Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C@:6]1([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][CH:9](OC(=O)C)[C@H:8]([O:15][C:16](=[O:18])[CH3:17])[C@@H:7]1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[NH:36]1[CH:43]=[CH:42][C:40](=[O:41])[NH:39][C:37]1=[O:38].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>C(#N)C>[C:16]([O:15][C@@H:8]1[C@H:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])([CH2:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:14][C@H:9]1[N:36]1[CH:43]=[CH:42][C:40](=[O:41])[NH:39][C:37]1=[O:38])(=[O:18])[CH3:17]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the anomeric mixture 33 (3.0 g, 6.17 mmol) and uracil (1.04 g, 9.26 mmol) in anhydrous acetonitrile (65 cm3) was added N,O-bis(trimethylsilyl)acetamide (9.16 cm3, 37.0 mmol). The reaction mixture was stirred for 1 h at room temperature and cooled to 0° C. Trimethylsilyl triflate (1.8 cm3, 10.0 mmol) was added dropwise and the solution was stirred at 60° C. for 2 h. The reaction was quenched by addition of a saturated aqueous solution of sodium hydrogencarbonate (10 cm3) at 0° C. and extraction was performed with dichloromethane (3×20 cm3). The combined organic phase was washed with brine (2×20 cm3) and was dried (Na2SO4). The solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give nucleoside 40 as a white solid material (2.5 g, 75%). δH (CDCl3) 9.57 (1H, br s, NH), 7.63 (1H, d, J 8.2, 6-H), 7.40-7.24 (10H, m, Bn), 6.18 (1H, d, J 4.5, 1′-H), 5.39-5.32 (2H, m, 2′-H, 5-H), 4.61 (1H, d, J 11.6, Bn), 4.49-4.40 (5H, m, 3′-H, Bn, 1″-Ha), 4.37 (1H, d, J 12.3, 1″-Hb), 3.76 (1H, d, J 10.1, 5′-Ha), 3.49 (1H, d, J 10.1, 5′-Hb), 2.09 (s, 3H, COCH3), 2.04 (3H, s, COCH3). δC (CDCl3) 170.47, 169.94 (C═O), 163.32 (C-4), 150.30 (C-2), 140.24 (C-6), 137.15, 136.95, 128.65, 128.52, 128.32, 128.19, 128.02, 127.77 (Bn), 102.57 (C-5), 87.41, 86.14 (C-1′, C-4′), 77.09, 74.84, 74.51, 73.75, 70.60, 63.73 (C-2′, C-3′, C-5′, C-1″, Bn), 20.79, 20.68 (COCH3). FAB-MS m/z 539 [M]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[CH2:8]([O:10][C:11](=[O:41])[CH2:12][C:13]1[CH:22]=[C:21]([C:23](=[O:39])[C:24]2[CH:29]=[CH:28][C:27]([S:30]([N:33]3CCNCC3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:40])[CH:19]=2)[CH:14]=1)[CH3:9].C=O.C([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[CH2:8]([O:10][C:11](=[O:41])[CH2:12][C:13]1[CH:22]=[C:21]([C:23](=[O:39])[C:24]2[CH:25]=[CH:26][C:27]([S:30]([N:33]3[CH2:7][CH2:6][N:3]([CH3:1])[CH2:4][CH2:5]3)(=[O:32])=[O:31])=[CH:28][CH:29]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:40])[CH:19]=2)[CH:14]=1)[CH3:9]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCNCC3)cc2)c2cc(F)ccc2c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)c2cc(F)ccc2c1
Reaction time: 0.25 h
Yield: 59 %

Procedure:
Triethylamine (0.04 mL, 0.27 mmol) was added to a stirred mixture of {6-fluoro-4-[4-(piperazine-1-sulfonyl)-benzoyl]-naphthalen-2-yl}-acetic acid ethyl ester (0.10 g, 0.17 mmol) in acetonitrile (4 mL) at 0° C. and the reaction mixture was stirred for 15 minutes. Formaldehyde (0.02 mL, 0.83 mmol) and sodium cyanoborohydride (0.017 g, 0.27 mmol) were added to the reaction mixture at 0° C., then the mixture was stirred for another 15 minutes. The reaction mixture was neutralized to pH ˜7 by gradual addition of acetic acid. The reaction mixture was concentrated, and the residue was made alkaline by the addition of a 2.0 N aqueous solution of KOH. The resulting mixture was extracted with diethyl ether (2×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. Silica gel (100-200 mesh) column chromatography (4:1 ethyl acetate-hexanes) afforded 0.05 g (60%) of {6-fluoro-4-[4-(4-methyl-piperazine-1-sulfonyl)-benzoyl]-naphthalen-2-yl}-acetic acid ethyl ester as an off-white sticky solid. MS cald. for C26H27FN2O5S ([M+H]+) 499, obsd. 499.3.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Si:22](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:22]([O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Yield: 99 %

Procedure:
The reactant ethyl 4-hydroxycyclohexanecarboxylate (5.4 g, 30.73 mmol) in DCM (100 mL) was treated with DIPEA (16.06 mL, 92.2 mmol), DMAP (4.13 g, 30.80 mmol) and TBDPS-Cl (11.8 mL, 46.1 mmol) at RT for 16 h. After concentrated in vacuum, the residue was purified by CombiFlash on silica gel column using EtOAC/Hexane as eluents to give ethyl 4-(tert-butyldiphenylsilyloxy)cyclohexanecarboxylate 157a, 12.6 g, 99% yield.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=O)[N:6]=1)([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:25]2[CH2:30][CH2:29][O:28][C:26]2=[O:27])C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=[C:25]2[CH2:30][CH2:29][O:28][C:26]2=[O:27])[N:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Reactant: O=C1OCCC1=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(C=C2CCOC2=O)nc(C(C)(C)C)c1O
Yield: 62.6 %

Procedure:
A solution of 4,6-bis(1,1-dimethylethyl)-5-hydroxypyrimidine-2-carboxaldehyde (0.5 g, 2.1 mmol) and α-triphenylphosphoranylidene-γ-butyrolactone (Katsumi, et al. Chem. Pharm. Bull. [Japan] 1986, 34, 619) (0.95 g, 2.8 mmol) in 50 mL of toluene is warmed to 60° C. overnight. The toluene is evaporated and the residue purified by flash chromatography (silica, 20% EtOAc/hexane). Recrystallization from hexane gives 0.4 g (62%) of α-[[4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]methylene]-γ-butyrolactone, mp 158°-160° C.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>C(O)C>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1
Reactant: COCCN
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Solvent: CCO
Product: COCCNc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Reaction time: 3 h

Procedure:
To a solution of 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 3.0 ml of ethanol were added 25.6 mg (0.337 mmol) of 2-methoxyethylamine, and then the reaction mixture was stirred at 60 for 3 h. Another 51.2 mg (0.674 mmol) of 2-methoxyethylamine were added, and the mixture was stirred at 60° C. for a further 12 h. This was followed by stirring in the microwave at 80° C. for a further 24 h and then at 120° C. for 45 min. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 15.3 mg (12% of theory)
Reaction SMILES: C([O:5][CH2:6][C:7]1[N:11]=[C:10]([NH2:12])[NH:9][N:8]=1)(=O)CO.[CH3:13][C:14]([CH2:16][C:17]([CH3:19])=O)=O>CCO.CC(O)=O>[CH3:13][C:14]1[CH:16]=[C:17]([CH3:19])[N:9]2[N:8]=[C:7]([CH2:6][OH:5])[N:11]=[C:10]2[N:12]=1
Reactant: Nc1nc(COC(=O)CO)n[nH]1
Reactant: CC(=O)CC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(CO)nc2n1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared by a slight modification of a reported procedure (Lippman, E.; Becker, V., Z. Chem., 1974, 14, 405): A solution of (5-amino-1H-1,2,4-triazol-3-yl)methanol glycolate (30.7 g, 0.161 mol, from Step 1, above) and 2,4-pentadione (32.3 g, 0.323 mol, 2 equiv) in a mixture of EtOH (750 mL) and AcOH (250 mL) was refluxed 20 h. At the beginning the reaction mixture was clear solution, then gradually turned yellow towards the end of the heating period. The solvent was removed under reduced pressure, and the resulting yellow paste triturated with EtOH (100 mL) and stirred for 15 min. The slurry was chilled to 5° C. (ice bath) with stirring for 30 min, filtered, and washed with cold (0-5° C.) EtOH. The product was dried in vacuo at 25-30° C. to give 24 g (83.7%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([N:20]3[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Fc1ccc2nc(-c3ccc(Cl)cc3)cc(Cl)c2c1
Solvent: Oc1ccccc1
Solvent: O
Product: NC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccc(F)cc23)CC1
Yield: 90.3 %

Procedure:
A mixture of 4.4 g (15 mmol) of 4-chloro-2-(4-chlorophenyl)-6-fluoroquinoline, 3.9 g (30 mmol) of isonipecotamide, and 6 g of phenol was stirred and heated in an oil bath at 165°-180° for 2 hr. It was then cooled and diluted with 100 ml of water. Crystallization was induced by scratching. The solid was collected and washed with ether to give 5.2 g of crude product, mp 258°-260° dec. Recrystallization from pyridine/water gave off-white needles, mp 259°-261°.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>ClCCl.Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: C1COCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(CBr)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirring solution of commercially-available 4-bromomethyl benzenesulfonyl chloride (1.0 g, 3.71 mmol) in dichloromethane (8 ml) at 0° C. under an argon atmosphere, is added triethylamine (0.575 ml, 4.1 mmol), in one portion, followed by morpholine (0.359 ml, 4.1 mmol). The reaction mixture is stirred for 20 h, warming up slowly to room temperature. The reaction mixture is then diluted with 2N HCl aq (40 ml) and extracted in dichloromethane (20 ml), dried (MgSO4) and evaporated to dryness in vacuo to afford the title compound. No mass ion detected.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C.[C:60]1([SH:66])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:60]1([S:66][C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: Nc1ncccc1Br
Reactant: Sc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Nc1ncccc1Sc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 3-bromopyridin-2-amine (167 mg, 0.966 mmol), Pd2dba3 (22.1 mg, 0.024 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (27.9=mg, 0.048 mmol), N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.9 mmol), thiophenol (121 mg, 1.1 mmol), and dioxane (10 mL) was heated at 100° C. under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, filtered and concentrated. The reaction mixture was purified by MPLC to afford 3-(phenylthio)pyridin-2-amine.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.Cl.[C:13]1([C:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:13]1([C:19]2[CH2:24][CH2:23][N:22]([CH2:3][C:4]3[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=3)[CH2:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CC=C(c3ccccc3)CC2)c(N)n1
Reaction time: 5 h
Yield: 21.4 %

Procedure:
A suspension of 9.7 g (0.050 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride, 9.8 g (0.050 mol) of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride and 13.8 g (0.1 00 mol) of dry potassium carbonate in 125 ml of dimethylformamide was stirred vigorously at 80° for 5 hours. The mixture was cooled, suction filtered, completely freed from the solvents and the residue was triturated in water. The resulting crystals were filtered off under suction and recrystallized from ethanol/water. 3.0 g (21%) of 5-(4-phenyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-2-methyl-pyrimidin-4-ylamine were obtained as yellow crystals; m.p. 165°-166°.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=1.F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:8]([C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CS(=O)(=O)c1ccc(-c2cn(-c3ccc([N+](=O)[O-])cc3)c(Cc3ccc(Br)cc3)n2)cc1

Procedure:
2-(4-Bromo-benzyl)-4-(4-methanesulfonyl-phenyl)-1H-imidazole (9.8 g, 25 mmol) was treated as described in general procedure B using 1-fluoro-4-nitrobenzene to give 2-(4-Bromo-benzyl)-1-(4-nitro-phenyl)-4-(4-methanesulfonyl-phenyl)-1H-imidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:12]=[C:13]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Product: CCOC(=O)c1ccc(-c2csc(-c3ccc(Cl)cc3)n2)cc1
Yield: 47 %

Procedure:
In the same manner as in Example 74, 4-chlorothiobenzamide was reacted with ethyl 4-bromoacetylbenzoate to obtain ethyl 4-[2-(4-chlorophenyl)-4-thiazolyl)benzoate. The product was recrystallized from ethanol. Yield: 47%. Pale yellow prisms. Melting point: 105 to 106° C.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:15][C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:29](=O)[CH:30]([CH3:32])[CH3:31].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(#N)C>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:15]([C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:29][CH:30]([CH3:32])[CH3:31])=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccccc1Nc1cc2c(cc1C)N(C(C)C)CCC2(C)C
Reactant: CC(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)c1ccccc1N(CC(C)C)c1cc2c(cc1C)N(C(C)C)CCC2(C)C
Yield: 34.4 %

Procedure:
Ethyl [(1-isopropyl-4,4,7-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate (Compound 20, 0.12 g, 0.32 mmol) was dissolved in a 10% acetic acid in acetonitrile solution (2.0 mL). The solution was treated with isobutyraldehyde (0.10 mL, 1.1 mmol) and then sodium cyanoborohydride (22 mg, 0.35 mmol) and the reaction stirred at room temperature for 7 hours. 1 M aqueous NaOH was added until pH=6 was reached and the solution was extracted with ether (2×), washed with brine, and dried (Na2SO4). The filtered solution was concentrated under reduced pressure and the residue purified using flash column chromatography (10% ethyl acetate in hexanes) to give the title compound (48 mg) as an oil.
Reaction SMILES: [C:1]([O:5]C)(=O)[CH:2]=[CH2:3].[NH2:7][C:8]1[NH:9][C:10]2[CH:16]=[C:15]([CH3:17])[C:14]([CH3:18])=[CH:13][C:11]=2[N:12]=1>C(O)C>[CH3:17][C:15]1[C:14]([CH3:18])=[CH:13][C:11]2[N:12]=[C:8]3[NH:7][C:1](=[O:5])[CH2:2][CH2:3][N:9]3[C:10]=2[CH:16]=1
Reactant: C=CC(=O)OC
Reactant: Cc1cc2nc(N)[nH]c2cc1C
Solvent: CCO
Product: Cc1cc2nc3n(c2cc1C)CCC(=O)N3
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.4 %

Procedure:
Methyl acrylate (15 g.) was added to a solution of 2-amino-5,6-dimethylbenzimidazole (27.2 g.) in ethanol (100 ml.). After stirring for 2 days at room temperature, the crystalline precipitate which had formed in the reaction mixture was separated by filtration, washed with ethanol and then with ether, to give 7,8-dimethyl-3,4-dihydropyrimido[1,2-a]-benzimidazol-2(1H)-one (37.2 g.), m.p. 322°-323° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=O)=[C:10]([F:17])[C:9]=1[O:18][CH3:19].C[N:21](C=O)C.N1C(Cl)=NC(Cl)=NC=1Cl>C(Cl)Cl>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]#[N:21])=[C:10]([F:17])[C:9]=1[O:18][CH3:19]
Reactant: CN(C)C=O
Reactant: COc1c(Br)ccc(C(=O)O)c1F
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1c(Br)ccc(C#N)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (20 mL) was added dropwise at 0° C. to a suspension of 4-bromo-2-fluoro-3-methoxybenzoic acid (8.30 g, 33.3 mmol) in 100 mL of DCM with 0.5 mL of DMF. The mixture was stirred at 25° C. for 2 hours and the clear solution was concentrated to dryness under reduced pressure. The residue dissolved in 60 mL of anhydrous acetonitrile was added to 600 mL of aqueous NH3.H2O at 0° C. and stirred for 2 hours then extracted with EtOAc twice. The combined EtOAc layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue (6.9 g) was dissolved in 60 mL of DMF and cooled to 0° C. with ice/water bath. Cyanuric chloride (7.70 g, 41.7 mmol) was added and stirred for 2 hours at 0° C. before poured to ice/water. The solid was collected by filtration and was washed with water, dissolved in DCM, dried over anhydrous Na2SO4 and concentrated to afford 4-bromo-2-fluoro-3-methoxybenzonitrile.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.Br[CH2:30][C:31]#[CH:32]>>[CH2:32]([O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)[C:31]#[CH:30]
Reactant: C#CCBr
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: C#CCOCCCc1c[nH]cn1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 5 mmol of 3-bromo-1-propyne are treated as described in Example 5. The title compound is crystallized in the form of the hydrogen oxalate from ethanol and diethyl ether.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>[OH-].[Na+]>[CH3:9][NH:8][C:6](=[O:7])[C:5]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:11][C:2]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cnc(Cl)cc1-c1ccccc1C
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of 3.2 g (12.2 mmol) 6-chloro-N-methyl-4-o-tolyl-nicotinamide in 6.7 ml (60.3 mmol)1-methylpiperazine was stirred at 100° C. for 2.5 h. The reaction mixture was cooled to r.t., treated with 10 ml 0.1N NaOH and extracted. The aqueous phase was separated and extracted twice with THF and the organic phases were washed twice with brine. The combined organic phases were dried over Na2SO4, the solvent was removed under reduced pressure and the residue purified by chromatography over silica gel (CH2Cl2:MeOH=99:1) to yield 3.3 g (83.7%) product as a beige foam.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[CH3:15][O:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:27](=[O:28])/[CH:26]=[CH:25]/[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[O:16][CH3:15])=[N:8]1
Reactant: COc1cccc(/C=C/C(=O)O)c1OC
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Product: COc1cccc(/C=C/C(=O)Nc2ccn(CCCCC(C)(F)F)n2)c1OC

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-(2,3-dimethoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.09 min; [M+H]+=394.28.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Li]CCCC.CCCCCC.F[C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C1COCC1>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([NH:31][S:28]([C:25]2[CH:26]=[CH:27][C:22]([NH:1][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:37][CH:36]=1
Reactant: O=S(=O)(Nc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: NCCN1CCOCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc(Cl)cc1)c1ccc(NCCN2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
N-(2aminoethyl)morpholine (293 μL, 2.25 mmol) was dissolved in THF (7.5 mL) and was cooled down to −78° C. A 2.5N solution of nBuLi in hexane (1 mL, 2.5 mmol) was added dropwise. After 5 min. at −78° C., the mixture was stirred 1 h at −40° C. N-aryl-benzenesulfonamide building block XIII, e.g. 4-fluoro-N-(4-chlorophenyl)benzenesulfonamide (214 mg, 0.75 mmol), was added as a solid. The reaction mixture was stirred 2 h at room temperature, then overnight at 60° C. The reaction was quenched at room temperature with NH4Cl saturated solution in water (5 mL). The desired product was extracted with three portions of ethyl acetate (3×10 mL). Combined organic phases were dried over magnesium sulfate before filtering and removal of solvent. The crude product was purified by flash chromatography, using pure ethyl acetate as eluent. The desired product, e.g. N-(4-chlorophenyl)-4-{[2-(4-morpholinyl)ethyl]amino}benzenesulfonamide (184.2 mg, 62% yield) was obtained as a colorless oil, in 97% purity by BPLC (MaxPlot detection between 230 and 400 nm). This intermediate was used in the next step without further purification.