Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][S:29][CH2:30][CH2:31][OH:32].Cl.N>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][S:29][CH2:30][CH2:31][OH:32])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCSCCCl
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1nc(SCCSCCO)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.2 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (50 ml). To the suspension were added potassium carbonate (100 mg, 0.73 mmol) and 2-(2-chloroethyl)thioethanol (170 mg, 1.2 mmol) in order. The mixture was stirred at room temperature for 24 hours. To the reaction mixture were added 2N hydrochloric acid and then 28% aqueous ammonia. The mixture was extracted with chloroform, the organic layer was dried on magnesium sulfate and then the solvent was removed in vacuo. The residue was purified by silica gel chromatography (5% methanol/chloroform) to give the subject compound (17 mg, yield 6%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH3:36])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[CH:24][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH3:36])=[N:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3cccc(C(F)(F)F)c3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 0.150 g (0.629 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 0.180 g (0.629 mmol) of the above prepared (example 2A]) 3-chloromethyl-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine, dissolved in 5.4 ml of abs. acetonitrile, was added 0.226 g of Cs2CO3 (0.692 mmol). The reaction was stirred for 3.5 h at ambient temperature. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=85/15) yielded 0.248 g of pure title compound as colorless oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[N+:14]([O-])=O>CO.[Pd]>[CH3:18][O:17][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:6]=1[NH2:14]
Reactant: COC(Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-])OC
Agent: [Pd]
Solvent: CO
Product: COC(Cc1cccc(N)c1N)OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.7 %

Procedure:
1-(2,2-Dimethoxy-ethyl)-2,3-dinitro-benzene (1.85 g, 7.19 mmol) was dissolved in 20 mL of MeOH and 90 mg of 10% by weight Pd/C was added. This mixture was stirred under 1 atmosphere of H2 for 14 hours at room temperature. The mixture was filtered over celite and purified by chromatography to afford 3-(2,2-dimethoxy-ethyl)-benzene-1,2-diamine (1.04 g, 73%). 1H NMR (CDCl3) δ 2.87 (2H, d, J=5.3 Hz), 3.37 (6H, s), 4.50 (1H, t, J=5.3 Hz), 7.60 (6.62-6.66, m, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl:50][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH:54]1[CH2:57][NH:56][CH2:55]1>CN(C=O)C>[Cl:50][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH:54]1[CH2:57][N:56]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:55]1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Reactant: Clc1ccccc1OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CC(Oc2ccccc2Cl)C1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 26.7 %

Procedure:
DIPEA (141 mg, 1.09 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (67 mg, 0.27 mmol) in DMF (3 mL) followed by HOBt (39 mg, 0.28 mmol) and EDCI (56 mg, 0.28 mmol). After 2 minutes of stirring, 3-(2-chloro-phenoxy)-azetidine hydrochloride (prepared by the method used for the synthesis of Intermediate 71) (60 mg, 0.27 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Partitioning with cold water and ethyl acetate and concentration of the organic layer after drying over sodium sulfate afforded a residue which was purified by column chromatography (using silica gel 60-120 and 100% EtOAc as eluent) to afford 30 mg (26.7% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[3-(2-chloro-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 411, 98.45%. 1H NMR (300 MHz, DMSO-d6): δ 8.34 (d, 1H), 8.28 (d, 1H), 8.12 (t, 1H), 7.72 (d, 1H), 7.44 (m, 3H), 7.38 (m, 1H), 7.26 (m, 1H), 6.8 (m, 1H), 6.7 (d, 1H), 5.1 (m, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 3.8 (m, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][C:7](N)=[C:6]([F:11])[CH:5]=2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:21].[K+]>O.C(Cl)Cl>[CH:1]1([C:4]2[CH:10]=[CH:9][C:7]([I:21])=[C:6]([F:11])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: [I-]
Reactant: Nc1ccc(C2CC2)cc1F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Fc1cc(C2CC2)ccc1I
Reaction time: 0.08 h
Yield: 71.1 %

Procedure:
To a stirred mixture of 4-cyclopropyl-2-fluoroaniline (1.63 g, 10.78 mmol) in water (20 mL) at 0° C. was added concentrated sulfuric acid (8.6 mL, 15.0 eq.) dropwise, while keeping the temperature constant at 0° C. A solution of sodium nitrite (781.0 mg, 11.32 mmol, 1.05 eq.) in water (2.7 mL) was added and stirred for 5 minutes. This resulting reaction mixture was then added to a solution of potassium iodide (3.76 g, 22.64 mmol, 2.1 eq.) in water (9.7 mL), and the reaction mixture was stirred at 60° C. for 3 h. DCM (400 mL) was added to the cooled reaction. The biphasic layers were separated, and the aqueous layer was extracted with DCM (2×150 mL). The combined organic layers were washed with saturated aqueous Na2S2O4, water, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified via flash column chromatography eluted with 100% heptane to give 2.01 g (71.28%) of 4-cyclopropyl-2-fluoro-1-iodobenzene as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, J=8.0, 6.9 Hz, 1H), 6.76 (dd, J=9.4, 1.9 Hz, 1H), 6.64 (dd, J=8.2, 1.9 Hz, 1H), 1.94-1.77 (m, 1H), 1.09-0.95 (m, 2H), 0.79-0.56 (m, 2H).
Reaction SMILES: [CH:1]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:24][C:25]([N:27]([CH2:32][CH2:33][NH:34][S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N+:44]([O-:46])=[O:45])(=[O:37])=[O:36])[CH2:28][C:29]([OH:31])=O)=[O:26])[C:20](=[O:47])[N:19]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O>C1COCC1>[CH:1]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:24][C:25]([N:27]2[CH2:32][CH2:33][N:34]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[N+:44]([O-:46])=[O:45])(=[O:36])=[O:37])[C:29](=[O:31])[CH2:28]2)=[O:26])[C:20](=[O:47])[N:19]=1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C(=O)C2)c(=O)n1)OC(c1ccccc1)c1ccccc1
Temperature: -20 °C
Yield: 77.3 %

Procedure:
To a solution of N-{[4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetyl}-N-[2-(2-nitro-benzenesulfonylamino)-ethyl]-glycine (1.20 g, 1.8 mmol) in THF (24 mL) was added N-methylmorpholine (0.6 mL, 5.42 mmol) and then the mixture was cooled to −20° C. After stirring for 5 min at the same temperature, isobutyl chloroformate (0.30 mL, 2.31 mmol) was added to the reaction mixture. The resulting mixture was slowly warmed to 0° C. for 1 h. Then the reaction mixture was evaporated in vacuo and dissolved in a mixture of ethyl acetate and acetonitrile. The solution was washed with saturated NaCl solution and dried over sodium sulfate and filtered. The filtrate was evaporated in vacuo and triturated with methanol to precipitate solid. The solid was filtered off, washed with methanol, and dried in vacuo to give the titled compound 0.9 g (77%). 1H-NMR (500 MHz; DMSO-d6) δ 8.35 (t, 1H), 8.12˜7.95 (m, 3H), 7.90 (d, 0.6H), 7.84 (d, 0.4H), 7.48˜7.28 (m, 10H), 6.95 (d, 0.6H), 6.94 (d, 0.4H), 6.79 (s, 1H), 4.82 (s, 1.2H), 4.73 (s, 0.8H), 4.45 (s, 0.8H), 4.27 (s, 1.2H), 4.10˜3.95 (m, 2.4H), 3.95˜3.80 (m, 1.6H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1.Cl.[NH2:17][CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[N:23]([CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[NH:31][C:30]1=[O:36])[CH2:22]2>CN(C=O)C>[O:36]=[C:30]1[CH:29]([N:23]2[CH2:22][C:21]3[C:25](=[CH:26][CH:27]=[C:19]([CH2:18][NH:17][C:11](=[O:13])[CH2:10][C:7]4[CH:6]=[CH:5][C:4]([S:3][C:2]([F:1])([F:15])[F:14])=[CH:9][CH:8]=4)[CH:20]=3)[C:24]2=[O:28])[CH2:34][CH2:33][C:32](=[O:35])[NH:31]1
Reactant: O=C(O)Cc1ccc(SC(F)(F)F)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(SC(F)(F)F)cc1)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 45.8 %

Procedure:
A stirred mixture of 4-(trifluoromethylthio)phenylacetic acid (0.38 g, 1.6 mmol), and CDI-(0.27 g, 1.7 mmol) in DMF (20 ml) was heated at 40° C. for 2 hrs. Then, 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.5 g, 1.6 mmol) was added to the mixture and allowed to stir for 3 h. The mixture was quenched with 4% aqueous HCl (30 mL). The precipitate was filtered and washed with H2O (50 mL) and dried in vacuo, providing N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-2-(4-trifluoromethylsulfanyl-phenyl)-acetamide as a white solid (0.36 g, 46% yield); mp 208-210° C.; HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4. 6.30 (98.81%); 1H NMR (DMSO-d6) δ 1.97-2.03 (m, 1H), 2.36-2.44 (m, 1H), 2.58-2.63 (m, 1H), 2.86-2.98 (m, 1H), 3.60 (s, 2H), 4.28 (d, 1H, J=17.4), 4.38-4.45 (m, 3H), 5.11 (dd, 1H, J=13.2, J=5.1), 7.38 (d, 1H, J=8.1), 7.44-7.46 (m, 3H), 7.65-7.68 (m, 3H), 8.75 (t, 1H, J=5.7), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 41.8, 42.3, 47.0, 51.5, 120.7 (q, J=1.9), 122.1, 122.9, 127.0, 129.6 (q, J=306), 130.4, 136.1, 140.2, 142.3, 143.6, 167.9, 169.5, 171.0, 172.9; LCMS: MH=492; Anal. Calcd for C23H20F3N3O4S+0.15H2O: C, 55.90; H, 4.14; N, 8.50. Found: C, 55.56; H, 4.09; N, 8.37.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@:5]1([CH3:22])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16](OCC)=O)[C:6]1=[O:21].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:28][C:27]=1[S:40]([NH2:43])(=[O:42])=[O:41].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@:5]1([CH3:22])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[CH:28][C:27]=3[S:40](=[O:41])(=[O:42])[N:43]=2)[C:6]1=[O:21]
Reactant: CCOC(=O)C1=C(O)c2ccccc2[C@@](C)(CCC(C)(C)C)C1=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Temperature: 100 °C

Procedure:
To a solution of the product of Example 49-4 (330.1 g, 0.999 mol) in toluene (1500 mL) was added the product of Example 17A-4 (287.1 g, 0.999 mol). The solution was heated to 100° C. for 4 h then cooled to RT. The solution was transferred to a pressure bottle and triethylamine (505.4, 4.99 mol) was added and the solution was heated to 100° C. for 26 h. The solution was concentrated to ⅓ of the original volume and ethyl acetate (1500 mL) was added. The organic layer was washed with 10% KH2PO4 and 10% NaCl then concentrated to a thick oil then chased with dichloromethane. The crude title compound (assay for 375.8 g, 68%) was used directly in the next step.
Reaction SMILES: N1C=CC=CC=1S(O)(=O)=O.[CH:11]([N:24]1[CH2:27][CH:26]([OH:28])[CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CS(C)=O.C(N(CC)CC)C>[CH:11]([N:24]1[CH2:27][C:26](=[O:28])[CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=S(=O)(O)c1ccccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 60 %

Procedure:
Under cooling with ice, pyridinesulfonic acid (19.7 g) in dimethyl sulfoxide (84 mL) was added dropwise to 1-benzhydrylazetidin-3-ol (4.79 g) in triethylamine (27.9 mL), and the resultant mixture was stirred at 50° C. for 40 minutes. The reaction mixture was partitioned between ice-water and ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as a solid (2.85 g, 60%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH2:28][C:29]4[CH:34]=[C:33]([O:35][CH2:36][CH3:37])[CH:32]=[CH:31][C:30]=4[O:38][CH2:39][CH3:40])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:39]([O:38][C:30]1[CH:31]=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[CH:34][C:29]=1[CH2:28][O:27][C:21]1[CH:20]=[C:19]([N:18]2[C:12]3[CH:11]=[C:10]([CH2:9][OH:8])[N:15]=[CH:14][C:13]=3[N:16]=[CH:17]2)[S:23][C:22]=1[C:24]([NH2:26])=[O:25])[CH3:40]
Reactant: CCOc1ccc(OCC)c(COc2cc(-n3cnc4cnc(CO[Si](C)(C)C(C)(C)C)cc43)sc2C(N)=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOc1ccc(OCC)c(COc2cc(-n3cnc4cnc(CO)cc43)sc2C(N)=O)c1
Temperature: 0 °C

Procedure:
A mixture of 450 mg of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[(2,5-diethoxybenzyl)oxy]thiophene-2-carboxamide in 20 ml THF is cooled to 0° C. At 0° C. 0.28 ml tetra-n-butylammonium fluoride (˜75% in H20) is added. The reaction mixture is allowed to warm to room temperature and stirred over night.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[NH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.[C:16]1([O:22][CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[NH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:19]1[CH:20]=[CH:21][C:16]([O:22][CH3:23])=[CH:17][CH:18]=1)=[O:15]
Reactant: NCCCC(=O)O
Reactant: COc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: COc1ccc(C(=O)CCCN)cc1
Temperature: 80 °C
Reaction time: 0.83 h
Yield: 78 %

Procedure:
Trifluoromethanesulfonic acid (4 ml) was ice-cooled, and 4-aminobutyric acid (1093 mg, 10.6 mmol) was added. Then, anisole (1 ml, 9.25 mmol) was added. The mixture was heated and stirred at 80° C. for 50 min. The mixture was cooled to room temperature and added dropwise to water (17 ml) under ice-cooling. The mixture was stirred under ice-cooling for 20 min and then at −10° C. for 30 min. The crystals were filtrated, washed with ice-cooled saturated brine, and dried under reduced pressure to give 4-amino-4′-methoxybutyrophenone trifluoromethanesulfonate (2.47 g, yield 78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[N:18][C:17]([C:20]#[N:21])=[C:16](Cl)[N:15]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][NH2:25]>CC(O)C.O>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]3[NH:24][N:25]=[C:20]([NH2:21])[C:17]3=[N:18][CH:19]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NN
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(C#N)c(Cl)n2)cc1
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cnc3c(N)n[nH]c3n2)cc1
Temperature: 120 °C

Procedure:
[4-(6-Chloro-5-cyano-pyrazin-2-yl)-phenyl]carbamic acid tert-butyl ester (1.0 g) was suspended in a mixture of 10 ml iPrOH and 10 ml 35% hydrazine in water at RT and heated to 120° C. by microwave irradiation for 70 min under stirring in a sealed vessel. The reaction mixture was left to cool to RT, and the precipitate was filtered off and washed with water to afford [4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-carbamic acid tert-butyl ester as a yellow solid after drying under vacuum. Yield: 815 mg (83%).
Reaction SMILES: Cl[Si](C)(C)C.O.Cl.[CH3:8][N:9]([CH:11]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1(CC1C=CC=C(C(F)(F)F)C=1)[OH:18])[CH3:10]>CC(=O)CC>[CH3:10][N:9]([CH:11]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])[CH3:8]
Reactant: CN(C)C(c1cccs1)C1CCCCC1(O)Cc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCC(C)=O
Solvent: O
Product: CN(C)C(c1cccs1)C1CCCCC1=O

Procedure:
0.31 g (12.6 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.46 g (12.6 mmole) of 3-chloromethylbenzotrifluoride dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.50 g (10.5 mmole) of the 2-(dimethylaminothiophen-2-ylmethyl)cyclohexanone prepared according to stage 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.33 g of crude base (79.6% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 20 ml of water and 5 ml of ammonia solution (25 vol. %), extracted three times with 20 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 0.63 g of crude base (15.0% of theory) was obtained, from which 0.39 g of 2-[dimethylaminothiophen-2-ylmethyl]-1(3-trifluoromethylbenzyl)cyclohexanol, hydrochloride (8.5% of theory) was obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 98° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[CH:14][C:13]=1[C:24]([F:27])([F:26])[F:25].[OH-].[K+].Cl>CN(C)C=O>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[CH:14][C:13]=1[C:24]([F:25])([F:27])[F:26])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ccccc2[N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-nitroaniline (6.91 g.) and 2-chloro-3,5-dinitrobenzotrifluoride (13.53 g.) in dry dimethylformamide (150 ml.) potassium hydroxide (8.0 g, pellets) was added in small portions over 15 minutes. During the addition, the temperature rose from 20° C. to 80° C. When the addition was complete the mixture was stirred for two hours at 60° C., after which concentrated hydrochloric acid was added to acidify the mixture. Industrial methylated spirit (50 ml.) was then added and the mixture stirred for 15 minutes at the ambient temperature. The solid precipitate was collected by filtration, washed with water and dried to yield 2(2-nitroanilino)-3,5-dinitrobenzotrifluoride, melting point 154°-156° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:18]2[C@@H:27]3[C@@H:22]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:21](=[O:28])[N:20]([CH:29]3[CH2:34][CH2:33][N:32](C4C=CC([N+]([O-])=O)=CC=4)[CH2:31][CH2:30]3)[N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]>>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:18]2[C@@H:27]3[C@@H:22]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:21](=[O:28])[N:20]([CH:29]3[CH2:34][CH2:33][N:32]([C:2]4[N:7]=[CH:6][CH:5]=[CH:4][N:3]=4)[CH2:31][CH2:30]3)[N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: Clc1ncccn1
Reactant: COc1ccc(C2=NN(C3CCN(c4ccc([N+](=O)[O-])cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Product: COc1ccc(C2=NN(C3CCN(c4ncccn4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from 2-Chloro-pyrimidine and starting compound A1 as described for compound 11. Crystallisation from methanol. M.p. 163-166° C.
Reaction SMILES: C(N1CCO[C@H](CC2C=CC=C(CO)C=2)C1)(OC(C)(C)C)=O.[CH2:23]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][C:31]1=[O:36])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Br:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41]Br>>[CH2:23]([N:30]1[CH2:35][CH2:34][O:33][CH:32]([CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[C:38]([Br:37])[CH:39]=2)[C:31]1=[O:36])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: BrCc1cccc(Br)c1
Reactant: O=C1COCCN1Cc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1
Product: O=C1C(Cc2cccc(Br)c2)OCCN1Cc1ccccc1

Procedure:
N-Benzyl-2-(3-bromobenzyl)-morpholin-3-one was prepared as described for example 71, intermediate (b), but using 4-benzylmorpholine-3-one and 3-bromobenzyl bromide and was isolated as a pale yellow oil.
Reaction SMILES: [C:1]([N:4]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[N:17][C:18](Cl)=[CH:19][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)(=[O:23])[CH3:22].C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:1]([N:4]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[N:17][C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:21](=[O:23])[CH3:22])=[CH:19][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1Cc2cc(Cl)ncc2C=Cc2ccccc21
Reactant: CC(=O)c1ccccc1B(O)O
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)c1ccccc1-c1cc2c(cn1)C=Cc1ccccc1N(C(C)=O)C2
Yield: 59.2 %

Procedure:
The title compound (12.0 mg, 70%) was prepared from 25E (16.0 mg, 0.055 mmol) and 2-acetylphenylboronic acid (13.8 mg, 0.079 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.05 min; LCMS Found: (M+H)+=367.