Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:12]3=[CH:11][C:10]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5][CH:4]=1)=[O:2].Cl([O-])=[O:28].[Na+].O.O.P([O-])(O)(O)=O.[Na+].O>CC(O)(C)C.CC(=CC)C.C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:12]3=[CH:11][C:10]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)([OH:28])=[O:2]
Reactant: [O-][Cl+][O-]
Reactant: CCOC(=O)c1cc2c(nc1COc1ccc(C=O)cc1)CCCCC2
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cc2c(nc1COc1ccc(C(=O)O)cc1)CCCCC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 89.1 %

Procedure:
Ethyl 2-(4-formylphenoxymethyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (3.05 g, 8.63 mmol) was dissolved in a mixed solution of 2-methyl-2-propanol (33.0 ml) and 2-methyl-2-butene (10.0 ml), and to the solution was added dropwise aqueous solution (26.0 ml) of sodium chlorite (80%, 4.88 g, 43.2 mmol) and sodium dihydrogenphosphate dihydrate (4.46 g, 28.6 mmol). Chloroform was added until insoluble matter was dissolved and then the solution was stirred at room temperature for 3.5 hours. The reaction solution was diluted with chloroform, mixed with water and then extracted with chloroform-methanol mixed solution (5:1). The thus obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=10:1) to obtain the title compound (2.84 g, 89.1%) as white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:24](=[O:26])=[O:25]>C1COCC1.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C>[C:1]([O:5][C:6]([NH:7][C:8]1[N:9]=[C:10]([CH2:14][C:24]([OH:26])=[O:25])[CH:11]=[CH:12][CH:13]=1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)n1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(CC(=O)O)n1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
(6-Methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.04 g, Pitts, J. Med. Chem., 43, 2000, 27) under an argon atmosphere in THF (40 mL) was cooled to −20° C. and treated dropwise at −20° C. with 5.5 mL of a 2 M solution of lithium diisopropylamide in THF/heptane/ethylbenzene (Fluka). The solution was stirred 1 h at −20° C., cooled to −70° C. and then treated with an access of dry ice. The mixture was allowed to warm to 10° C. and partitioned between aqueous 1N HCl and AcOEt, the layers were separated, the organic layer dried over Na2SO4, filtered, evaporated and the residue was purified by flash chromatography (MeOH/CH2Cl2 0-15%). The obtained material was triturated with ether, the crystalline solid obtained was filtered off by suction and dried in vacuo to give (6-tert-butoxycarbonylamino-pyridin-2-yl)-acetic acid as an off-white solid (0.3 g). MS (ESI−): 251.1 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N+:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:8]=2)[S:4][C:3]=1[CH3:24].[Br-:25]>C(O)(C)C>[Br-:25].[CH3:1][C:2]1[N:6]=[C:5]([N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH2+:10][N:11]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:4][C:3]=1[CH3:24]
Reactant: Cc1nc(-[n+]2nc(-c3ccccc3)nn2-c2ccccc2)sc1C
Agent: [Br-]
Solvent: CC(C)O
Product: Cc1nc(N2N=C(c3ccccc3)[NH2+]N2c2ccccc2)sc1C
Reaction time: 4 h

Procedure:
Ten μl of thiazolyl blue tetrazolium bromide solution (5 mg/ml in PH 7.4 PBS) was added to each well containing 100 μl of medium and cells, followed by incubation at 37° C. for 4 hours in the dark. Isopropanol (100 μl, 0.04 N HCl) was added to dissolve blue dye. After dissolved completely, absorbance was measured with plate-reader (Synergy 2, BioTek Instrument) at test wavelength 570 nm and reference wavelength 670 nm. Cell viability was determined by absorbance at 570 nm and reported as ratio to control cells (without OGD).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[CH:12]([N:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][CH2:17]Cl)([CH3:14])[CH3:13]>>[CH:12]([N:15]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:16][CH2:17][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])([CH3:13])[CH3:14]
Reactant: CC(C)N(CCCl)Cc1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Product: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)Cc1ccccc1

Procedure:
By using isatin and the 2-(N-isopropylbenzylamino)ethyl chloride, a method analogous to that described in Reference Example 7 was carried out, and the reaction product was purified with silica gel column chromatography (eluent: chloroform) to obtain 1-[2-(N-isopropylbenzylamino)ethyl]isatin in an oil (yield: 43.4%).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11](=[O:21])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2]>S(Cl)(Cl)=O>[Cl:20][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][C:11]2[O:21][C:1]([CH3:2])=[N:4][C:5]=2[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)CCc1cccc(Cl)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nc(C)oc1CCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (180 ml) was added to the product of step (iii) (45.5 g) at 0° C. The mixture was stirred at room temperature for 2 hours and heated at reflux for 40 min. The residue after evaporation under reduced pressure was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was dried (MgSO4) and solvent evaporated under reduced pressure. Purification was by chromatography eluting with 1-2% ethanol in dichloromethane to give the subtitle product as an orange oil.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:40])=[C:36]([CH:39]=1)[CH2:37]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:37][C:36]3[CH:39]=[C:32]([F:31])[CH:33]=[CH:34][C:35]=3[CH3:40])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Cc1ccc(F)cc1CBr
Product: Cc1ccc(F)cc1Cn1ccc2c(-c3ccc4c(c3)CCCO4)c(C(OC(C)(C)C)C(=O)O)c(C)nc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 5-fluoro-2-methylbenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.42 (m, 1 H), 7.26-7.21 (m, 1 H), 7.18-7.12 (m, 1 H), 6.98-6.85 (m, 3 H), 6.66 (dt, J=3.3, 9.5 Hz, 1 H), 6.25 (dd, J=3.5, 12.3 Hz, 1 H), 5.62-5.56 (m, 1 H), 5.47-5.34 (m, 2 H), 4.27 (t, J=5.0 Hz, 2 H), 2.94-2.77 (m, 2 H), 2.73-2.66 (m, 3 H), 2.31 (d, J=3.3 Hz, 3 H), 2.14-2.06 (m, 2 H), 1.01-0.91 (s, 9 H); LC/MS (m/z) ES+=517.31 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=1)[O:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[CH3:27][C:28]([O:31][C:32]([NH:34][C@H:35]([C:39](O)=[O:40])[CH2:36][C:37]#[CH:38])=[O:33])([CH3:30])[CH3:29].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:28]([O:31][C:32]([NH:34][C@@H:35]([CH2:36][C:37]#[CH:38])[C:39]([NH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=1)[O:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]1)=[O:40])=[O:33])([CH3:30])([CH3:29])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C#CCCCN)c2)CC1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC#Cc1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of tert-butyl 4-(3-(5-aminopent-1-ynyl)phenoxy)piperidine-1-carboxylate (0.59 g, 1.6 mmol), Boc-L-propargylglycine (0.35 g, 1.6 mmol), N-ethyldiisopropylamine (0.73 ml, 4.1 mmol) in DMF (20 ml) was added HBTU (0.81 g, 2.1 mmol). The resulting solution was stirred at room temperature overnight. (S)-tert-Butyl 4-(3-(5-(2-(tert-butoxycarbonylamino)pent-4-ynamido)pent-1-ynyl)phenoxy)piperidine-1-carboxylate was isolated and purified over Gilson HPLC as a colorless oil. MH+ 554.44
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([NH:29]C(=O)C)(C(OCC)=O)[C:19]([O:21]CC)=[O:20])([O:6]CC)=[O:5])C>Cl>[P:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH:18]([NH2:29])[C:19]([OH:21])=[O:20])([OH:6])([OH:5])=[O:3]
Reactant: CCOC(=O)C(Cc1ccccc1CCP(=O)(OCC)OCC)(NC(C)=O)C(=O)OCC
Agent: Cl
Product: NC(Cc1ccccc1CCP(=O)(O)O)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 7.9 g (16.8 mmol) of ethyl 3-[2-(2-diethylphosponoethyl)-phenyl]-2-acetamido-2-carboethoxypropanoate in 40 mL of 6N HCl was stirred at vigorous reflux for 14 h. After cooling to room temperature the reaction mixture was concentrated at reduced pressure yielding an oil. This oil was washed with four 25 mL portions of water then dissolved in 20 mL 95% ethanol and propylene oxide added dropwise. The precipitated crude acid was collected by filtration. Recrystallization from dilute ethanol yielded 4.1 g (90%) as a white solid, mp 241°-243° C. IR(Nujol): 1712.5 cm-1 (C=O). 1H NMR(D2O) δ 1.5-2.2 (m, 2H); 2.6-3.3 (m, 4H); 3.9-4.2 (t, 1H); 7.2 (m, 4H). Anal. Calcd. for C11H16NO5P: C, 48.35; H, 5.90; N, 5.13. Found: C, 48.69; H, 6.16; N, 4.95.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:12][CH:11]=[CH:10]2.CN(C)[CH:28]=[O:29]>O1CCCC1>[CH:28]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:12][CH:11]=[CH:10]2)=[O:29]
Reactant: CN(C)C=O
Reactant: O=C(Nc1nccc2cc(Br)ccc12)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 29 mL of n-BuLi (1.6 M in hexane) in 40 mL of dry tetrahydrofuran under a nitrogen atmosphere at −78° C. was added dropwise a solution of 2.5 g of 1e in 60 mL of dry tetrahydrofuran over a period of 15 min. After stirring for 30 min a mixture of 34 mL of N,N-dimethylformamide and 20 mL of tetrahydrofuran was added fast. The cooling bath was removed, the reaction mixture was allowed to come to 0° C. and was poured into ice cold aqueous hydrochloric acid (60 mL, 0.5 N). The mixture was adjusted to pH 6, brine was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was dried (MgSO4) and concentrated under reduced pressure. Purification on silica gel (toluene/ethyl acetate:3/1) gave 1.3 g of aldehyde 1f. 1H-NMR 200 MHz (CDCl3) δ: 7.12 (1H, d, J=7 Hz). 7.40-8.51 (9H, m), 9.26 (1H, d, J=8 Hz), 10.23 (1H, s).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)=[CH:10][CH:9]=1.Cl.[CH2:20]([NH2:22])[CH3:21].O>C(Cl)Cl>[CH2:20]([NH:22][C:15](=[O:17])[CH:14]([C:11]1[CH:10]=[CH:9][C:8]([Br:7])=[CH:13][CH:12]=1)[CH3:18])[CH3:21]
Reactant: CC(C(=O)O)c1ccc(Br)cc1
Reactant: CCN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)C(C)c1ccc(Br)cc1
Reaction time: 2 h

Procedure:
16.6 g (130 mmol) oxalyl chloride are added to 15.0 g (65 mmol) 2-(4-bromo-phenyl)-propionic acid (Bioorg. Med. Chem. Lett. 2010, 20, 887) in 75 mL DCM at 0° C. The cooling is removed and the mixture is stirred for 2 h under reflux. After that time, the solvent is evaporated and the residue is taken up in 70 mL THF. 3.20 g (39 mmol) ethylamine hydrochloride and 66.0 g (655 mmol) TEA are added and the mixture is stirred for 16 h at rt. After that time, iced water is added, the mixture is extracted with EtOAc and the organic layer is dried over sodium sulphate. The solvent is evaporated and the residue is purified by column chromatography (silica gel).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:21][C@@H:22]5[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]5)=[O:20])[CH:17]=4)[NH:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:21][C@@H:22]5[CH2:27][CH2:26][CH2:25][N:24]([CH2:34][C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=6)[CH2:23]5)=[O:20])[CH:17]=4)[NH:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(N[C@@H]1CCCNC1)c1ccc2[nH]nc(-c3ccc4c(c3)CCO4)c2c1
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(N[C@@H]1CCCN(Cc2ccccn2)C1)c1ccc2[nH]nc(-c3ccc4c(c3)CCO4)c2c1
Reaction time: 0.25 h

Procedure:
In a flask, dichloromethane (1 mL) and acetic acid (2 drops) was added to (R)-3-(2,3-dihydrobenzofuran-5-yl)-N-(piperidin-3-yl)-1H-indazole-5-carboxamide (12 mg) and picolinaldehyde (7 mg). The reaction was stirred for 15 minutes. Sodium triacetoxyborohydride (28 mg) was added in one portion. The reaction was stirred overnight. The reaction was concentrated in vacuo and purified using prep LC/MS.
Reaction SMILES: B.[CH2:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.Cl>O1CCCC1>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][OH:15])=[CH:17][CH:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of 125 ml. of 1 molar borane in tetrahydrofuran chilled in an ice bath is added 19.3 g. of p-heptyloxybenzoic acid in 160 ml. of tetrahydrofuran over a period of 45 minutes. The mixture is stirred at room temperature for 5.5 hours, poured into ice and water and 30 ml. of concentrated hydrochloric acid added. The mixture is filtered and the solid washed with water to give the product as a white waxy solid.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25].[F:30][C:31]([F:43])([F:42])[CH:32]([CH3:41])[O:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1>>[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:40]([C:37]3[CH:38]=[CH:39][C:34]([O:33][CH:32]([CH3:41])[C:31]([F:30])([F:42])[F:43])=[CH:35][CH:36]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(Oc1ccc(N)cc1)C(F)(F)F
Product: CC(Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4C(F)(F)F)CC3)C2=O)cc1)C(F)(F)F

Procedure:
Light brown solid. MS (ESI): 551.14 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethyl-benzenesulfonyl chloride and 4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:12]1([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24]3[N:29]=[CH:28][C:27](Br)=[CH:26][N:25]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.[NH:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]1=[O:37]>[Cu](I)I.O>[CH:12]1([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24]3[N:29]=[CH:28][C:27]([N:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]4=[O:37])=[CH:26][N:25]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Brc1cnc(OC2CCN(C3CCCC3)CC2)nc1
Reactant: O=c1cccc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccccn1-c1cnc(OC2CCN(C3CCCC3)CC2)nc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
Potassium carbonate (40 mg) and copper iodide (40 mg) were added to a DMF solution (5 ml) of 2-(1-cyclopentylpiperidin-4-yloxy)-5-bromopyrimidine (130 mg) and 1H-pyridin-2-one (19 mg), and stirred at 150° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to it and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, chloroform:methanol=9:1) to obtain the entitled compound (11 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH:15]([S:16]CC2C=CC(OC)=CC=2)[CH2:14][CH2:13][N:12]([S:26]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:28])=[O:27])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([O:8][CH2:9][CH:10]1[CH:15]([SH:16])[CH2:14][CH2:13][N:12]([S:26]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:28])=[O:27])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CSC2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2COCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc2ccccc2c1)N1CCC(S)C(COCc2ccccc2)C1
Reaction time: 2 h
Yield: 61.1 %

Procedure:
84 mg (0.153 mmol) (3SR,4RS)-3-Benzyloxymethyl-4-(4-methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-piperidine were dissolved in 2 ml TFA and treated at 0° C. with 0.244 ml (1.53 mmol) of triethylsilane. After 2 h at 0° C. and 18 h at room temperature, the mixture was evaporated and purified by precipitation with Et2O/pentane to give 40 mg (61%) of (3SR,4RS)-3-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-piperidine-4-thiol, MS: 427 (M).
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+].CO>CCOCC.O>[CH2:10]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: O=C1C(Cc2ccccc2)CCCCCC1Cc1ccccc1
Temperature: 25 °C

Procedure:
2,8-Dibenzylcyclooctanone is prepared by stirring 25 grams of cyclooctanone, 54 grams of benzaldehyde, 30 grams of potassium hydroxide and 500 milliliters of methanol at reflux temperatures for 4 hours. The mixture is then cooled to room temperature and 200 milliliters of water are added followed by 300 milliliters of ether. The ether layer is separated and the ether and methanol are then removed by distillation. The residue is taken up in 200 milliliters of ethanol and hydrogenated at 1,000 p.s.i.g. and ambient temperature using a 10 percent palladium on carbon catalyst. The catalyst is removed by filtration and the solvent is removed by distillation. Recrystallization of the crude product is effected by dissolving in 150 milliliters of methanol and seeding with crystalline 2,8-dibenzylcyclooctanone (m.p. 75°-77° C.). Cooling of the seeded methanolic solution gives 16 grams of crystals with melting point 60°-67° C. A second recrystallization of this material from methanol gives one isomer of 2,8-dibenzylcyclooctanone, melting point 75°-77° C., as a first crop and a second isomer of 2,8-dibenzylcyclooctanone, melting point 66°-68° C., as a second crop.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[S:13][CH:14]=[CH:15][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[S:13][CH:14]=[CH:15][C:8]=2[C:7]=1[N:27]1[CH2:26][CH2:25][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:29][CH2:28]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2ccsc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccsc2[nH]c1=O

Procedure:
In another method, intermediate 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyrdine-5-carboxylic acid ethyl ester, depicted by formula (42), was reacted with tert-butyl-1-piperazine carboxylate to yield 4-(4-tert-butoxycarbonyl-piperazin-1-yl)-6-oxo-6,7-dihydro-thieno[2,3-b]-pyridine-5-carboxylic acid ethyl ester, depicted by formula (45). This intermediate was either reacted with an appropriate halide (R1—X) or boronic acid (R1—B(OH)2) to yield intermediate of structure (46), which was deprotected and reacted with an appropriate acid chloride (R3—COCl) or acid (R3—COOH) to yield target compounds of structure (III) with R2 as ethyl carboxylate, and R1 and R3 as defined above, as shown in Scheme 24.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[S:23][C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:5]=2[C:4](=[O:31])[NH:3]1.[CH:32]1([CH:38]2[CH2:40][O:39]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH:32]1([C:38](=[O:39])[CH2:40][N:3]2[C:4](=[O:31])[C:5]3[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[S:23][C:6]=3[N:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)[C:2]2=[O:1])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCC(C2CO2)CC1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CC(=O)C3CCCCC3)c(=O)c3cc(CC(F)(F)F)sc32)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 22.6 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.0 g), 2-cyclohexyloxirane (0.98 g) and N,N-dimethylformamide (7 mL) was added potassium carbonate (0.63 g), and the mixture was stirred at 80° C. for 24 hr. To the reaction mixture was added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. A mixture of the obtained residue, tetrapropylammonium perruthenate (0.011 g), 4-methylmorpholine-N-oxide (0.15 g), molecular sieves 4A (0.12 g) and methylene chloride (3 mL) was stirred at room temperature for 24 hr. The reaction mixture was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.29 g, 79%).