Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)=[N:11][N:10]=[C:9]1[C:23]([F:40])=[C:24]([F:39])[C:25]([NH:27][NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)=[N:11][N:10]=[C:9]1[C:23]([F:40])=[C:24]([C:25]1[O:38][C:29]([C:30]2[CH:31]=[CH:32][C:33]([C:36]#[N:37])=[CH:34][CH:35]=2)=[N:28][N:27]=1)[F:39]
Reactant: CS(=O)(=O)c1ccc(-c2nnc(C(F)=C(F)C(=O)NNC(=O)c3ccc(C#N)cc3)n2-c2ccccc2Cl)nc1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2nnc(C(F)=C(F)c3nnc(-c4ccc(C#N)cc4)o3)n2-c2ccccc2Cl)nc1
Reaction time: 2 h

Procedure:
4-Cyano-benzoic acid N′-{3-[4-(2-chloro-phenyl)-5-(5-methanesulfonyl-pyridin-2-yl)-4H-[1,2,4]triazol-3-yl]-2,3-difluoro-acryloyl}-hydrazide 11 was dissolved into dichloromethane (10 mL) and triphenylphosphine (0.27 g, 1.02 mmol), carbon tetrabromide (0.34 g, 1.02 mmol) and triethylamine (0.18 mL, 1.30 mmol) were added. The reaction mixture was kept at ambient temperature for 2 h. The final compound was purified by column chromatography (eluting with methanol/DCM 1/99-5/95) to give 4-(5-{2-[4-(2-chloro-phenyl)-5-(5-methanesulfonyl-pyridin-2-yl)-4H-[1,2,4]triazol-3-yl]-1,2-difluoro-vinyl}-[1,3,4]oxadiazol-2-yl)-benzonitrile as a solid. Yield: 0.05 g, 13%.
Reaction SMILES: [OH:1][C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:15][C:16]([CH3:18])=[CH2:17])[CH2:3][CH2:4][N:5]([C:10]([CH3:14])([C:12]#[CH:13])[CH3:11])[C:6](=[O:9])[O:7][CH3:8].[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[N+:26]=[N-:27].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>O.CC(O)(C)C.[O-]S([O-])(=O)=O.[Cu+2].O>[OH:1][C:2]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH2:15][C:16]([CH3:18])=[CH2:17])[CH2:3][CH2:4][N:5]([C:10]([C:12]1[N:27]=[N:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:13]=1)([CH3:14])[CH3:11])[C:6](=[O:9])[O:7][CH3:8]
Reactant: C#CC(C)(C)N(CCC(O)(CC(=C)C)c1ccccc1)C(=O)OC
Reactant: [N-]=[N+]=Nc1ccccc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: C=C(C)CC(O)(CCN(C(=O)OC)C(C)(C)c1cn(-c2ccccc2)nn1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44 %

Procedure:
To a stirred solution of methyl 3-hydroxy-5-methyl-3-phenylhex-5-enyl(2-methylbut-3-yn-2-yl)carbamate (26 mg, 0.081 mmol) and azidobenzene (29 mg, 0.24 mmol) in H2O (1 mL) and t-BuOH (1 mL) was added ascorbic acid (3.2 mg, 0.016 mmol)followed by CuSO4.H2O (0.5 mg, 0.002 mmol). The mixture was stirred at rt for 2 d. Additional azidobenzene (29 mg, 0.24 mmol), ascorbic acid (3.2 mg, 0.016 mmol) and CuSO4.5H2O (0.5 mg, 0.002 mmol) were added. The mixture was stirred for 4 h at rt and purified by prep HPLC to afford methyl 3-hydroxy-5-methyl-3-phenylhex-5-enyl(2-(1-phenyl-1H-1,2,3-triazol-4-yl)propan-2-yl)carbamate (16 mg, 44%) as an oil. LC-MS Method 1 tR=2.00 min, m/z=449.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[NH:3]1.C(O)(C(F)(F)F)=O>ClCCl>[NH:3]1[C:4]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:5][CH2:6][CH2:7][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCC(=O)N2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCCC2(CCNCC2)N1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of tert-butyl 2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate [1031927-12-4] (920 mg, 3.26 mmol) in dichloromethane (10 mL) was added TFA (2.53 mL, 32.6 mmol). The solution was stirred for 40 min at rt. After completion of the reaction the mixture was evaporated under reduced pressure and dried under high vacuum (1.90 g, 100%). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.59-8.35 (m, 2H), 7.83 (s, 1H), 3.27-3.14 (m, 2H), 3.12-2.98 (m, 2H), 2.17-2.04 (m, 2H), 1.80-1.57 (m, 8H); LCMS RtA=0.20 min, [M+H]+=169.2].
Reaction SMILES: [ClH:1].N1C=CC=CC=1.Cl.[C:9]([C:11]1[S:12][C:13](=[NH:28])[N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:26]C)=[C:19]([O:24]C)[CH:20]=3)[C:15]=12)#[N:10].Cl>O>[OH2:24].[OH2:24].[ClH:1].[C:9]([C:11]1[S:12][C:13](=[NH:28])[N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([OH:26])=[C:19]([OH:24])[CH:20]=3)[C:15]=12)#[N:10]
Reactant: COc1cc2c(cc1OC)-c1c(C#N)sc(=N)n1CC2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1sc(=N)n2c1-c1cc(O)c(O)cc1CC2

Procedure:
20.0 g. of pyridine hydrochloride are added to 6.0 g. of 1-cyano-3-imino-8,9-dimethoxy-3,4,5,6 -tetrahydro-1,3-thiazolo[4,3-a]isoquinoline hydrochloride, and the mixture is kept for 2 hours in an oil bath of 210°-220°C. The mixture is cooled and a mixture of 6 ml. of concentrated hydrochloric acid and 14 ml. of water is added. 5.2 g. of crystalline 1-cyano-3-imino-8,9-dihydroxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline hydrochloride dihydrate are obtained; m.p.: graduallly decomposes from 280°C (after recrystallization from hot water).
Reaction SMILES: [C:1]1(=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH2:4][CH2:3][NH:2]1.I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:23][C:22]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]3=[CH:7][CH:6]=2)[C:1]1=[O:15]
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2ccc3ccccc3c21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc3ccccc3c2C1=O
Yield: 55.4 %

Procedure:
Using analogous reaction conditions as described in Example 1, 3,4-dihydro-2H-benzo[h]isoquinolin-1-one (I-10d: 200 mg, 1.015 mmol) was reacted with 3-iodo-4-methyl-pyridine (266 mg, 1.214 mmol), 1,4-dioxane (15 mL), copper iodide (19 mg, 0.10 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (43 mg, 0.302 mmol) and potassium phosphate (538 mg, 2.53 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 162 mg of the product (55.47% yield).
Reaction SMILES: [O:1]=[C:2]([N:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][O:12][C:11]1=[O:21])[CH2:3]P(=O)(OC)OC.CC(C)([O-])C.[K+].[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>C1COCC1>[Cl:28][C:29]1[CH:36]=[CH:35][C:32](/[CH:33]=[CH:3]/[C:2]([N:10]2[C@H:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:13][O:12][C:11]2=[O:21])=[O:1])=[CH:31][CH:30]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COP(=O)(CC(=O)N1C(=O)OC[C@H]1c1ccccc1)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(Cl)cc1)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
A solution of (R)-dimethyl 2-oxo-2-(2-oxo-4-phenyloxazolidin-3-yl)ethylphosphonate (60.7 g, 177.8 mmol) in dry THF (275 ml) under an atmosphere of N2 was cooled to 0° C. in an ice-water bath. Potassium tert-butoxide (23.9 g, 213.4 mmol, 1.0 M solution in THF) was added over a period of 45 min in a dropwise manner and the reaction mixture stirred at 0° C. for 30 min. A solution of 4-chlorobenzaldehyde (25.0 g, 177.84 mmol) in dry THF (100 ml) was added over a period of 20 min and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was cooled to 0° C. and quenched with saturated solution of ammonium chloride (250 mL) and diluted with EtOAc (1.5 L). The biphasic system was stirred at ambient temperature for 10 min and the layers were separated. The organic layer was washed with brine (250 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by SiO2 column using a gradient elution of 0-25% EtOAc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to provide the product (43.0 g, 74%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Cl[CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[C:22]([F:27])=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[O:19][CH2:18][C:17]1=[O:28].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][N:16]3[C:21]4[C:22]([F:27])=[C:23]([F:26])[CH:24]=[CH:25][C:20]=4[O:19][CH2:18][C:17]3=[O:28])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: O=C1COc2ccc(F)c(F)c2N1CCCCl
Reactant: C1CC(OCC2CC2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2ccc(F)c(F)c2N1CCCN1CCC(OCC2CC2)CC1
Yield: 53.7 %

Procedure:
4-Cyclopropylmethoxypiperidine (0.037 g, 0.24 mmol), 4-(3-chloropropyl)-5,6-difluoro-4H-benzo[1,4]oxazin-3-one (0.065 g, 0.25 mmol), K2CO3 (0.066 g, 0.48 mmol), and KI (0.072 g, 0.48 mmol) were mixed according to GP3. Purified by prep TLC (SiO2; heptanes/EtOAc 1:1) to give the title compound (0.049 g, 54%). Rf=0.21 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) δ 6.84-6.70 (m, 2H), 4.48 (s, 2H), 4.48 (s, 2H), 4.08-4.02 (m, 2H), 3.34-3.26 (m, 1H), 3.24 (d, J=6.8 Hz, 2H), 2.75-2.68 (m 2H), 2.38 (t, J=7.2 Hz, 2H), 2.18-2.06 (m, 2H), 1.92-1.81 (m, 4H), 1.63-1.52 (m, 2H), 1.06-0.96 (m, 2H), 0.52-0.47 (m, 2H), 0.18-0.14 (m, 2H); 13C NMR (CDCl3) δ 165.0, 147.5 (dd, J=242.3 Hz, J=13.2 Hz), 143.9, 140.7 (dd, J=250.2 Hz, J=17.3 Hz), 119.9, 111.7 (dd, J=7.3 Hz, J=3.5 Hz), 110.9 (d, J=18.9 Hz), 74.5, 72.7, 68.5, 55.5, 51.2, 42.7 (d, J=10.4 Hz), 31.1, 25.5, (d, J=2.6 Hz), 11.1, 3.2.
Reaction SMILES: [CH2:1]1[C:12]2[C:4](=[C:5]([C:13](=[O:15])[CH3:14])[C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.C([OH:18])C>N1C=CC=CC=1>[CH2:9]1[C:10]2[C:6](=[C:5]([C:13](=[O+:15][O-:18])[CH3:14])[C:4]3[CH2:3][CH2:2][CH2:1][C:12]=3[CH:11]=2)[CH2:7][CH2:8]1
Reactant: CC(=O)c1c2c(cc3c1CCC3)CCC2
Reactant: CCO
Solvent: c1ccncc1
Product: CC(=[O+][O-])c1c2c(cc3c1CCC3)CCC2
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A mixture of 1-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-ethanone (33 grams), ethanol (250 mL) hydroxylamine hydrochloride (58.5 grams) and pyridine (80 mL) was heated to reflux for a period of 12 hours. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was then treated with 500 mL of water and extracted with chloroform-methanol. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to afford 32 grams of the title compound as a mixture of E and Z isomers, 178.6-182.3° C.
Reaction SMILES: C(O[C:6](=[O:35])[NH:7][CH:8]([CH3:34])[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=[O:33])[NH:18][CH:19]1[CH2:23][C:22](=[O:24])[O:21][CH:20]1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:10])(C)(C)C.[C:36]([NH:39][C:40]1[CH:48]=[CH:47][C:43](C(O)=O)=[CH:42][C:41]=1[Cl:49])(=[O:38])[CH3:37].O=C1OC(OCCC2C=CC=CC=2)C(NC(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)C1>>[CH2:26]([O:25][CH:20]1[CH:19]([NH:18][C:17]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][N:11]2[C:9](=[O:10])[CH:8]([NH:7][C:6](=[O:35])[C:43]2[CH:47]=[CH:48][C:40]([NH:39][C:36](=[O:38])[CH3:37])=[C:41]([Cl:49])[CH:42]=2)[CH3:34])=[O:33])[CH2:23][C:22](=[O:24])[O:21]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1CCCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1Cl
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(=O)Nc1ccc(C(=O)NC(C)C(=O)N2CCCCC2C(=O)NC2CC(=O)OC2OCc2ccccc2)cc1Cl
Yield: 47 %

Procedure:
Prepared from {2-[2-(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-piperidin-1-yl]-1-methyl-2-oxo-ethyl}-carbamic acid tert butyl ester and 4-acetylamino-3-chlorobenzoic acid by the procedure used in the preparation of 98a to give the title compound (71 mg, 47% yield). 1H-NMR (500 MHz, CDCl3) δ 1.10-1.97 (m, 10H), 2.10-2.68 (m, 5H), 2.73-3.24 (m, 2H), 3.62-3.92 (m, 1H), 4.24-5.27 (m, 5H), 5.48-5.59 (m, 0.5H), 5.75-5.85 (m, 0.5H), 6.51-6.61 (d, 1H), 7.05-7.45 (m, 4H), 7.52-8.12 (m, 4H). Analytical HPLC 8.30 min. LC-MS (ES+) m/e=585.3 (MH+).
Reaction SMILES: [C:1]([C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:20][C:21]1[CH:22]=[C:23]([OH:28])[C:24](=[CH:26][CH:27]=1)O.Cl>C1C=CC=CC=1.C(OCC)C>[CH3:20][C:21]1[CH:27]=[CH:26][C:24]2[O:8][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:28][C:23]=2[CH:22]=1
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: Cc1ccc(O)c(O)c1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C1(c2ccccc2)Oc2ccc(C)cc2O1
Temperature: 25 °C
Yield: 15.7 %

Procedure:
To a solution of ethyl benzoylformate (520 mg, 2.92 mmoL) in dry benzene 5 mL) was added PCl5 (608 mg, 1.0 equiv). After stirring at reflux for 16 h TLC analysis indicated that all the starting material appeared consumed. The solvent was removed in vacuo and the crude dichloride (Rf=0.61 6:1 hexane/ethyl acetate) was mixed with 4-methyl-catechol (724 mg 2.0 equiv) and heated to 175° C. until HCl evolution ceased (ca. 20 min). The mixture was cooled to rt and the glue-like material was dissolved in diethyl ether and washed several times with 1N NaOH and then brine. The organic was dried over anhydrous MgSO4 and concentrated in vacuo and the residue was chromatographed on a silica column eluting with hexane/ethyl acetate (20:1). Removal of the solvent afforded 130 mg (16%) of the titled compound. Rf=0.57 (6:1 hexane/ethyl acetate).
Reaction SMILES: [CH:1]12[CH2:14][CH:7]([CH:8]3[CH:10]1[CH:9]3[C:11](O)=[O:12])[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[CH:1]12[CH2:14][CH:7]([CH:8]3[CH:10]1[CH:9]3[C:11]([Cl:18])=[O:12])[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C1C2C3CC(C4CCCC43)C12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1C2C3CC(C4CCCC43)C12
Reaction time: 2 h

Procedure:
To a solution of tetracyclo[5.3.1.02,6.08,10]undecane-9-carboxylic acid (0.43 g, 2.2 mmol, Bennani, Y. L., et al., US2004077617) in dichloromethane (11 mL) was added oxalyl chloride 0.21 mL, 2.4 mmol) and a catalytic amount of dimethylformamide (2 drops). The mixture was stirred for 2 hours and then concentrated under reduced pressure to afford tetracyclo[5.3.1.02,6.08,10]undecane-9-carbonyl chloride. To a suspension of the product of Example 46A (0.30 g, 1.1 mmol) and triethylamine (0.46 mL, 3.3 mmol) in tetrahydrofuran (5 mL) was added a solution of tetracyclo[5.3.1.02,6.08,10]undecane-9-carbonyl chloride (0.23 g, 1.2 mmol) in tetrahydrofuran (1 mL). The mixture was heated at reflux for 14 hours, then cooled to room temperature and diluted with water and CH2Cl2. The layers were separated and the organic extract was washed with water and brine, dried (Na2SO4), and concentrated. Purification by column chromatography (SiO2, 10-35% ethyl acetate/hexanes gradient) afforded the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 0.94 (d, J=10.5 Hz, 1H), 1.22 (d, J=11.9 Hz, 1H), 1.45-1.76 (m, 6H), 1.87-1.98 (m, 2H), 2.17 (s, 3H), 2.20 (s, 3H), 2.32 (s, 2H), 2.35-2.43 (m, 3H), 3.30 (s, 3H), 3.70 (t, J=5.3 Hz, 2H), 4.20-4.33 (m, 2H); MS (DCI/NH3) m/z 361 (M+H)+. Anal. Calculated for C20H28N2O2S: C, 66.63; H, 7.83; N, 7.77. Found: C, 66.49; H, 7.91; N, 7.53.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]2[N:21]([C@H:24]3[CH2:29][CH2:28][C@H:27]([C:30]4[O:34][N:33]=[C:32]([CH:35]([CH3:37])[CH3:36])[N:31]=4)[CH2:26][CH2:25]3)[N:22]=[CH:23][C:16]=12.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:35]([C:32]1[N:31]=[C:30]([C@H:27]2[CH2:28][CH2:29][C@H:24]([N:21]3[C:17]4=[N:18][CH:19]=[N:20][C:15]([O:13][C:10]5[CH:11]=[CH:12][C:7]([N:6]6[C:2]([CH3:1])=[N:3][N:4]=[N:5]6)=[CH:8][CH:9]=5)=[C:16]4[CH:23]=[N:22]3)[CH2:25][CH2:26]2)[O:34][N:33]=1)([CH3:37])[CH3:36]
Reactant: CC(C)c1noc([C@H]2CC[C@H](n3ncc4c(Cl)ncnc43)CC2)n1
Reactant: Cc1nnnn1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nnnn1-c1ccc(Oc2ncnc3c2cnn3[C@H]2CC[C@H](c3nc(C(C)C)no3)CC2)cc1
Temperature: 180 °C

Procedure:
A mixture of 4-(5-methyl-tetrazol-1-yl)-phenol (Chembridge Corporation, San Diego, Calif., USA; 76 mg, 0.43 mmol), 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-trans-cyclo-hexyl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 26; 150 mg, 0.43 mmol), and potassium carbonate (72 mg, 0.52 mmol) in dimethylformamide (5 mL) was heated in a microwave at 180° C. for 10 min. The mixture was filtered. The filtrate was concentrated and purified using a Supelco 23 g column, eluting with 0-3% methanol/dichloromethane to give 1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-trans-cyclohexyl]-4-[4-(5-methyl-tetrazol-1-yl)-phenoxy]-1H-pyrazolo[3,4-d]pyrimidine (86 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:13][C:8]3([NH:12][CH2:11][CH2:10][NH:9]3)[C:6]=2[CH:7]=1.[CH2:14](Cl)[C:15](=[CH2:17])[CH3:16]>CO>[ClH:1].[CH2:16]([S:13][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:8]1[NH:12][CH2:11][CH2:10][N:9]=1)[C:15](=[CH2:14])[CH3:17]
Reactant: Clc1ccc2c(c1)C1(NCCN1)S2
Reactant: C=C(C)CCl
Solvent: CO
Product: C=C(C)CSc1ccc(Cl)cc1C1=NCCN1
Product: Cl

Procedure:
32 Parts of 4-chlorobenzothietane-2-spiro-2'-imidazolidine is reacted in 400 parts of methanol with 13.6 parts of methallyl chloride as described in Example 11. The yield is 42 parts (92% of theory) and the melting point is 228° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.COC1C=CC(C[N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[N:40]=[CH:39][C:38]([NH2:41])=[CH:37][N:36]=4)=[C:28]3[C:27]([CH3:42])=[N:26]2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([NH:41][C:38]3[CH:37]=[N:36][C:35]([O:34][C:33]4[CH:32]=[CH:31][N:30]=[C:29]5[NH:25][N:26]=[C:27]([CH3:42])[C:28]=45)=[N:40][CH:39]=3)=[O:17])=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ncc(N)cn4)ccnc32)cc1
Product: Cc1n[nH]c2nccc(Oc3ncc(NC(=O)c4ccnn(-c5ccc(F)cc5)c4=O)cn3)c12
Yield: 4.6 %

Procedure:
Prepared by 2-step process (Example 19, Step D and Example 13 Step D) from 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.103 g, 0.442 mmol obtained from Example 19, step C), and 2-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyrimidin-5-amine (0.04 g, 0.110 mmol). The crude material was purified by preparative TLC (1.0 mm thickness, EtOAc) to afford 2.3 mg (9%) of the desired product. LRMS M+1 (459.0) observed. 1H NMR (400 MHz, CDCl3) δ 11.88 (s, 1H), 9.04 (s, 2H), 8.51 (br s, 1H), 8.40 (m, 1H), 8.27 (m, 1H), 7.59 (m, 2H), 7.23 (m, 2H), 6.94 (m, 1H), 2.50 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8][C:7]([CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([C:21]([F:24])([F:23])[F:22])[C:6]=2[CH:36]=1.[I-:37].[Na+].CNCCNC>O1CCOCC1.C(OCC)(=O)C.[Cu](I)I>[I:37][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8][C:7]([CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([C:21]([F:24])([F:23])[F:22])[C:6]=2[CH:36]=1
Reactant: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(Br)ccc32)cc1
Reactant: [I-]
Agent: I[Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(I)ccc32)cc1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
To a solution of N-{[6-bromo-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide (1.18 g, 2.08 mmol), copper iodide (I) (79 mg, 0.416 mmol) and sodium iodide (624 mg, 4.16 mmol) in dioxane (4.2 mL), N,N′-dimethylethylene diamine (89 μL, 0.832 mmol) was added at room temperature. The reaction solution was stirred for 5 hours under heating at 110° C. The temperature of the solution was brought to room temperature, and the solution was diluted with ethyl acetate, which was washed sequentially with a saturated aqueous ammonium chloride solution and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The resulting solid was washed with hexane and ethyl acetate, whereby the objective compound (995 mg, 78%) was obtained as a white solid.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)=[O:4].[NH2:17][CH2:18][CH2:19][CH2:20][NH2:21].[C:22]([O:26][C:27](=[O:46])NCCNC(C1NC2C(C=1)=CC=C([N+]([O-])=O)C=2)=O)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:46])[NH:17][CH2:18][CH2:19][CH2:20][NH:21][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)=[O:4])([CH3:25])([CH3:24])[CH3:23]
Reactant: NCCCN
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Reactant: COC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Product: CC(C)(C)OC(=O)NCCCNC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 95 %

Procedure:
Compound 121 was prepared from compound 34 with 1,3-diaminopropane, followed by Boc-protection according to the procedure for compound 35. Yield: 95%.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28].[CH2:37]([NH:39][CH2:40][CH2:41][OH:42])[CH3:38]>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:27](=[O:28])[N:2]([C@H:3]2[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:39]([CH2:37][CH3:38])[CH2:40][CH2:41][OH:42])[CH2:7][CH2:8]2)[CH3:1])=[CH:31][CH:32]=1
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CCNCCO
Solvent: O=C(O)C(F)(F)F
Product: CCN(CCO)CCCCC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.Trifluoroacetic acid salt and 4-chlorophenyl chloroformate were reacted, followed by treatment with 2-ethylamino-ethanol to give trans-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester, MS: 425 (MH+, 1Cl).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([SH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:27][CH2:28][CH2:29][CH2:30]Br>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([S:17][CH2:30][CH2:29][CH2:28][OH:27])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1cc2c(S)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(SCCCO)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 15.3 %

Procedure:
Sodium hydride (20 mg) was added to a stirred solution of ethyl N-(3,4-dichlorobenzyl)-4-mercaptoindole-2-carboxylate (170 mg) in DMF (7.5 ml). After 1 hour, 3-hydroxyprop-1-yl bromide (89 mg) was added and stirring continued for 16 hours. The reaction mixture was partitioned between water and ethyl acetate and combined organic extracts were dried (MgSO4), concentrated in vacuo and the residue purified by column chromatography using dichloromethane as eluent to give the product as a yellow gum (30 mg, 14%); M/z (+) 480.1 (MH+).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1([C:9](=O)[CH2:10][C:11]#[N:12])[CH2:8][CH2:7][CH2:6][CH2:5]1.[OH-].[Na+]>O>[CH:4]1([C:9]2[CH:10]=[C:11]([NH2:12])[O:3][N:2]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: N#CCC(=O)C1CCCC1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(C2CCCC2)no1
Temperature: 50 °C
Yield: 60.3 %

Procedure:
Hydroxylamine hydrochloride (6 g, 86 mmol) and 3-cyclopentyl-3-oxopropanenitrile (10 g, 73 mmol) were added to a solution of NaOH (9 g, 225 mmol) in water (100 mL) and the resulting mixture was heated at 50° C. overnight. The precipitate was collected by filtration, washed with water, and dried to give 3-cyclopentylisoxazol-5-amine (6.7 g, 61% yield). 1H NMR (400 MHz, DMSO-d6): δ 6.43 (s, 2 H), 4.77 (s, 1 H), 2.84 (m, 1 H), 1.87-1.51 (m, 8 H); MS (ESI) m/z: 153.1 (M+H+).