Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(C)C=C(C)C=1S(ON)(=O)=O.FC(F)(F)C(OC(C(F)(F)F)C(F)(F)F)C(F)(F)F.[Na].[F:35][C:36]([F:45])([F:44])[CH:37]([O:42][NH2:43])[C:38]([F:41])([F:40])[F:39].Cl.[Cl:47][C:48]1[CH:60]=[C:59]([O:61][CH2:62][CH:63]=[C:64]([Cl:66])[Cl:65])[CH:58]=[C:57]([Cl:67])[C:49]=1[O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH:55]=O>C(OCC)C>[F:35][C:36]([F:44])([F:45])[CH:37]([O:42][N:43]=[CH:55][CH2:54][CH2:53][CH2:52][CH2:51][O:50][C:49]1[C:57]([Cl:67])=[CH:58][C:59]([O:61][CH2:62][CH:63]=[C:64]([Cl:66])[Cl:65])=[CH:60][C:48]=1[Cl:47])[C:38]([F:40])([F:39])[F:41]
Reactant: O=CCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: NOC(C(F)(F)F)C(F)(F)F
Agent: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: Cl
Agent: FC(F)(F)C(OC(C(F)(F)F)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: FC(F)(F)C(ON=CCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(F)(F)F
Yield: 50 %

Procedure:
To a mixture of 1.29 g of O-(2,4,6-trimethylbenzenesulfonyl)hydroxylamine (which had been produced according to the method as described in Synthesis, 1-17 (1977)) and 10 ml of diethyl ether was added 1.14 g of sodium 1,1,1,3,3,3-hexafluoro-2-propyloxide with stirring under ice cooling, and the mixture was stirred for 2 hours. The suspended reaction mixture was filtered through Celite to give a filtrate which was a solution of O-(1,1,1, 3,3,3-hexafluoro-2-propyl)hydroxylamine in diethyl ether. The addition of diethyl ether to this filtrate made the diethyl ether solution have the weight of 30 g. Then, 10 g of the diethyl ether solution and 0.1 ml of concentrated hydrochloric acid were poured into a reaction vessel containing 0.37 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentanal. After stirring at room temperature for 2 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to preparative thin layer chromatography, which afforded 0.27 g (yield, 50%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentanal O-(1,1,1,3,3,3-hexafluoro-2-propyl)oxime, nD24.5 1.4850.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=1.Cl.Cl.[CH:24]1([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:7][O:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([N:32]2[CH2:33][CH2:34][N:29]([CH2:28][CH:24]3[CH2:25][CH2:26][CH2:27]3)[CH2:30][CH2:31]2)=[O:19])=[C:12]([CH3:20])[CH:11]=1
Reactant: COC(=O)c1ccc(CC(=O)O)c(C)c1
Reactant: C1CC(CN2CCNCC2)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CC(=O)N2CCN(CC3CCC3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
Oxalyl chloride (0.36 ml, 3.3 mmol) was added to a solution of 4-carboxymethyl-3-methyl-benzoic acid methyl ester from Example E32 (687 mg, 3.3 mmol) in dichloromethane (20 ml) and few drops of DMF. The mixture was stirred for 3 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (10 ml) and added to a solution of 1-cyclobutylmethyl-piperazine dihydrochloride (750 mg, 3.3 mmol) in dichloromethane (10 ml) and DIEA (1.73 ml, 9.9 mmol) at 0° C. The mixture was stirred for 20 h at room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 3% methanol:97% dichloromethane) to yield the title compound (528 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[Cl:13][S:14](O)(=[O:16])=[O:15].S(Cl)(Cl)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][CH:11]=[C:10]([S:14]([Cl:13])(=[O:16])=[O:15])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2ncc[nH]2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=S(=O)(Cl)c1c[nH]c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C

Procedure:
2-(4-chlorophenyl)imidazole (6 g., 0.034 mole) was added portionwise at room temperature with stirring to chlorosulfonic acid (30 ml.). The mixture was heated 2 hours at 100° and cooled to room temperature. Thionyl chloride (3 g.) was added and the mixture again heated for 2 hours at 100°. After cooling to room temperature the mixture was added cautiously to ice and water. A semi-solid separated and was extracted with ether. The ether layer was dried and concentrated to yield 2-(4-chlorophenyl)-4-chlorosulfonylimidazole (1.3 g., 0.005 mole).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[SH:34][CH2:35][CH2:36][OH:37]>C(Cl)Cl>[OH:37][CH2:36][CH2:35][S:34][CH:2]1[C:8]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2
Reactant: OCCS
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CC2
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)C(SCCO)c1ccccc1CC2
Temperature: 25 °C

Procedure:
In 15.3 ml of methylene chloride was suspended 0.51 g of methyl 5-hydroxy-10,11-dihydro-5 H-dibenzo[a,d]-cyclohepten-3-carboxylate. Under ice cooling, 0.27 ml of trifluoroacetic anhydride was added to the suspension followed by stirring at room temperature for an hour. Then, 0.14 ml of 2-mercaptoethanol was added to the mixture followed by stirring for further an hour. After 10 ml of methylene chloride was added to the reaction mixture, the mixture was washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) and recrystallized from toluene to give 0.51 g of the objective compound as light yellow crystals.
Reaction SMILES: C1(C(C2C=CC=CC=2)([C@@H]2CCCN2)O)C=CC=CC=1.COB(OC)OC.CSC.B.[Br:31][C:32]1[N:37]=[C:36]([C:38](=[O:43])[CH2:39][CH2:40][CH2:41][CH3:42])[CH:35]=[CH:34][CH:33]=1>C1COCC1>[Br:31][C:32]1[N:37]=[C:36]([C@H:38]([OH:43])[CH2:39][CH2:40][CH2:41][CH3:42])[CH:35]=[CH:34][CH:33]=1
Reactant: CCCCC(=O)c1cccc(Br)n1
Agent: B
Agent: COB(OC)OC
Agent: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Solvent: C1CCOC1
Solvent: CSC
Product: CCCC[C@@H](O)c1cccc(Br)n1
Reaction time: 0.08 h
Yield: 88.6 %

Procedure:
To a stirring solution of (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (α,α-diphenyl-L-prolinol) (840 mg, 3.32 mmol) in THF (3 mL) was added drop-wise trimethylborate (0.45 mL, 3.97 mmol) at ambient temperature under nitrogen. After stirring for 1 h at this temperature, borane dimethylsulfide (2M in THF, 2.5 mL, 5.00 mmol) drop-wise over 3-4 minutes. After the effervescence had stopped, 1-(6-bromo-2-pyridinyl)-1-pentanone (797 mg, 3.29 mmol) in THF (3.6 mL) was added over 1 h using a syringe pump. The mixture was stirred for an additional 5 minutes and the reaction was then quenched with aqueous HCl (2N, 5 mL) and the reaction mixture stirred overnight at ambient temperature. The mixture was then reduced under vacuum and the residue partitioned between EtOAc (30 mL) and water (30 mL) and the layers separated. The aqueous was then re-extracted with EtOAc (30 mL) and the combined organic layer washed with brine (50 mL) and then reduced under vacuum to give an oil. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 100:1 to 3:1) afforded the title compound as an oil (712 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:2]=1.Cl.[NH2:13][C:14]1[C:15]2[C:25]([O:26][CH2:27][C@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][NH2+:29]3)=[CH:24][CH:23]=[CH:22][C:16]=2[NH:17][S:18](=[O:21])(=[O:20])[N:19]=1>>[NH2:13][C:14]1[C:15]2[C:25]([O:26][CH2:27][C@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3[C:9](=[O:11])[CH2:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:24][CH:23]=[CH:22][C:16]=2[NH:17][S:18](=[O:20])(=[O:21])[N:19]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: O=C(O)CCc1cccnc1
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)CCc3cccnc3)c21
Yield: 27.1 %

Procedure:
Prepared as in Example 15 from 3-(pyridine-3-yl)propanoic acid and (R)-4-amino-5-(piperidin-2-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (Example 15a) in 27.1% yield. 1H NMR (DMSO-d6, 400 MHz, 60° C.): 1.20-1.40 (m, 1H), 1.45-1.67 (m, 4H), 1.74 (m, 1H), 2.68 (m, 2H), 2.86 (m, 2H), 3.17 (s, 1H), 3.76 (br s, 1H), 4.17 (br s, 1H), 4.45 (t, J=9.6 Hz, 1H), 5.13 (br s, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 7.24 (m, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.64 (m, 1H), 7.74 (br s, 1H), 8.07 (br s, 1H), 8.36 (m, 1H), 8.46 (s, 1H), 10.74 (s, 1H). (444 MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][CH2:22][C@H:23]4[NH:28][S:29]([CH2:32][C:33]([OH:35])=O)(=[O:31])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].ON1C2C=CC=CC=2N=N1.C(Cl)CCl.[CH3:50][NH:51][CH3:52]>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][CH2:22][C@H:23]4[NH:28][S:29]([CH2:32][C:33]([N:51]([CH3:52])[CH3:50])=[O:35])(=[O:31])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NS(=O)(=O)CC(=O)O)no2)cc1C#N
Reactant: CNC
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NS(=O)(=O)CC(=O)N(C)C)no2)cc1C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 16.8 %

Procedure:
Prepared using General Procedure 9: To a stirring solution of (R)-2-(N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamoyl) acetic acid 34 (15 mg, 0.05 mmol) in DMF (0.5 mL) was added N-hydroxybenzotriazole (6.1 mg, 0.05 mmol) and EDC (8.7 mg, 0.05 mmol). After 5 min, dimethylamine (40 wt % solution in THF, 50 μL, 0.09 mmol) was added and the reaction mixture was stirred 18 h at room temperature. The crude reaction was diluted with sat NaHCO3 and extracted with EA. The combined organic layers were dried over Na2SO4 and purified by preparative HPLC to give 4.41 mg (28%) of (R)-2-(N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamoyl)-N,N-dimethylacetamide 40. LCMS-ESI (m/z) calculated for C26H29N5O5S: 523.6; found 546.2 [M+Na]+, tR=3.58 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.1 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 7.96 (dd, J=7.7, 1.2 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 5.36 (t, J=17.3 Hz, 1H), 4.88-4.73 (m, 2H), 4.27 (d, J=14.6 Hz, 1H), 4.07 (d, J=14.6 Hz, 1H), 3.24-3.09 (m, 4H), 3.09-2.97 (m, 4H), 2.23-2.08 (m, 2H), 2.10-1.84 (m, 2H), 1.47 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 172.75, 169.37, 163.15, 162.77, 137.79, 136.92, 134.13, 133.90, 132.50, 130.18, 126.36, 126.17, 116.79, 115.25, 113.55, 103.96, 72.74, 55.46, 53.05, 38.22, 35.98, 29.84, 28.10, 21.73, 19.10.
Reaction SMILES: C[Mg]Br.[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:15]([C:19]1[N:20]=[C:21]([C:24]2[O:25][C:26]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]4[C:42]5[C:37](=[CH:38][C:39]([CH2:43]I)=[CH:40][CH:41]=5)[C:36]([C:45]#[N:46])=[CH:35]4)=[CH:29][C:27]=3[CH:28]=2)[S:22][CH:23]=1)([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[C:15]([C:19]1[N:20]=[C:21]([C:24]2[O:25][C:26]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]4[C:42]5[C:37](=[CH:38][C:39]([CH2:43][CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])=[CH:40][CH:41]=5)[C:36]([C:45]#[N:46])=[CH:35]4)=[CH:29][C:27]=3[CH:28]=2)[S:22][CH:23]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(CI)ccc54)ccc3o2)n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc2c(c1)c(C#N)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.7 %

Procedure:
A mixture of 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(chloromethyl)indole-3-carbonitrile (0.65 g) and potassium iodide (0.91 g) in acetone (5 ml) was stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure and the residue was dissolved with dichloromethane. After removal of the resulting insolble mass by filtration, and the filtrate was evaporated under reduced pressure to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(iodomethyl)indole-3-carbonitrile (0.88 g). Methyl magnesium bromide (1M) in tetrahydrofuran solution (15 ml) was added dropwise to diethyl malonate (5.41 g) under ice-cooling. After the mixture was stirred at room temperature for 1.5 hours, 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(iodomethyl)indole-3-carbonitrile (0.88 g) was added to the mixture. After several hours, the resulting mixture was partitioned between diluted hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing the objective compounds were combined and concentrated under reduced pressure to give ethyl 3-{1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-3-cyanoindol-5-yl}-2-(ethoxycarbonyl)propionate (0.78 g).
Reaction SMILES: [OH:1][C:2]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].Br[CH2:22][C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][C:2]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:22][C:23]#[N:24])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9]
Reactant: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(O)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(OCC#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
[2-Hydroxy-2-(4-hydroxyphenyl)cyclopentyl][(methylethyl)sulfonyl]amine (650 mg, 2.17 mmol, prepared in example 47), bromoacetonitrile (292 mg, 1.1 eq), and potassium carbonate (360 mg, 1.2 eq) were combined with acetone (40 mL) and stirred overnight at room temperature under a nitrogen atmosphere. The solution was then filtered and the filtrate was concentrated under reduced vacuum to yield 694 mg as an oil. This two spot material was separated and purified via silica gel chromatography employing the Chromatotron® and using a 4000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 9:1 to yield the intermediate title compound (390 mg, 54%) as a white foam (top spot by TLC). Ion Spray M.S. 337.2 (M*−1) Calculated for C16H22N2O4S: Theory: C, 56.79; H, 6.55; N, 8.28. Found: C, 56.51; H, 6.46; N, 8.24.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[C:15]([CH3:16])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=2)[N:6]=[N:5][N:4]=1.S(Cl)([Cl:23])=O.O>ClCCl.CN(C)C=O>[Cl:23][CH2:2][C:3]1[N:7]([C:8]2[C:15]([CH3:16])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=2)[N:6]=[N:5][N:4]=1
Reactant: Cc1cc(C#N)c(C(F)(F)F)cc1-n1nnnc1CO
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C#N)c(C(F)(F)F)cc1-n1nnnc1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 4-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-5-methyl-2-(trifluoromethyl)benzonitrile (Intermediate 63, 147 mg, 0.519 mmol) in dichloromethane (3 mL) and N,N-Dimethylformamide (0.5 mL), cooled in an ice bath under argon, was added dropwise thionyl chloride (0.040 mL, 0.545 mmol). The reaction was stirred at 25° C. for two hours. To the reaction was added water (20 mL) and DCM (50 mL) and the reaction partitioned through a hydrophobic frit. The organic layer was evaporated to dryness under vacuum to afford 133 mg of the title compound as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=[N:12][C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][NH:12][C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)N=CN2c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NCN2c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-oxo-1-phenyl-1,3,7-triaza-spiro[4.5]dec-2-ene-7-carboxylic acid tert-butyl ester (130 mg, 0.39 mmol) in methanol (3 ml) was added sodium borohydride (22 mg, 0.59 mmol). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo. The residue was dissolved with EtOAc (5 ml) and washed with a saturated solution of sodium bicarbonate (10 ml). The aqueous phase was extracted with further EtOAc (5 ml). The organics portions were combined, dried (MgSO4) and concentrated in vacuo to afford an oil. Purification of the crude product by chromatography on silica eluting with 0-50% EtOAc in iso-hexane afforded the title compound.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:16][CH2:15]1
Reactant: OC1CCNCC1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 15.8 %

Procedure:
To a 20 ml N,N-dimethylformamide solution of 1.0 g (5.95 mmol) of ethyl 4-fluorobenzoate, 662 mg (6.54 mmol) of 4-hydroxypiperidine and 1.23 g (8.92 mmol) of potassium carbonate were added, and the mixture was stirred for 24 hours at 120° C. The reaction mixture was returned to room temperature, and the solvent was distilled off under reduced pressure. Then, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Then, the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and precipitated crystals were collected to obtain 234 mg (16%) of the captioned compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C:7]1[CH:8]=[C:9]([CH:30]([O:33][CH3:34])[O:31][CH3:32])[CH:10]=[C:11]2[C:19]=1[CH:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[C:17]1([O:26][C:27](=[O:29])[CH3:28])[O:25][N:12]2[CH2:13][CH:14]2[CH:16]1[NH:15]2)(=[O:5])[CH3:4].CI.[C:37](O)(=O)C>O1CCCC1>[C:3]([O:6][C:7]1[CH:8]=[C:9]([CH:30]([O:31][CH3:32])[O:33][CH3:34])[CH:10]=[C:11]2[C:19]=1[CH:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[C:17]1([O:26][C:27](=[O:29])[CH3:28])[O:25][N:12]2[CH2:13][CH:14]2[CH:16]1[N:15]2[CH3:37])(=[O:5])[CH3:4]
Reactant: CC(=O)O
Reactant: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3NC3C(OC(C)=O)(O1)C2COC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3C(N3C)C(OC(C)=O)(O1)C2COC(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of sodium hydride (60% in oil, 4 mg) in tetrahydrofuran (0.5 ml) was added a solution of B-isomer of 8-carbamoyloxymethyl-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (20 mg) in tetrahydrofuran (2.0 mg) in an ice-water bath. To this solution was added methyl iodide (0.4 ml) in an ice-water bath. After stirring for 3 hours at ambient temperature, acetic acid (0.1 ml) was added to the reaction mixture in an ice-water bath. The resultant mixture was evaporated in vacuo and the residual oil was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (8:1, v/v) to afford 8-carbamoyloxymethyl-4-dimethoxymethyl-11-methyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (11 mg).
Reaction SMILES: [NH:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([Cl:10])=[CH:5][N:4]=1)N>[Ni].CO>[NH2:1][C:3]1[C:8]([F:9])=[CH:7][C:6]([Cl:10])=[CH:5][N:4]=1
Reactant: NNc1ncc(Cl)cc1F
Agent: [Ni]
Solvent: CO
Product: Nc1ncc(Cl)cc1F
Reaction time: 12 h
Yield: 87 %

Procedure:
Charged in a hydrogenation reactor were 100 ml of methanol, 16.1 g of the compound obtained in Step 4 and 8.13 g of Raney nickel catalyst, and H2 gas was introduced therein. The reactor was kept at room temperature for 12 hours, and the reaction mixture was filtered through Cellite® to remove the catalyst. The filtrate was concentrated under a reduced pressure to obtain 12.7 g of the title compound as a solid (purity: 98.5%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[N:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[N:32]C=1N1CCNCC1>>[NH:32]1[C:33]2[C:34](=[C:4]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([C:18]6[N:23]=[CH:22][CH:21]=[CH:20][N:19]=6)[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:5]=[CH:6][CH:8]=2)[CH:35]=[N:30]1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCN(c4ncccn4)CC3)cc2n1
Reactant: c1cnc(N2CCNCC2)nc1
Product: c1cnc(N2CCN(Cc3cc4nc(-c5cccc6[nH]ncc56)nc(N5CCOCC5)c4s3)CC2)nc1

Procedure:
Prepared via 2-Chloro-4-morpholin-4-yl-6-(4-pyrimidin-2-yl-piperazin-1-ylmethyl)-thieno[3,2-d]pyrimidine, prepared from 1-(2-pyrimidyl)piperazine.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:9]([C:12]1[CH:37]=[CH:36][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23]=[C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)[CH:25]=2)[C:20](Cl)=[O:21])=[CH:14][CH:13]=1)([O-:11])=[O:10].N1C=CC=CC=1>C1C=CC=CC=1>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23]=[C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)[CH:25]=2)[C:20]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:1]2=[O:8])=[O:21])=[CH:36][CH:37]=1)([O-:11])=[O:10]
Reactant: O=C(Cl)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: O=C1CCCCCN1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C1NCCCCC1C(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A solution of ε-caprolactam (14.82 g, 0.131 mol) in 400 ml of benzene is added to the above reactor containing 0.131 mol of 3,5-bis(4-nitrophenoxy)benzoyl chloride. The mixture is heated to 80°-90° C., and after all the reactants are dissolved, 150 ml of pyridine is added. The solution is stirred at 90° C. for 3 hours and the pyridine/acid chloride salt removed by filtration, the filtrate being kept in a freezer. White crystals formed from the filtrate are collected by filtration and dried. In order to remove traces of the 3,5-bis(4-nitrophenoxy)benzoic acid, the product is further purified by chromatography using silica gel as filler and ethyl acetate as eluate to yield 65 percent of white crystals: mp 157°-158° C.