Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:15]=[C:14]([C:16]4[S:17][C:18]5[C:24]([C:25]6[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=6)=[C:23]([C@H:32]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:22]([CH3:43])=[CH:21][C:19]=5[N:20]=4)[CH:13]=[CH:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH:44]1(B(O)O)[CH2:46][CH2:45]1.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:39]([O:38][C@@H:32]([C:23]1[C:22]([CH3:43])=[CH:21][C:19]2[N:20]=[C:16]([C:14]3[CH:13]=[CH:12][N:11]=[C:10]([C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[N:1]([CH:44]4[CH2:46][CH2:45]4)[N:2]=[CH:3]5)[CH:15]=3)[S:17][C:18]=2[C:24]=1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH3:42])([CH3:41])[CH3:40]
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5[nH]ncc5c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(cnn5C5CC5)c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
To a solution of (S)-ethyl 2-(2-(2-(1H-indazol-5-yl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (30 mg, 0.049 mmol) in dichloroethane (1 mL) was added Cu(OAc)2 (9 mg, 0.049 mmol), 2-2′-dipyridyl (7.7 mg, 0.049 mmol), cyclopropylboronic acid (8.4 mg, 0.1 mmol), Na2CO3 (10.4 mg, 0.1 mmol). The reaction mixture was heated at 70° C. for 3 hours under air. The reaction mixture was washed by water, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down, purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C37H35ClN4O3S: 651.2 (M+H+). found: 651.3.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH3:27][C:25]1[NH:24][N:23]=[C:22]([NH:21][C:13]2[N:12]=[C:11]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:26]=1
Reactant: OCCN1CCCCC1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(OCCN3CCCCC3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-piperidin-1-yl-ethanol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-[1-(2-piperidin-1-yl-ethoxy)-isoquinolin-3-yl]-amine. LC-MS m/e 352(MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Temperature: 110 °C
Yield: 100.1 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (3.12 g), 4-hydroxybenzaldehyde (1.83 g), potassium carbonate (2.28 g) and dimethylformaide (40 ml) was stirred under heating at 110° C. for 1 hour. The reaction solution was poured into ice-cold water, and the crystals which separated out were collected by filtration to give 4-(5-methyl-2-phenyl-4-oxazolyl)methoxybenzaldehyde (4.40 g, 99.8%). Recrystallization from ether-hexane yielded colorless prisms, m.p. 112°-113° C. Elemental analysis for C18H15NO3 ; Calcd.: C, 73.71; H, 5.15; N, 4.87. Found: C, 73.87; H, 5.26; N, 4.81.
Reaction SMILES: [O:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([CH2:13][N:14]2[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]2=[O:24])[CH2:5][N:4]3[CH2:3][CH2:2]1.[Br:25]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:25][C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([O:1][CH2:2][CH2:3][N:4]3[CH2:5][CH:6]2[CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1CC1CN2CCOc3cccc1c32
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC1CN2CCOc3cc(Br)cc1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (rac)-2-(2,3,5,6-tetrahydro[1,4]oxazino[2,3,4-hi]indol-6-ylmethyl)-1H-isoindole-1,3(2H)-dione (0.030 g, 0.094 mmol) in DMF (1.0 mL) was added the solution of N-bromosuccinimide (0.018 g, 0.098 mmol). The reaction mixture was stirred at room temperature for 1 hour and water (10.0 mL) was added. The aqueous solution was extracted with EtOAc (3×) and the combined EtOAc solution was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness to give 0.035 g (94%) of light yellow oil as the desired product: 1H NMR (400 MHz, CDCl3) δ 7.82-7.79 (m, 2 H), 7.70-7.63 (m, 2 H), 6.81 (s, 1 H), 6.70 (s, 1 H), 4.34-4.29 (m, 2 H), 3.93-3.81 (m, 2 H), 3.63-3.59 (m, 1 H), 3.27-3.23 (m, 1 H), 3.19-3.15 (m, 1 H), 3.05-3.00 (m, 1 H), 2.98-2.89 (m, 1 H); MS (EI) m/z 399 (M++H), 401 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=3)[C:14](=[O:18])[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CCN1
Reactant: FC(F)(F)c1cccnc1Br
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1CN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CCN1c1ncccc1C(F)(F)F
Yield: 10 %

Procedure:
Amidation of 4-(3,4-dichloro-benzenesulfonyl)-piperazin-2-one (150 mg, 0.49 mmol) with 2-bromo-3-trifluoromethyl pyridine (164.5 mg, 0.73 mmol) was carried out according to a similar procedure described for example 15A using powdered anhydrous potassium carbonate (134.1 mg, 0.97 mmol) as base, CuI (9.2 mg, 0.049 mmol) as catalyst, N,N′-dimethyl-1,2-ethylenediamine (5.2 μL, 0.049 mmol) as ligand, and anhydrous 1,4-dioxane (1.8 mL) as solvent. 4-(3,4-dichloro-benzenesulfonyl)-1-(3-trifluoromethyl-pyridin-2-yl)-piperazin-2-one was obtained in 10% yield (21 mg) as an off-white solid.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.[H-].[Na+].[C:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.CN(C)C=O>[C:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:13]2[C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=4)[C:9]=3[CH:11]=[CH:12]2)=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(CBr)cc1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Cn2ccc3c4c(N)nc(N)nc4ccc32)cc1
Reaction time: 3 h

Procedure:
In a manner similar to that of Example 2, 7.97 g. 7-H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 350 ml. dry dimethylformamide is converted to the Nind-sodium salt with 2.31 g. ca. 50% sodium hydride-mineral oil dispersion and the salt is treated with 4-acetylbenzyl bromide (10.23 g.) in 10 ml. dry dimethylformamide. After stirring for 3 hours, the reaction mixture is treated with 5 ml. gl. acetic acid and freed of solvent. The residue is stirred with excess aqueous potassium carbonate solution, washed with water, with ether, and dried. Two recrystallizations of the crude product from methanol and thorough drying provide 9.82 g. of title compound, m.p. 224°-225°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([NH:8][C:9]2[S:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:6][CH:7]=1.[SH:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(N(C(C)C)C(C)C)C>>[O:18]([C:4]1[CH:3]=[C:2]([S:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:7]=[N:6][C:5]=1[NH:8][C:9]1[S:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[CH:13][N:12]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CCS
Reactant: Brc1cnc(Nc2nc3cccnc3s2)c(Oc2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(Nc2nc3cccnc3s2)c(Oc2ccccc2)c1
Yield: 75 %

Procedure:
Prepared according to the method of Example 13 from N-(5-bromo-3-phenoxypyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine, methyl 3-mercaptopropanoate and N-ethyl-N-isopropylpropan-2-amine in 75% yield. 1H NMR (d6-DMSO) δ 2.59 (t, 2H), 3.09 (t, 2H), 3.56 (s, 3H), 7.12 (d, 2H), 7.20 (t, 1H), 7.38-7.46 (m, 4H), 7.91 (bs, 1H), 8.24 (s, 1H), 8.36 (d, 1H), 11.53 (bs, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([N+:11]([O-])=O)[CH:10]=[C:4]2[CH2:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([NH2:11])[CH:10]=[C:4]2[CH2:3]1
Reactant: CN1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CN1CCn2nc(N)cc2C1
Reaction time: 8 h
Yield: 127.9 %

Procedure:
To a solution of 5-methyl-2-nitro-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (67 mg, 0.37 mmol) in ethanol (15 mL) was treated with palladium on carbon (10%, 20 mg) and flushed with argon. The resulting mixture was stirred under a hydrogen (1 atm) overnight. The reaction mixture was filtered through a celite pad, and the pad washed with ethanol. The filtrate was concentrated in vacuo to give 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (72 mg, quantitative) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[NH2:11][C:5]1[C:6]([C:8]([NH2:10])=[O:9])=[N:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: NC(=O)c1nc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(F)ccc1N

Procedure:
A solution of 6-fluoro-3-nitropyridine-2-carboxamide (1.50 g, 8.10 mmol) in EtOAc (80 mL) is hydrogenated over 5% Pd-C (0.30 g) at 60 psi for 2 h. After removal of the catalyst by filtration, the solvent is removed under reduced pressure, to give a residue of crude 3-amino-6-fluoropyridine-2-carboxamide which is used directly in the next step. Triethyl orthoformate (60 mL) is added and the mixture is then heated under reflux with vigorous stirring for 18 h. The cooled mixture is diluted with an equal volume of petroleum ether, and the resulting precipitate collected by filtration and is washed well with petroleum ether to give 6-fluoro-3H-pyrido[3,2-d]pyrimid-4-one (1.26 g, 84%). 1H NMR (DMSO) δ 12.72 (1H, brs), 8.31 (1H, dd, J=8.6, 7.7 Hz), 8.20 (1H, s), 7.66 (1H, dd, J=8.6, 3.0 Hz).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>ClCCl>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19]([N:2]2[C:1]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:5][CH2:4][CH2:3]2)=[O:20])=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Reaction time: 3 h
Yield: 65.9 %

Procedure:
To a solution of tetrahydroisoquinoline (3.99 g, 30 mmol) in triethyl amine (6 g, 60 mmol) and dichloromethane (150 mL) cooled in ice bath was added p-nitrophenyl chloroformate (6.06 g, 30 mmol) drop wise over a period of 1 h. The reaction mixture was srirred at room temperature for 3 h and then washed with water (3×100 mL), dried over sodium sulfate and concentrated to afford an oil which was triturated with ether:hexane to afford the titled compound as yellow solid (5.9 g, 65%).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH2:12][C:13]1[C:14]([C:20]([NH:22][NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=O)=[N:15][C:16]([Br:19])=[CH:17][N:18]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:19][C:16]1[N:15]=[C:14]([C:20]2[O:29][C:24]([C:25]([CH3:26])([CH3:27])[CH3:28])=[N:23][N:22]=2)[C:13]([NH2:12])=[N:18][CH:17]=1
Reactant: CC(C)(C)C(=O)NNC(=O)c1nc(Br)cnc1N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nnc(-c2nc(Br)cnc2N)o1
Temperature: 70 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
p-Toluenesulfonyl chloride (164 g, 861.60 mmol) was added portion wise to a suspension of 3-amino-6-bromo-N′-pivaloylpyrazine-2-carbohydrazide (227 g, 718.00 mmol) and N,N-diisopropylethylamine (297 mL, 1795.01 mmol) in acetonitrile (2200 mL). The mixture was stirred for 2 hours at 70° C. The reaction was left to cool to room temperature overnight. The reaction mixture was partitioned between ethyl acetate (2 L) and sodium bicarbonate solution (2 L). The organic layer was washed with saturated brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting brown/beige solid was triturated with hot MTBE (1000 mL) and isolated by filtration and dried to afford 5-bromo-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine as a yellow solid (187 g, 87%). The mother liquors were evaporated to dryness. The crude solid was triturated with MTBE (500 mL) filtered and washed with 100 mL of MTBE. The resulting solid was air dried overnight to afford a second crop of 5-bromo-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (36 g, 17%): 1H NMR Spectrum: (DMSO-d6) 1.43 (9H, s), 7.70 (2H, s), 8.39 (1H, s); Mass Spectrum [M+H]+=298.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9](O)=[O:10])[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1.[Cl-].[Na+].O.[Cl-].[NH4+].C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cccc(Br)n1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: OCCc1cccc(Br)n1
Reaction time: 2 h

Procedure:
A solution of (6-bromopyridin-2-yl)acetic acid (1.1 g, 5.09 mmol) in tetrahydrofuran (20 ml) was cooled to 0° C. Sodium borohydride (0.385 g, 10.18 mmol) was slowly added followed by the addition of boron trifluoride diethyl etherate (1.29 ml, 10.18 mmol). The reaction was allowed to come to room temperature. After 2 hrs, the reaction was diluted with brine, ammonium chloride and ethyl acetate. After layer separation, the organic layer was dried over sodium sulfate, filtered and concentrated. The crude residue was purification by silica gel chromatography (3:7 hexane:ethyl acetate) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:36][N:37]([CH3:52])[C:38]([C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39]>>[CH3:36][N:37]([CH3:52])[C:38]([C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:41][CH2:42][N:43]([CH2:29][CH2:28][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH2:44][CH2:45]1)=[O:39]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CN(C)C(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)N(C)C)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid dimethyl-amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[C:6]1[CH:10]=[CH:9]O[CH:7]=1)[CH2:2][CH2:3][CH3:4].BrC1C=C[S:22]C=1>>[CH2:1]([Sn:5]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[C:6]1[CH:10]=[CH:9][S:22][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Brc1ccsc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccoc1
Product: CCCC[Sn](CCCC)(CCCC)c1ccsc1

Procedure:
Using the method for the preparation of 3-tributylstannylfuran, 2.50 g (15.39 mmoles) of 3-bromothiophene gave 1.31 g (Y: 23%) of the title product. 1H NMR (CDCl3): δ7.46 (m, 1H), 7.34 (d, J=2.3 Hz, 1H), 7.16 (d, J=4.6 Hz, 1H), 1.52 (m, 6H), 0.132 (m, 6H), 1.05 (t, J=8.2 Hz, 6H), 0.89 (t, J=7.2 Hz, 9H). MS (DCI)m/e: 375 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([NH2:9])=[C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Cl)cc1Oc1ccccc1
Yield: 143.8 %

Procedure:
2-Fluoro-4-chloro-nitrobenzene (0.50 g), phenol (0.27 g) and potassium carbonate (0.40 g) in dry DMSO (10 ml) were stirred at RT for 2 h. The mixture was diluted with water, extracted with diethylether, dried and evaporated under reduced pressure to give a yellow oil (0.90 g). The oil was dissolved in glacial acetic acid (20 ml) and treated with reduced iron powder (0.90 g). The mixture was vigorously stirred at RT for 2 h, filtered through celite, washed with DCM and the filtrate evaporated under reduced pressure, yield 0.9 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Product: CC(C)(C)OC(=O)NCCCCCC(=O)Nc1ccc(Cl)c(C(=O)O)c1

Procedure:
For the preparation of the starting material [MS: 456 (1, M+H)], 6-(1-t-butyoxyformamido)hexanoic acid and 5-amino-2-chlorobenzoic acid are coupled to give 5-[6-(1-t-butoxyformamido)hexanamido]-2-chlorobenzoic acid, MS: 385 (2, M+H), the latter is coupled with β-alanine methyl ester to give N-[5-[6-(1-t-butoxyformamido)hexanamido]-2-chlorobenzoyl-β-alanine methyl ester, MS: 470 (14, M+H), and this is then saponified in methanolic sodium hydroxide solution.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[OH:23])=[N:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC.CN(C=O)C>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[O:23][CH3:24])=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(Cl)cnc(-c3cccc(Cl)c3O)c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc2c(Cl)cnc(-c3cccc(Cl)c3OC)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.3 %

Procedure:
A mixture of methyl 4-chloro-1-(3-chloro-2-hydroxyphenyl)isoquinoline-7-carboxylate (150 mg), potassium carbonate (119 mg), iodomethane (245 mg), and DMF (3 mL) was stirred at room temperature for one day. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and concentrated under reduced pressure. The resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 4-chloro-1-(3-chloro-2-methoxyphenyl)isoquinoline-7-carboxylate (130 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[C:14]=3[F:22])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.O>O1CCCC1.C(OCC)(=O)C>[NH2:19][C:15]1[C:14]([F:22])=[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:8][CH:9]=2)=[O:12])[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1cccc([N+](=O)[O-])c1F)c1c[nH]c2ncc(Br)cc12
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 60 °C
Yield: 46.7 %

Procedure:
To (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-nitro-phenyl)-methanone (18, 2.27 g, 6.23 mmol) in 200 mL of tetrahydrofuran and 200 mL of ethyl acetate, stannous chloride, dehydrate (4.85 g, 2.15 mmol) is added. The reaction is heated at 60° C. for 3 days, then 300 mL of water and 200 mL of ethyl acetate are added. The mixture is treated with celite and filtered. Brine is added, the organic layer is separated, dried over magnesium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (19, 972 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12]2[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)([O-:3])=[O:2].[CH2:21](O)[CH2:22][OH:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:22]1[O:23][CH:19]([C:18]2[C:12]3[NH:11][C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N+:1]([O-:3])=[O:2])=[N:14][C:13]=3[CH:15]=[CH:16][CH:17]=2)[O:20][CH2:21]1
Reactant: O=Cc1cccc2nc(-c3ccccc3[N+](=O)[O-])[nH]c12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1-c1nc2cccc(C3OCCO3)c2[nH]1
Temperature: 25 °C
Yield: 62.2 %

Procedure:
2-(2-Nitrophenyl)-benzimidazole-4-carboxaldehyde 4 (6.27 g, 23.5 mmol) was dissolved in benzene (150 mL), and mixed with ethylene glycol (6.5 mL, 118 mmol) and p-toluenesulfonic acid monohydrate (0.450 g, 2.35 mmol). The mixture was heated to reflux overnight and the water was removed by azeotropic distillation. The resulting solution was allowed to cool to room temperature, and was then neutralized with saturated NaHCO3, washed with water and brine and dried over Na2SO4. The compound was purified by column chromatography on silica gel using hexane/ethyl acetate (1:2) as the eluent to give 2-(2-nitrophenyl)-benzimidazole-4-carboxaldehyde ethylene acetal (4.552 g, 62.2%) as a yellow solid. Rf=0.24 (hexane/ethyl acetate=1:2); 1H NMR (200 MHz, CDCl3) δ 4.11 (m, 2H), 4.20 (m, 2H), 6.15 (s, 1H), 7.30 (m, 2H), 7.57-7.83 (m, 3H), 7.93 (d, J1=7.8 Hz, J2=1.3 Hz, 1H), 8.13 (d, J1=7.7 Hz, J2=1.5 Hz, 1H), 10.48 (broad s, 1H). HRMS: Calcd. for C16H13N3O4 311.0906, found 311.0915.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[H-].[Na+].[Cl:11][CH2:12][CH2:13][CH2:14]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:11][CH2:12][CH2:13][CH2:14][O:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: ClCCCI
Reactant: Cc1ccc(O)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCCCCl)cn1
Temperature: 25 °C
Yield: 134.5 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-hydroxy-2-methylpyridine (2.00 g, 18.3 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.825 g of an 80% dispersion in mineral oil, 27.5 mmol) in DMF (15 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. Next, 1-chloro-3-iodopropane (4.49 g, 22.0 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 4 h. Water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 4.57 g of an oil.