Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][N+:14]#[C-:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CS(C)=O>[CH2:30]([O:29][C:27]([C:22]1([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:13]([N+:14]#[C-:15])([S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:28])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOC(=O)C1(CCCCCBr)CCCC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: [C-]#[N+]C(CCCCCC1(C(=O)OCCCC)CCCC1)(CCCCCC1(C(=O)OCCCC)CCCC1)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
Under a N2 atmosphere, NaH (60% (%) in mineral oil, 7.55 g, 189 mmol) was added portion wise to a solution of TosMIC (12.48 g, 62.6 mmol) and Bu4NI (2.56 g, 6.93 mmol) in dry DMSO (200 mL) while stirring vigorously and cooling with a water bath. After 30 min, butyl 1-(5-bromo-pentyl)-cyclopentanecarboxylate (44.46 g, >90% pure by GC, 125 mmol) was added drop wise to the mixture in 20 min and after 1 h of stirring, another portion of NaH (60% (%) in mineral oil, 1.20 g, 30.0 mmol) was added. After 1 h, the reaction mixture was slowly poured into ice-cold H2O (500 mL) and the resulting mixture was extracted with Et2O (3×250 mL). The combined organic layers were washed with aqueous NaCl (10%, 250 mL) and brine (2×200 mL), dried (Na2SO4) and filtered through a layer of silica (150 g). The residue was washed with Et2O (250 mL) and the combined filtrate and washings were evaporated in vacuo. The remaining oil was purified by column chromatography (silica, heptane:EtOAc=8:1) to give butyl 1-{11-[1-(butoxycarbonyl)cyclopentyl]-6-isocyano-6-[(4-methylphenyl)sulfonyl]undecyl}-1-cyclopentanecarboxylate as a yellow oil (32.79 g). This oil (32.79 g) was dissolved in CH2Cl2 (400 mL), and cont aqueous HCl (150 mL) was added. After stirring vigorously for 4.5 h, H2O (500 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×100 mL) and the combined organic layers were washed with saturated H2O (200 mL), saturated aqueous NaHCO3 (500 mL) and brine (500 mL), dried (Na2SO4) and evaporated in vacuo. The remaining residue was purified by column chromatography (silica, heptane:EtOAc=6:1) to give butyl 1-{11-[1-(butoxycarbonyl)cyclopentyl]-6-oxoundecyl}-1-cyclopentanecarboxylate (24.11 g, 90% pure by 1H NMR, 69%) as a slightly yellow liquid. 1H NMR (CDCl3): δ=4.06 (t, J=6.6 Hz, 4H), 2.36 (t, J=7.4 Hz, 4H), 2.15-2.06 (m, 4H), 1.65-1.52 (m, 20H), 1.49-1.32 (m, 8H), 1.27-1.19 (m, 8H), 0.94 (t, J=7.4 Hz, 6H). 13C NMR (CDCl3): δ=210.9, 177.6 (2×), 63.8 (2×), 54.0 (2×), 42.5 (2×), 38.9 (2×), 35.8 (4×), 30.6 (2×), 29.5 (2×), 25.6 (2×), 24.7 (4×), 23.4 (2×), 19.0 (2×), 13.5 (2×). HRMS calcd for C31H54O5 (M+): 506.3971. found: 506.3981.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([OH:29])=O)=[CH:17][CH:16]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[NH2:30][C:31]1[NH:35][N:34]=[N:33][N:32]=1>>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([NH:30][C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[O:29])=[CH:17][CH:16]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1nnn[nH]1
Reactant: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2ccccc2C(=O)Nc2nnn[nH]2)cc1

Procedure:
2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5-(methoxymethyl)imidazole (1.0 g) was first converted to the corresponding acid chloride and then coupled to 5-aminotetrazole by the procedure in Example 78, Part C to yield 0.87 g of a yellow glass. Flash chromatography in 100% ethyl acetate over silica gel yielded 77.1 mg of a white solid; m.p. 169°-173°. NMR (200 MHz, CDCl3, DMSO-d6)δ12.0 (br s, 1H); 7.73-7.30 (m, 6H); 7.00 (d, 2H, J=7 Hz); 5.18 (s, 2H); 4.23 (s, 2H); 2.55 (t, 2H, J=7 Hz) 1.63 (t of t, 2H, J=7,7 Hz); 1.31 (t of q, 2H, J=7,7 Hz); 0.84 (t, 3H, J=7 Hz). Anal. Calcd. for C24H26ClN7O2 · (H2O)2 : C, 55.87; H, 5.86. Found: C, 56.01; H, 6.01.
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12]([NH:15][CH2:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:8]([CH3:19])([CH3:18])[CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=1.CCOCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:14]2[CH:13]=[C:12]([N:15]([CH2:16][CH3:17])[C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=3)[CH:11]=[CH:10][C:9]=2[C:8]([CH3:18])([CH3:19])[CH2:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCNc1ccc2c(c1)C(C(C)(C)C)=CCC2(C)C
Reactant: O=C(O)c1ccc(F)nc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN(c1ccc2c(c1)C(C(C)(C)C)=CCC2(C)C)c1ccc(C(=O)O)cn1
Temperature: 125 °C
Yield: 8.6 %

Procedure:
To a mixture of 85 mg (0.37 mmol) of (8-t-butyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethyl-amine (Compound 169) and 0.11 g (0.78 mmol) of 6-fluoro-nicotinic acid was added a small amount of ether and toluene to help stirring. The resulting mixture was heated at 100-150° C. for 1 h. The mixture was cooled. The product was purified by flash chromatography (silica, 50% ethyl acetate in hexanes to give the title compound as a white solid (12 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:13](=[O:14])[CH2:12][CH2:11][N:10]([C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:9][CH2:8]1.[I-:27].[Na+]>>[Cl:25][C:20]1[CH:19]=[C:18](/[CH:17]=[CH:16]/[C:15]([N:10]2[CH2:11][CH2:12][C:13](=[O:14])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:27])[CH2:8][CH2:9]2)=[O:26])[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: [I-]
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCCCl)CC1
Agent: [Na+]
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCCI)CC1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
In analogy to the procedure described in example 6D, 4-(5-chloro-pentyl)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one and sodium iodide were stirred at 90° C. for 20 h to give the title compound as orange oil. MS: 509.2 (MH+, 2Cl).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=O)[CH2:6][C:7]([O:9][CH3:10])=[O:8].CO.C([O-])=O.[NH4+].[BH3-]C#[N:21].[Na+]>Cl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]([NH2:21])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: [BH3-]C#N
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CC(N)CC(=O)OC
Yield: 75.1 %

Procedure:
Dimethyl-3-oxoglutarate (10 g, 57 mmol) was added to methanol (225 ml) followed by ammonium formate (36 g, 570 mmol) and NaBH3CN (3.7 g, 57 mmol) at 25° C. After 24 hours the methanol was removed in vacuo to leave a white mass. Methylene chloride was added and the mixture filtered. The methylene chloride was evaporated resulting in an oil which was dissolved in 1N HCl (200 ml) and extracted with ether (100 ml). The ether layer was discarded and the aqueous layer was made basic using solid K2CO3. The product was extracted into methylene chloride dried over Na2SO4 and evaporated to give dimethyl-3-aminoglutarate (7.5 g). 1H NMR (d6 -DMSO) δ 1.76 (bs, 2H), 2.45 (dd, 4H, J=8.08 Hz, 16.64 Hz), 3.69 (s, 6H), 5.45 (m, 1H); MS (FAB) m/e 176.0 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C@@H:6]1[C@H:11]2[CH2:12][CH2:13][N:8]([CH2:9][C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>CCO>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4]([C@@H:6]1[C@H:11]2[CH2:12][CH2:13][N:8]([C:9](=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:16]
Reactant: O=Cc1ccccc1
Reactant: CCN(CC)C(=O)[C@H]1CN2CC[C@H]1C(=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)C(=O)[C@H]1CN2CC[C@H]1C(=O)C2=Cc1ccccc1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A mixture of 13 (34.6 g, 154 mmole), benzaldehyde (17.4 g, 164 mmole) and NaOH (6.5 g, 164 mmole) in EtOH (400 ml) was refluxed for 3 hours. After cooling the reaction mixture to room temperature, the resulting yellow crystal was collected by filtration and washed with cold EtOH and dried in vacuo to give 14 (38.4 g, 128 mmole). The filtrate was concentrated under reduced pressure to give a second crop (3.3 g, 11 mmole) (total 41.7 g, 139 mmole, 90%).
Reaction SMILES: [OH:1][CH:2]([CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH2:3][N:4]=[N+]=[N-].[H][H]>[OH-].[OH-].[Pd+2]>[OH:1][CH:2]([CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH2:3][NH2:4]
Reactant: [N-]=[N+]=NCC(O)CN1CCOCC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Product: NCC(O)CN1CCOCC1
Yield: 84.4 %

Procedure:
A methanolic solution of 81 (11 g, 59.14 mmol), was shaken with 20% palladium hydroxide on Carbon (2 g) under 40 psi pressure of hydrogen for 20 hours. The mixture was filtered through celite and the filter cake was thoroughly washed with methanol and dichloromethane. The solvent was removed under vacuum to give 82 (8 g, 93%) as a light yellow oil; 1H NMR (300 MHz, CDCl3) δ3.8-3.6 (m, 4H), 3.42 (m, 1H), 2.8 (br d, 1H), 2.7-2.55 (m, 2H), 2.55-2.2 (m, 6H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]>[OH-].[Na+].O1CCOCC1>[CH2:16]([O:15][C:13]([NH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)Cl
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CCOC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 34.2 g (217.5 mmol) of trans 4aminomethylcyclohexanecarboxylic acid (Aldrich) in 217 mL of 2M aq. NaOH and 217 mL of dioxane was cooled to 15° C. To this solution was added 25 mL (235 mmol) of allyl chloroformate (Aldrich) in a slow stream. After the addition, the cold bath was removed, and the solution was stirred overnight at ambient temperature. The reaction mixture was poured slowly into a rapidly stirred mixture of 1L of 1M aq. citric acid and ice. The resulting mixture was stirred for 0.5 h and the precipitate collected by filtration, washed with water, and dried to a constant weight of 49.3 g (94%) of the title compound as a colorless solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[C:10](=[O:29])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:28])[NH:24][CH:25]3[CH2:27][CH2:26]3)=[CH:19][CH:18]=2)[N:16]=1)=[O:4].[Li+].[OH-].CC(O)=O>C1COCC1.CO.O>[CH:25]1([NH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:15]3[N:16]=[C:12]([NH:11][C:10]([C@H:6]4[CH2:7][CH2:8][CH2:9][C@H:5]4[C:3]([OH:4])=[O:2])=[O:29])[S:13][CH:14]=3)=[CH:18][CH:19]=2)=[O:28])[CH2:26][CH2:27]1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1C(=O)Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@H]3CCC[C@H]3C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Rac-cis-2-[4-(4-Cyclopropylcarbamoyl-phenyl)-thiazol-2-ylcarbamoyl]-cyclopentanecarboxylic acid methyl ester (100 mg) was dissolved in THF:MeOH:H2O (2:2:1, 5 mL) and treated with LiOH (10 eq. 45 mg) and stirred at room temperature for 15 hours. The mixture was neutralized with HOAc, and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the product. MS: 400.5 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([OH:9])=O)=[N:4][O:5][N:6]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:14]([C:13]1[CH:12]=[C:11]([NH:10][C:7]([C:3]2[C:2]([CH3:1])=[N:6][O:5][N:4]=2)=[O:9])[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: Cc1nonc1C(=O)O
Reactant: N#Cc1cccc(N)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nonc1C(=O)Nc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
4-Methyl-1,2,5-oxadiazole-3-carboxylic acid (200 mg, 1.6 mmol) and bromotris(pyrrolydino)phophonium hexafluorophosphate was dissolved in a 1/1 mixture of DMF/DCM. To the mixture was added DMAP (120 mg, 0.95 mmol) and 3-amino-benzonitrile (184 mg, 1.6 mol) followed by N,N-diisopropylethylamine. The reaction mixture was stirred at rt overnight. The volatiles were removed in vacuo and the residue dissolved with chloroform and loaded onto a 40 g Silica ISCO cartridge eluting with 25%-50% EtOAc/Hexane to afford a white powder (25 mg). MF=C11H8N4O2; LCMS calculated for C11H9N4O2(M+H)+: m/z=229.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[S:24](Cl)(=[O:26])=[O:25]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:24]([C:17]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=2[F:15])(=[O:25])=[O:26])[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c(F)c1
Reactant: Nc1cncc(Br)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Nc2cncc(Br)c2)c(F)c1
Yield: 75.9 %

Procedure:
5-Bromopyridin-3-amine (500 mg, 2.89 mmol) was dissolved in dichloromethane (14 ml) and pyridine (4 ml) was added. To this mixture 2-fluoro-4-methoxybenzene-1-sulfonyl chloride (1 g, 4.45 mmol) was added dropwise and the mixture stirred at reflux for 5 h. Once at room temperature, the reaction mixture was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography (0% to 50% DCM/AcOEt) to give 792 mg (76% yield) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15](O)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[F:59][C:60]([F:69])([F:68])[CH:61]1[CH2:66][CH:65]([NH2:67])[CH2:64][CH2:63][NH:62]1>CN(C=O)C.C(#N)C.O>[F:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([NH:67][CH:65]3[CH2:64][CH2:63][NH:62][CH:61]([C:60]([F:69])([F:59])[F:68])[CH2:66]3)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Reactant: NC1CCNC(C(F)(F)F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NC3CCNC(C(F)(F)F)C3)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.7 %

Procedure:
A mixture of 57 mg 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (0.171 mmol) from Example 4A, 72 mg of HATU (0.188 mmol) and 0.179 ml (1.025 mmol) of N,N-diisopropylethylamine in 1.1 ml of DMF was stirred at RT for 20 min. Subsequently, 42 mg (0.205 mmol) of 2-(trifluoromethyl)piperidine-4-amine hydrochloride (Example 36A) were added and the mixture was stirred at RT overnight. The reaction mixture was admixed with water and acetonitrile and purified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.05% formic acid). 22 mg of the target compound were obtained (27% of theory).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:29])[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:19][N:20]([CH3:29])[C:21]([N:23]1[CH2:24][CH2:25][N:26]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]=3[CH:10]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CN(C)C(=O)N1CCNCC1
Product: CN(C)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde (General Procedure D-2) and piperazine-1-carboxylic acid dimethylamide using General Procedure B-3 yielded 4-(2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid dimethylamide.
Reaction SMILES: C(O[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1)=[O:5])C.O.[OH-].[Li+].C(N(CC)CC)C.Cl.[CH3:33][NH:34][O:35][CH3:36].CCN=C=NCCCN(C)C.Cl>C(O)C.O.C(Cl)Cl>[CH3:36][O:35][N:34]([CH3:33])[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1)=[O:5]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1c1c[nH]c2ccc(C#N)cc12
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)[C@@H]1CCC[C@H]1c1c[nH]c2ccc(C#N)cc12
Reaction time: 2 h
Yield: 41.3 %

Procedure:
A solution of cis-2-(5-cyano-1H-indol-3-yl)-cyclopentanecarboxylic acid ethyl ester (1.06 g, 3.75 mMol) and lithium hydroxide monohydrate (1.54 g, 37.5 mMol) in ethanol (50 mL) and water (10 mL) was heated to reflux for 3 h. The solution was concentrated in vacuo, and the residue was dissolved in water (20 mL) and HCl was added to pH<2. The reaction was extracted with ethyl acetate (4×10 mL), dried with magnesium sulfate, and evaporated in vacuo. The residue was suspended in methylene chloride with triethylamine (2.62 mL, 18.8 mMol). To this was added N,O-dimethylhydroxylamine hydrochloride (733 mg, 7.5 mMol) and EDC hydrochloride (1.58 g, 8.26 mMol) and the reaction was stirred for 2 h. Water (20 mL) was added and the reaction was extracted with methylene chloride (10 mL). The organic layers were dried with magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel with ethyl acetate/hexanes (60%) to provide the product as a clear oil (460 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 8.36 (1H, bs), 8.01 (1H, s), 7.28–7.41 (2H, m), 7.13 (1H, d, J=1.9 Hz), 3.74 (1H, m), 3.38 (3H, s), 3.38 (1H, buried), 3.11 (3H, s), 1.84–2.32 (5H, m), 1.37 (1H, sextet, J=7.6 Hz); MS m/e 320.2 (M+Na).
Reaction SMILES: F[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.O.[ClH:32]>CS(C)=O.CO.C(OCC)C>[ClH:32].[N:15]1([S:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:3][CH:4]=2)(=[O:14])=[O:13])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: C1CNCCN1
Reactant: O=S(=O)(c1ccc(F)c2ccccc12)N1CCCc2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: O=S(=O)(c1ccc(N2CCNCC2)c2ccccc12)N1CCCc2ccccc21
Yield: 83 %

Procedure:
The final product was prepared according to Method F: A stirred solution of 1-[(4-fluoro-1-naphthyl)sulfonyl]-1,2,3,4-tetrahydroquinoline (50 mg, 0.15 mmol) and piperazine (80 mg, 0.9 mmol) in DMSO (1 ml) was heated at 95° C. over night. The reaction mixture was allowed to reach room temperature and was subsequently added dropwise into water. The formed solid was isolated, re-dissolved in MeOH and treated with an excess of 1M HCl in diethyl ether. Removal of the solvents in vacuo afforded the title compound (60 mg, 83%) as a white solid. 1H NMR (DMSO) δ 9.17 (br s, 2H), 8.23–8.06 (m, 3H), 7.61–7.55 (m, 1H), 7.48–7.38 (m, 2H), 7.29–7.23 (m, 1H), 7.19–7.12 (m, 1H), 7.09–6.98 (m, 2H), 3.78–3.71 (m, 2H), 3.44–3.30 (m, 8H), 2.42–2.32 (m, 2H), 1.57–1.48 (m, 2H); MS m/z (M+1) 408.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](OCC)=[O:24])[N:20]=[C:19]([C:28](OCC)=[O:29])[CH:18]=1)(=[O:12])=[O:11])([O-:3])=[O:2].[BH4-].[Na+].[Cl-].[Cl-].[Ca+2].O>C(O)C>[OH:24][CH2:23][C:21]1[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:13][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])[CH:18]=[C:19]([CH2:28][OH:29])[N:20]=1
Reactant: CCOC(=O)c1cc(OCCNS(=O)(=O)c2ccccc2[N+](=O)[O-])cc(C(=O)OCC)n1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCOc1cc(CO)nc(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a solution of 1.3 g of diethyl 4-[2-(2-nitro-benzenesulfonylamino)-ethoxy]-pyridine-2,6-dicarboxylate in 200 mL of ethanol was successively added 315 mg of sodium borohydride and 941 mg of CaCl2. The mixture was stirred for 1 hour 30 minutes at room temperature and 50 ml of water were then added thereto. The ethanol was removed under reduced pressure and 50 ml of water were added to the residue obtained; the aqueous phase was extracted 3× with EtOAc. The organic phases were combined, washed with saturated NaCl solution, dried over MgSO4 and concentrated under reduced pressure. 1.06 g of N-[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-2-nitro-benzenesulfonamide were obtained. LC/MS (A): tr=0.57 min; [M+H]+: m/z 384.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[C:5]([F:19])[CH:6]=[CH:7][C:8]=2[F:18])[C:3]1=[O:20].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[F:18][C:8]1[CH:7]=[CH:6][C:5]([F:19])=[C:4]2[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:11][N:2]([NH:1][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]2=[O:20]
Reactant: Nn1nc(-c2ccccn2)c2c(F)ccc(F)c2c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(Nn1nc(-c2ccccn2)c2c(F)ccc(F)c2c1=O)c1ccccc1

Procedure:
The product of part C, 2-amino-5,8-difluoro-4-(2-pyridyl)-(2H)-1-phthalazinone (0.01 mol) is stirred overnight with benzoylchloride in dichloromethane at room temperature. The product is recrystallized to yield the title compound (R1=benzyl, Y1=—NH—C(O), R2=2-pyridyl, A=benzene, R3=F, F, m=2, p=0).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](O)[CH2:6][CH2:5]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]=[CH:5]2
Reactant: OC1CCc2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Brc1ccc2c(c1)C=CC2
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of 5-bromoindan-1-ol (5.00 g, 23.5 mmol) and p-Toluenesulfonic acid monohydrate (100 mg, 0.5 mmol) in benzene (150.00 mL) was heated to reflux for 2 h and water was continuously removed from the reaction mixture with a Dean-Stark trap. After cooling to room temperature, the benzene solution was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the residue by flash chromatography (hexane) yielded pure 5-bromoindene (4.0 g, 87%).