Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:38]([F:39])[C:30]=2[F:29])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: O=C(Cl)c1cccc(F)c1F
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4F)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 2,3-difluorobenzoyl chloride gave the title compound. ES-MS m/e (%): 539.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1)[C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1.[CH2:28](O)CC.S(=O)(=O)(O)O>O>[CH3:1][N:2]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH2:24][CH3:28])=[O:21])=[CH:16][CH:15]=1)[C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2nnc3cc(Cl)ccc3n2)cc1
Reactant: CCCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCOC(=O)C(C)Oc1ccc(N(C)c2nnc3cc(Cl)ccc3n2)cc1

Procedure:
A mixture of ethyl 2-{4-[N-methyl-N-(7-chloro-1,2,4-benzotriazin-3-yl)amino]phenoxy}propionate (80 g, compound No. 21, Example 7), n-propanol (800 ml) and concentrated sulfuric acid (3 ml) was heated under reflux for a period of 6 hours. A small volume of water was added and the mixture was concentrated. Dichloromethane was added and the mixture was washed first with dilute aqueous potassium carbonate solution and then with water. The organic phase was dried (over anhydrous magnesium sulfate) and the solvent was removed by distillation under reduced pressure to give the title compound (80 g) as a red oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[C:58]([F:66])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:63])[F:64])=[C:58]([F:66])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(C(F)(F)F)c(F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(C(F)(F)F)c(F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 106 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 16 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 138 mg light yellow solid (91%). MS (ISP) 497.4 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[CH:6]=[C:5]([CH2:11][NH:12][CH:13]=O)[N:4]=1.P(Cl)(Cl)(Cl)=O.O1CCOCC1.C(=O)(O)[O-].[Na+]>O>[CH3:1][S:2][C:3]1[N:4]2[CH:13]=[N:12][CH:11]=[C:5]2[CH:6]=[C:7]([S:9][CH3:10])[N:8]=1
Reactant: CSc1cc(CNC=O)nc(SC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CSc1cc2cncn2c(SC)n1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A mixture of 3.00 g (13.1 mmole) of 2,4-bis(methylthio)-6-formylaminomethylpyrimidine, 2.25 g (14.2 mmole) of phosphorous oxychloride and 50 ml of dioxane was stirred at 20° C. for 20 hours, then heated at reflux for 0.5 hour. The mixture was poured into 100 ml of water, neutralized with solid sodium bicarbonate and extracted with chloroform. The chloroform extracts were combined, washed with water and dried over magnesium sulfate. Evaporation of the solvent provided a light yellow solid, 5,7-bis(methylthio)imidazo[1,5-c]pyrimidine. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[C:12](=[O:15])([O-])[O-].[K+].[K+].C=O.Br[CH2:21][CH3:22]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:21]([O:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][OH:15])[CH3:22]
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: O=C([O-])[O-]
Reactant: CCBr
Agent: C=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1c(CO)c(C(F)(F)F)nn1C
Temperature: 25 °C
Yield: 83 %

Procedure:
In 100 ml of DMF were suspended 16.6 g (0.10 mole) of the 5-hydroxy-1-methyl-3-trifluoromethylpyrazole synthesized in Reference Example 1 and 20.9 g (0.15 mole) of potassium carbonate. In this suspension being stirred at room temperature was placed 4.5 g (0.15 mole) of paraformaldehyde, followed by stirring at the same temperature for 1 hour. Then, 41.8 g (0.30 mole) of potassium carbonate was added. Thereto was dropwise added 21.8 g (0.20 mole) of bromoethane. The reaction mixture was heated to 60° C. and stirred for 8 hours to give rise to a reaction. After the reaction, 200 ml of ethyl acetate and 200 ml of water were added. The organic layer, which appeared by phase separation, was separated. The aqueous layer was subjected to re-extraction with 50 ml of ethyl acetate. The two organic layers were combined and washed with 50 ml of water, 30 ml of a saturated aqueous ammonium chloride solution and 30 ml of a saturated aqueous sodium chloride solution in this order. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 22.5 g (purity: 82.7%, yield: 83.0%) of a crude solution of title compound. The crude solution was subjected to vacuum distillation to obtain a title compound as a colorless transparent solution.
Reaction SMILES: C(OCC)(=O)C.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]([N:18]([CH:27]([CH3:29])[CH3:28])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:17])=[C:10]([N+:30]([O-])=O)[CH:9]=1.[H][H]>[Pd].C(O)C>[NH2:30][C:10]1[CH:9]=[C:8]([F:7])[CH:13]=[CH:12][C:11]=1[NH:14][CH2:15][C:16]([N:18]([CH:27]([CH3:29])[CH3:28])[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)=[O:17]
Reactant: COc1ccc(N(C(=O)CNc2ccc(F)cc2[N+](=O)[O-])C(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(N(C(=O)CNc2ccc(F)cc2N)C(C)C)cc1
Yield: 83.3 %

Procedure:
A solution of 30 mL ethyl acetate, 175 mL ethanol, and 2.50 g of 2-(4-Fluoro-2-nitrophenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (6.92 mmol) was combined with 0.25 g of palladium on carbon (10 wt %) and hydrogenated under a hydrogen balloon over 16 hrs. The reaction mixture was filtered and evaporated in vacuo to provide 1.91 g of the title compound as a solid. 1H NMR (300 MHz, CDCl3) d 7.03 (m, 2H), 6.94 (m, 2H), 6.36 (m, 3H), 4.99 (m, 1H), 4.37 (b, 3H), 3.86 (s, 3H), 3.39 (s, 2H), 1.07 (d, 6H, J=6.8); low resolution MS (FAB)m/e 332 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:14]=[N:13][S:12][N:11]=2)=[C:6]([CH:9]=1)[CH:7]=O.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:14]=[N:13][S:12][N:11]=2)=[C:6]([CH:9]=1)[CH2:7][NH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1
Reactant: O=Cc1cc(Cl)ccc1-c1cnsn1
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNCc2cc(Cl)ccc2-c2cnsn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 5-chloro-2-(1,2,5-thiadiazol-3-yl)benzaldehyde (0.155 g, 0.69 mmol), 4-methoxybenzylamine (0.09 mL, 0.69 mmol) and acetic acid (0.05 mL, 0.83 mmol) in 1,2-dichloroethane (5.2 mL) was added sodium triacetoxyborohydride (0.731 g, 3.45 mmol). The solution was stirred at ambient temperature for 16 h then partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic phase was dried (Na2SO4) and reduced in vacuo. The residue was purified by automated preparative chromatography on silica (eluting with 5% CH2Cl2/EtOAc/hexanes gradient, 5–50% EtOAc). N-[5-Chloro-2-(1,2,5-thiadiazol-3-yl)benzyl]-N-(4-methoxybenzyl)amine was isolated as an oil. 1H NMR (CDCl3, 400 MHz) δ 3.74 (s, 2H), 3.81 (s, 3H), 3.82 (s, 2H), 6.86 (d, J=8.6 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 8.84 (s,1H); MS m/z=346.5.
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:19][CH3:20])=[C:12]2[C:17]=1[O:16][CH2:15][CH:14]([OH:18])[CH2:13]2.C(OC(=O)C)(=O)C>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:19][CH3:20])=[C:12]2[C:17]=1[O:16][CH2:15][C:14](=[O:18])[CH2:13]2
Reactant: COc1ccc(Br)c2c1CC(O)CO2
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(Br)c2c1CC(=O)CO2
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
To a solution consisting of dry pyridine and CH2Cl2 (120 ml, dried over P2O5) CrO3 (435 mg, 4.35 mmol) was added. The mixture was stirred for 15 min and 8-bromo-5-methoxy-3-chromanol (293 mg, 1.13 mmol) was dissolved in 10 ml dry CH2Cl2 was added and immediately thereafter acetic acid anhydride (0.41 ml, 4.35 mmol) was added to the solution. The mixture was stirred for 10 min and then sucked through a short silica column (13 g SiO2) with vacuum. The column was washed with CH2Cl2 and the solvent evaporated yielding 237 mg (81%) of the product. An analytic sample was obtained from recrystallization in light petroleum-ether, m.p. 97°-100° C. 1H NMR (CHCl3) δ 3.55 (s,2H), 3.80 (s,3H), 4.45 (s,2H), 6.5 (d,1H), 7.4 (d,1H). GC/M (HP-5970A) m/e=258 (64) M+1, 256 (57) M-1, 134 (100), 50 (11), 76 (11).
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1.[C:25]([O-])(=[O:27])C.[Na+]>O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:16]([CH:25]=[O:27])=[CH:17][C:18]=1[CH:4]=[O:5]
Reactant: CN(C)C=O
Reactant: COc1cccc(N2CCOCC2)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cc(N2CCOCC2)c(C=O)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DMF (10 mL) was treated dropwise with phosphorus oxychloride (1.3 g, 14 mmol). The reaction was kept at 25° C. bycooling on ice. The reaction mixture was treated with 4-(3-methoxyphenyl)-morpholine (2.5 g, 13 mmol) in small portions, stirred for 30 min at room temperature, then stirred at 100° C. for 4 h. After cooling, the mixture was poured into aqueous sodium acetate (1 M, 40 mL) and 25 mL of water was added. The resulting precipitate was collected by filtration, washed with water (10 mL), air dried, and purified by flash chromatography (silica gel, 4×15 cm, eluted with 80/20 CHCl3/ether) to yield A and B as white solids: A: (1.0 g, 35%), B: (0.3 g, 9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:10][C:3]=12.[C:16]1([C:22](=[C:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:23]#[N:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:15])[C:12]([N:28]3[CH2:27][CH2:26][C:25](=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:23]#[N:24])[CH2:30][CH2:29]3)=[O:14])=[CH:9][NH:10][C:3]=12
Reactant: O=C(O)C(=O)c1c[nH]c2c(Cl)ccnc12
Reactant: N#CC(=C1CCNCC1)c1ccccc1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(Cl)ccnc23)CC1)c1ccccc1
Reaction time: 20 h
Yield: 11 %

Procedure:
To a solution of (7-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-oxo-acetic acid (1.5 g, 6.7 mmol) and phenylpiperidine-4-ylidene acetonitrile (1.3 g, 6.7 mmol) in DMF (50 mL) was added DEPBT (3.15 g, 10.5 mmol) and ethyl diisopropylamine (6.1 mL, 35 mmol). The solution was stirred 20 h, concentrated under vacuum and partitioned between 5% Na2CO3(aq) (80 mL) and EtOAc (5×100 mL). The combine organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by Biotage Chromatography (SiO2, 30% EtOAc/Hex to 100% EtOAc) and by preparative HPLC to yield the title compound (300 mg, 0.74 mmol, 11%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][C:20](C2C=CC=CC=2)(C2C=CC=CC=2)[C:21]2[CH:26]=CC=CC=2)=[CH:17][CH:18]=1)[C:5]([OH:15])([C:10]#[C:11][CH:12]1[CH2:14][CH2:13]1)[C:6]([F:9])([F:8])[F:7].N1C=CC=CC=1.BrC(C)C(Br)=[O:48]>CCOCC>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[NH:19][C:20](=[O:48])[C@H:21]([CH3:26])[O:15][C@:5](/[CH:10]=[CH:11]/[CH:12]3[CH2:14][CH2:13]3)([C:6]([F:9])([F:8])[F:7])[C:4]=2[CH:3]=1
Reactant: OC(C#CC1CC1)(c1cc(Cl)ccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F
Reactant: CC(Br)C(=O)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: C[C@@H]1O[C@](/C=C/C2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred ice-cooled solution of 987 mg of trans-6-amino-3-chloro-α-cyclopropyletheayl-α-(trifluoromethyl)benzyl alcohol (from Example 5, Part B) in 50 mL of dry ether was added 0.350 mL of dry pyridine aid 1.66 g of α-bromopropionyl bromide. The cooling bath was removed and then after 30 min at ambient temperature, the reacation mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residte was dissolved in 50 mL of dry DMF, 2.35 g of lithium iodide and 2.3 g of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature for 3 days. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to crude product. The title compound was obtained by crystallization from ethyl acetate/hexanes, and recrystallization from ethyl acetate afforded 650 mg of pure title corpound: mp 171-172°; HRMS: Calcd. for C16H168NO2F3Cl (M+H)+ : 346.082166. Found: 346.080681: mp 147-147.5°; HRMS: Calcd. for C17H18NO2F3Cl (M+H)+ : 360.097816. Found: 360.097869
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][S:13][C:14]3[N:15]([CH3:24])[C:16](=[O:23])[C:17]4[S:22][CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][N:3]=1.[N:29]1([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>N1C=CC=CC=1>[ClH:1].[CH3:24][N:15]1[C:16](=[O:23])[C:17]2[S:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:14]1[S:13][CH2:12][C:11]1[CH:25]=[CH:26][C:8]([C:6](=[O:7])[C:5]2[CH:27]=[CH:28][C:2]([N:38]3[CH2:39][CH2:40][CH:35]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:36][CH2:37]3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)nc3)cc2)nc2ccsc2c1=O
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: c1ccncc1
Product: Cl
Product: Cn1c(SCc2ccc(C(=O)c3ccc(N4CCC(N5CCCCC5)CC4)nc3)cc2)nc2ccsc2c1=O
Yield: 62.7 %

Procedure:
A solution of 2-[4-(6-chloronicotinoyl]benzylthio]-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (427 mg) and 4-piperidinopiperidine (202 mg) in pyridine (10 ml) was stirred at 80° C. for 10 hours. This reaction mixture was concentrated, the residue was dissolved in chloroform, and the solution was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia=50:1:0.1) and treated with HCl/ethyl acetate for conversion to hydrochloride to provide the title compound as colorless solid (373 mg).
Reaction SMILES: OC1C=C(O)C=CC=1[CH:9]([C:16]([CH:18]([C:25]1[CH:30]=[CH:29]C(O)=CC=1O)C1C=CC=CC=1)=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CC[O:36]CC1.[CH2:39]([O:41][CH:42]([O-])[O-])[CH3:40]>CN(C)C=O>[OH:36][C:29]1[CH:40]=[C:39]2[C:18]([C:16](=[O:17])[C:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:42][O:41]2)=[CH:25][CH:30]=1
Reactant: O=C(C(c1ccccc1)c1ccc(O)cc1O)C(c1ccccc1)c1ccc(O)cc1O
Reactant: C1COCCN1
Reactant: CCOC([O-])[O-]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Yield: 91.9 %

Procedure:
50 g (0.219 mole) of a mixture of 2,4-dihydroxy-phenyl-benzyl-ketone, 20 ml of dimethyl-formamide, 2.6 ml of morpholine and 39.06 g (0.26 mole) of ethyl-orthoformate is stirred for 7 hours at 80°-90° C. After 25 minutes crystallization can be observed. At the end of the reaction time the crystallized suspension is diluted with 120 ml of chloroform and it is crystallized at 0° C. for 2 hours. After filtration the product is covered twice with 45 ml of chloroform and dried. 47.9 g of 7-hydroxy-isoflavone are obtained.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6]([OH:8])=[O:7].C1CCC(NC2CCCCC2)CC1.S(=O)(=O)(O)O.[F:35][C:36]1[C:41](O)=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.O1CCOCC1.CCOCC>[F:35][C:36]1[C:41]([O:7][C:6](=[O:8])[C@H:5]([CH2:4][CH2:3][CH2:2][CH3:1])[NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46]
Reactant: CCCCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
10.0g (24.3 mmoles) of BOC--Nle--OH.DCHA are added to a mixture of 75 ml of ether and 25 ml of 2 n aqueous sulfuric acid, and the mixture is shaken until the dissolution is complete. The phases are separated, and the etheral solution is washed again with 25 ml of 2 n aqueous sulfuric acid and water. The etheral solution is evaporated in vacuo. The resulting 5.44 g of oily residue and 4.42 g (24 mmoles) of pentafluorophenol are dissolved in 30 ml of ethyl acetate, the solution is cooled to 0° C., and 4.63 g (22.5 mmoles) of dicyclohexyl carbodiimide are added. The suspension is allowed to stand at a cold place for 1 hour, thereafter it is filtered, and the filtrate is evaporated in vacuo. The residue is dissolved in 50 ml of n-hexane and the solution is washed with 5×20 ml of 5% aqueous sodium bicarbonate solution and 2×20 ml of water. The organic solution is dried and evaporated in vacuo. The oily residue solidifies upon cooling. 8.12 g (91%) of BOC--Nle--OPFP are obtained; m.p.: 55°-57° C., [α]D : -26.8° (c=1.0, in dioxane), Rf2 =0.80Rf4 =0.85.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][OH:9])[CH:5]=[CH:4][N:3]=[N:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[N:2]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCn1ccnn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCn1ccnn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
3-(1,2,3-triazol-1-yl)propanol (2.5 g, 19.66 mmol) was dissolved in dichloromethane (50 mL), and the solution was cooled to 0° C. Then, triethylamine (5.53 mL, 39.32 mmol) and methane sulfonyl chloride (2.3 mL, 29.5 mmol) were added thereto. The reaction mixture was warmed to room temperature, stirred for 2 hours, extracted with dichloromethane and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the title compound (3.01 g, 75%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19](=[O:28])[NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C:19](=[O:28])[NH:20][CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76.4 %

Procedure:
Dissolve oxalyl chloride (18.4 mL, 211 mmol) in CH2Cl2 (1000 mL), cool below −70° C., and add DMSO (18.0 mL, 253 mmol) via syringe pump over 30 min. Stir for 45 min, and then add portionwise a suspension of trans-(4-hydroxy-cyclohexyl)-carbamic acid benzyl ester (35.00 g, 140 mmol) in CH2Cl2 (1000 mL), while maintaining the temperature below −70° C. Add the suspension by removing a stopper from the reaction flask and quickly pouring in as much of the suspension as possible while keeping the temperature below −70° C., resulting in a slightly turbid solution upon complete addition. Stir the reaction for 90 min, then add triethylamine (97.8 mL, 702 mmol) slowly via syringe. Stir for another hour, and allow the reaction to slowly warm to room temperature overnight. Wash sequentially with water (1500 mL), brine (2×1500 mL), and saturated aqueous NaHCO3 (2×1500 mL). Separate the organic portion and dry (MgSO4), filter, and concentrate under reduced pressure. Triturate the crude residue twice with 4:1 Hexane/EtOAc (500 mL, then 250 mL). (Alternatively, triturate with 15% EtOAc/Hexane. Then only one trituration is required.) Filter and collect the solids and dry at 35° C. in a vacuum oven to obtain 26.44 g of the product. Combine the filtrates of the triturations and concentrate under reduced pressure, followed by trituration of the residue in 9:1 hexane/EtOAc (100 mL) to afford a second crop of 5.70 g, for a combined yield of 32.14 g (93%). ESI MS: m/z 248 [C14H17NO3+H]+; 1H NMR (300 MHz, CDCl3): δ 1.63-1.78 (m, 2H), 2.22-2.27 (m, 2H), 2.32-2.49 (m, 4H), 3.95-4.04 (m, 1H), 4.75 (br s, 1H), 5.11 (s, 2H), 7.29-7.42 (m, 5H)