)(CC)CC)C2
Reactant: C1CCOC1
Agent: B(C1CCCCC1)C1CCCCC1
Product: CC[Si](CC)(CC)OCC1(C)Cc2cc(C)c(CCO)c(C)c2C1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
To the stirred solution of compound 8 (0.85 g, 2.45 mmol) in dry THF was added (Cy)2BH (0.87 g, 4.91 mmol) slowly at 0° C. under argon atmosphere. The reaction mixture was warmed to room temperature and stirred for 12 h. The reaction mixture was quenched with 2N NaOH (6 mL) and H2O2 (3 mL) at 0° C. and allowed to stir for 4 h. Then crude reaction mixture was extracted with ethyl acetate (40 mL), washed with water (10 mL), brine (10 mL) dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 8 to 10% EtOAc in petroleum ether eluant) gave pure compound 9 (0.72 g, 81%) as gummy syrup.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].BrC1C=C(NC2C=C3CN([CH:31]4[CH2:34][O:33][CH2:32]4)CCN3N=2)C(=O)N(C)C=1.C([O-])([O-])=O.[K+].[K+].BrCCOC>C(#N)C>[CH3:34][O:33][CH2:32][CH2:31][N:9]1[CH2:10][CH2:11][N:6]2[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:7]2[CH2:8]1
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Agent: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 80 °C

Procedure:
To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (190 mg, 1.13 mmol) 125i in acetonitrile (10 mL) was added K2CO3 (311.9 mg, 2.26 mmol) and 1-bromo-2-methoxyethane (188.3 mg, 1.36 mmol). The reaction mixture was heated at 80° C. for 17 h under microwave irradiation. Analysis of reaction mixture by LCMS showed complete conversion to the desired product. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford 304a as a white solid (230 mg, 90%), which was used in the next step without further purification. MS-ESI: [M+H]+ 227.0
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13](O)=[CH:14][CH:15]=1.C1(C)C=CC=CC=1.[O-2:24].[Ba+2:25].[Ba]>O.C(O)CCCCCCC>[CH2:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[O-:24])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1].[Ba+2:25].[CH2:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[O-:24])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: [O-2]
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: [Ba+2]
Agent: [Ba]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCCCO
Product: CCCCCCCCCc1ccccc1[O-]

Procedure:
Nonylphenol 110 g (0.5 mole), toluene 80 g, octanol 20 g and barium oxide 115 g (0.75 mole) were stirred and treated with 13.5 g water. Reaction proceeded with exothermic heat, and was continued nder reflux for 1 hour. After cooling, the mixture was filtered and there was obtained a black-green liquid overbased barium nonylphenolate complex, which was analyzed to find barium: 28% metal ratio:6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18].O>C1(C)C=CC=CC=1>[C:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:6][CH:7]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC(=O)Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 45 %

Procedure:
Using a method similar to Example 11, 6.0 g (29.8 millimoles) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 8a) are reacted with 4.05 g (44.7 millimoles) of acryloyl chloride in toluene. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized from a dimethylformamide/water mixture. 3.5 g (45% of theory) of 2-(p-acryloylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one, hydrated with one mole of water per four moles of compound, are isolated as almost colorless crystals of melting point 240°-241° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)CCC>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3)c2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Product: CCOC(=O)c1nc(-c2ccncc2)c2snc(-c3ccccc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 3 from 7-bromo-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 4-(tributylstannyl)pyridine: MS (m/z) 378.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH2:4][C:5](=O)[C:6]([F:9])([F:8])[F:7].[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:16]=1[NH:25][NH2:26]>CO>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:6]([F:9])([F:8])[F:7])[N:25]([C:16]2[C:17]([Cl:24])=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[Cl:14])[N:26]=1
Reactant: NNc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: O=[N+]([O-])c1cc(Cl)c(-n2nc(C(F)(F)F)cc2C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1,1,5,5,5-Hexafluoro-2,4-pentanedione (0.56 g, 2.70 mmol) is added to a solution of 2,6-dichloro-4-nitrophenylhydrazine (0.30 g, 2.35 mmol) in 20 ml of methanol chilled in an ice bath. The mixture is stirred overnight at RT, after which the methanol is removed in vacuo. The residue is dissolved in toluene and a catalytic amount of p-toluenesulfonic acid (pTSOH) added. The mixture is heated under reflux and stirred for 2 hours, after which it is allowed to cool to RT and the solvent is removed in vacuo. The resulting crystals are dissolved in xylene, 40 mg of pTSOH is added and the mixture is heated under reflux for 2 hours. The resulting mixture is cooled, washed with methylene chloride, concentrated in vacuo and purified by flash chromatography to give 3,5-bis(trifluoromethyl)-1-(2,6-dichloro-4-nitrophenyl)pyrazole. Following the procedure of Example 5, the nitrophenylpyrazole is reduced by treatment with platinum dioxide and hydrogen to give 3,5-dichloro-4-[3,5-bis-(trifluoromethyl)-1-pyrazolyl]aniline.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].Br[CH:23]([CH:26]=O)[CH:24]=[O:25].CN(C)C(=O)C>O>[OH:25][CH2:24][C:23]1[S:21][C:19]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])=[N:20][CH:26]=1
Reactant: O=CC(Br)C=O
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Nc1cccc2cc(-c3ncc(CO)s3)[nH]c12)c1cccs1
Temperature: 90 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (1.12 g), bromomalonaldehyde (0.90 g) and N,N-dimethylacetamide (15 mL) was stirred at 90° C. for 1 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. To a mixture of the obtained crystals, tetrahydrofuran (10 mL) and methanol (10 mL) was added sodium borohydride (0.13 g) at 0° C., and the mixture was stirred at the same temperature for 1 hr. To the reaction mixture was added 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.70 g, yield 60%) was obtained as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). melting point 209-210° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2
Reactant: Sc1ccc2ccccc2c1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3ccc4ccccc4c3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 2-naphthyl-mercaptan and 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]([CH2:23][O:24][C:25]([C:27]2[S:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:26])=[C:21]2[C:16]([NH:17][C:18]([CH3:35])([CH3:34])[C:19](=[O:33])[NH:20]2)=[CH:15][CH:14]=1.CI.[C:38](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]([CH2:23][O:24][C:25]([C:27]2[S:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:26])=[C:21]2[C:16]([NH:17][C:18]([CH3:35])([CH3:34])[C:19](=[O:33])[N:20]2[CH3:38])=[CH:15][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: COCOc1ccc(-c2ccc3c(c2COC(=O)c2ccc(C)s2)NC(=O)C(C)(C)N3)c(OC)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COCOc1ccc(-c2ccc3c(c2COC(=O)c2ccc(C)s2)N(C)C(=O)C(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A mixture of 7-(2-methoxy-4-methoxymethoxyphenyl)-8-(5-methylthiophen-2-ylcarbonyloxymethyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 11, 1.58 g, 3.18 mmol), methyl iodide (400 μL, 6.43 mmol), and cesium carbonate (2.24 g, 6.87 mmol) was suspended in anhydrous N,N-dimethylformamide (30 mL) and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (150 mL), washed with water (150 mL) and saturated brine (150 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.38 g) as a pale yellow amorphous product. (Yield 85%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([O:9][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][S:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1I
Reactant: OCCc1ccsc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OCCc2ccsc2)c(I)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution 6-chloro-2-iodopyridin-3-ol (6.75 g, 26.4 mmol), 2-(3-thienyl)ethanol (3.79 mL, 34.4 mmol), and triphenylphosphine (9.01 g, 34.4 mmol) in tetrahydrofuran (140 mL) was added diisopropyl azodicarboxylate (6.76 mL, 34.4 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by column on silica gel (eluted at EtOAc/Hexanes=1:20) to give 5.5 g of 6-chloro-2-iodo-3-(2-(thiophen-3-yl)ethoxy)pyridine. Yield: 58%. 1H NMR (DMSO, 400 MHz): δ7.50-7.43 (m, 3H), 7.34 (d, J=1.6 Hz, 1H), 7.17 (d, J=4.8 Hz, 1H), 4.29 (t, J=6.4 Hz, 2H), 3.10 (t, J=6.4 Hz, 2H). LC-MS (ESI): m/z=366 [M+H]+
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:3]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([CH2:43][C:44](Cl)=[O:45])=[CH:35]1>ClCCl.C(OCC)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]([NH:10][CH:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:2]([NH:1][C:44](=[O:45])[CH2:43][C:36]2[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[NH:34][CH:35]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:12])=[CH:15][CH:16]=1
Reactant: O=C(Cl)Cc1c[nH]c2ccccc12
Reactant: NC(c1ccccc1)C(NC(=O)Nc1ccc(Cl)cc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(Cc1c[nH]c2ccccc12)NC(c1ccccc1)C(NC(=O)Nc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
To a solution of [S-(R*,R*)] and [R-(R*,R*)]-N-(2-amino-1,2-diphenylethyl)-N'-(4-chlorophenyl)urea (0.1 g, 0.27 mmol) in dichloromethane (5 mL) is added triethyl amine (0.03 g, 0.27 mmol) followed by indole-3-acetic acid chloride (0.05 g, 0.27 mmol). The mixture is stirred 1.5 hours at room temperature before diluting with diethyl ether and washing with aqueous 2M HCl, aqueous 1M NaOH, saturated aqueous NaCl, and drying (MgSO4). Filtration and concentration gives an oil which is purified by flash chromatography (SiO2, EtOAc/hexane eluent) to provide 0.05 g (33%) of desired product, mp 224°-227° C. IR (KBr): 3360, 1549, 1492, 1226, 698 cm-1 ; NMR (DMSO-d6): 3.56 (s, 2H), 5.07 (m, 2H), 6.78-7.45 (m, 20H), 8.65 (m, 2H), 10.81 (s, 1H). Analysis calculated for C31H27ClN4O2.0.5H2O: C, 69.98; H, 5.30; N, 10.53. Found: C, 69.65; H, 5.41; N, 10.56.
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=O)[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.[C:19]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:31])[CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].N1C=CC=CC=1.S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[C:1]1(=[O:18])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[C:20]([C:19]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=CCCCCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)C(=CCCCCCN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A solution of 2.95 ml of titanium tetrachloride in 8 ml of carbon tetrachloride was added dropwise while stirring under a nitrogen atmosphere to 50 ml of dry tetrahydrofuran at 0°. The resulting yellow suspension was treated with a solution of 2.45 g of 6-phthalimidohexan-1-al and 3.55 g of dibenzyl malonate in 40 ml of tetrahydrofuran and the mixture was stirred at 0° for 2 hours. A solution of 4.5 g of dry pyridine in 12 ml of dry tetrahydrofuran was added dropwise to give a blood-red suspension. The mixture was left to come to room temperature and was stirred for 18 hours while maintaining the nitrogen atmosphere. 200 ml of 2M sulfuric acid were added and the mixture was extracted four times with dichloromethane. The combined extracts were washed with sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel using ethyl acetate/n-hexane (1:2) for the elution to give 3.6 g of dibenzyl 2-(6-phthalimidohexylidene)malonate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:12]=O)[C:5]([CH:18]([CH3:20])[CH3:19])=[C:4]([Cl:21])[N:3]=1.Cl.[OH:23][NH2:24].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:12]=[N:24][OH:23])[C:5]([CH:18]([CH3:20])[CH3:19])=[C:4]([Cl:21])[N:3]=1
Reactant: NO
Reactant: Cc1cc(C=O)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C=NO)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 25 °C
Yield: 36.9 %

Procedure:
A mixture of (69) (11.66 g, 35.8 mmol), hydroxyamine hydrochloride (2.98 g, 42.96 mmol), and triethyl amine (7.48 ml, 53.7 mmol) in ethanol (100 ml) was refluxed for 2 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexanes (1:9)) to afford 4.5 g (37%) of a white solid. m.p. 185-187° C.; 1H NMR (200 MHz, CDCl3) δ 1.40 (6H, d, J=7.0 Hz), 2.40 (3H, s), 3.58 (1H, m), 6.94 (1H, s), 7.16 (1H, s), 7.28 (1H, s), 7.51 (1H, s), 8.10 (1H, s).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:23])[C:9]3[CH2:14][CH:13]([CH3:15])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][N:35]([C:2]2[N:7]=[C:6]3[N:8]([CH3:23])[C:9]4[CH2:14][CH:13]([CH3:15])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=4[C:5]3=[CH:4][CH:3]=2)[C:34](=[O:38])[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1Cc2c(c3ccc(Br)nc3n2C)CN1C(=O)OC(C)(C)C
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: CC1Cc2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc3n2C)CN1C(=O)OC(C)(C)C
Yield: 57.6 %

Procedure:
tert-Butyl 2-bromo-7,9-dimethyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (200 mg, 0.520 mmol) and 4-(benzyloxy)pyridin-2(1H)-one (115 mg, 0.520 mmol) were reacted following the procedure for Example 2 (step e) to provide the title compound (150 mg, 57%) as a yellow oil: ESI MS m/z 501 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH3:13])[C:7]2=[O:12].[CH:14]1([CH2:21][C:22](O)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[CH:14]1([CH2:21][C:22]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([CH3:13])[C:7]3=[O:12])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cn1ccc2c(N)cccc2c1=O
Reactant: O=C(O)CC1CCCCCC1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc2c(NC(=O)CC3CCCCCC3)cccc2c1=O

Procedure:
5-Amino-2-methyl-2H-isoquinolin-1-one (50 mg, 0.0003 mol), 2-cycloheptylacetic acid (90 mg, 0.0006 mol), fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (200 mg, 0.0006 mol), N,N-diisopropylethylamine (100 mg, 0.0009 mol) were stirred in methylene chloride (2 mL, 0.03 mol) at room temperature over 72 hours. The mixture was purified via flash chromatography (12 g of silica gel, 0-50% EtOAc/Hexane) to give a yellow solid. 1H NMR δ (CDCl3) δ: 8.31 (d, J=7.9 Hz, 1H), 7.95-7.92 (m, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.20 (br, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.41 (d, J=7.5 Hz, 1H), 3.60 (s, 3H), 2.37 (d, J=7.3 Hz, 2H), 2.17 (br, 1H), 1.86-1.25 (12H).