Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([CH:4]1[CH:3]=[C:2]([CH3:1])[CH2:7][CH2:6][C:5]1=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CC1=CCC(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=CC(Cc2ccccc2)C(=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of the above (18) (6.1 g) in dry THF (100 mL) at -78° C. was added a solution of lithium bis-trimethylsilylamide (50 ml, 1N in THF). The solution was stirred for 20 min then benzylbromide (30 mL) was added in one portion. The reaction was stirred for 6 h at -78° C. then allowed to slowly warm to room temperature. After evaporation of the solvent, the remaining mixture was taken up in hexane, washed with saturated NaCl, dried over MgSO4 and evaporated. The product (19) was obtained by flash chromatography on silica gel eluted with 2.5% ethyl acetate in hexane. (4.15 g, 39%): GC RT 7.29 min. (HP 530 mμ×20 m methylsilicone column, He carrier flow rate 20 mL/min., 100° C., 1 min. , 100°-180° C. 10° C./min.; TLC Rf 0.31 (5% ethyl acetate, n-hexane); 1H NMR (CDCl3) δ1.73(3H, br s), 2.2-3.3(7H, m), 5.35(1H, br s), 7.28(5H, m).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]([NH2:15])=[NH:14])[CH2:2][CH2:3][CH3:4].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.O>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[NH:15][C:19](=[O:18])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCCOc1ccccc1NC(=N)N
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccccc1Nc1ncc(C(=O)OCC)c(=O)[nH]1
Temperature: 100 °C
Yield: 86.8 %

Procedure:
A mixture of N-(2-butoxyphenyl)guanidine (11.6 g) and diethyl ethoxymethylenemalonate (12.1 g) in DMF (70 ml) is heated at 100° C. for 9 hours. After cooling, water (50 ml) is added to the reaction mixture, and the precipitate is collected by filtration, washed with ethanol and recrystallized from a mixture of DMF and water to give ethyl 2-(2-butoxyanilino)-1,6-dihydro-6-oxo-5-pyrimidinecarboxylate (16.1 g). M.p. 211°-213° C.
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:9]([OH:11])=O)[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:52]([O:59][C:60]([N:62]1[CH2:66][CH:65]([C:67](=[O:75])[NH:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:64]2[NH:76][CH2:77][CH2:78][CH:63]12)=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN1C(=O)CCC1.CCOCC>[CH2:52]([O:59][C:60]([N:62]1[CH2:66][CH:65]([C:67](=[O:75])[NH:68][C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[CH:64]2[N:76]([C:9](=[O:11])[CH:2]([NH:1][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]3)[CH2:77][CH2:78][CH:63]12)=[O:61])[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: O=C(Nc1ccccc1)C1CN(C(=O)OCc2ccccc2)C2CCNC12
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(C(=O)Nc1ccccc1)CN2C(=O)OCc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
A solution of Boc-Chg-OH (222 mg, 0.86 mmol) in NMP (5 mL) was cooled to 0° C. and treated with HATU (328 mg, 0.86 mmol) and DIPEA (0.17 mL, 0.98 mmol) followed, in 15 min, by the addition of 38 (300 mg, 0.82 mmol). The reaction mixture was allowed to warm to ambient temperature. After 18 h, the solution was diluted with Et2O, washed with H2O, 1M HCl, H2O, saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by column chromatograhpy on silica gel with 2:1 hexane:EtOAc afforded 39 (460 mg) as a white foam. 1H NMR (CDCl3, 300 MHz), mixture of rotamers: δ9.96 (d, J=18.9 Hz, 0.5H), 7.68 (d, J=9 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.39-7.28 (m, 7H), 7.10 (dd, J=7.2, 15 Hz, 1H), 5.32-5.28 (m, 0.5H), 5.20-5.12 (m, 2.5H), 4.81-4.78 (m, 0.5H), 4.70 (d, J=6.6 Hz, 0.5H), 4.55-4.49 (m, 1H), 4.39-4.27 (m, 1.5H), 4.02-3.99 (m, 1H), 3.54-3.40 (m, 2H), 3.22-3.09 (m, 2H), 2.51-2.26 (m, 1H), 2.10-2.09 (m, 0.5H), 1.94-1.62 (m, 8H), 1.52-1.43 (m, 11H), 1.18-0.86 (m, 6H) ppm. Mass spectrum, m/z [605.7] (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:5]=[C:6]([F:8])[CH:7]=1.[Li]CCCC.[S:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>C1COCC1>[CH3:15][C:10]1[N:9]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([C:24]3([OH:27])[CH2:25][CH2:26][S:21][CH2:22][CH2:23]3)=[C:6]([F:8])[CH:5]=2)[C:13]([CH3:14])=[CH:12][CH:11]=1
Reactant: Cc1ccc(C)n1-c1cc(F)cc(F)c1
Reactant: O=C1CCSCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(F)c(C2(O)CCSCC2)c(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To the solution of 1-(3,5-difluorophenyl)-2,5-dimethyl-1H-pyrrole (Step 1, 16.7 g, 80.6 mmol) in anhydrous THF (161 mL) at −78° C. under N2 is added n-BuLi (1.6 M in hexanes, 51.8 mL, 82.9 mmol) dropwise. After stirring at −78° C. for 1 h, the reaction mixture is treated with tetrahydrothiopyran-4-one (5.35 g, 46.1 mmol) in anhydrous THF (46 mL) dropwise and then stirred at −78° C. for 2 h and at 0° C. for 3 h. The reaction is then quenched by the slow addition of saturated aqueous ammonium chloride (50 mL), diluted with H2O (50 mL) and Et2O (50 mL) and the layers are separated. The organic phase is washed with H2O (50 mL) and saline (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue is purified by silica gel chromatography (650 mL, 10-20% EtOAc/Hexanes eluent) to give the title compound, mp 125-126° C.; MS (ESI+) for C17H19F2NOS m/z 324 (M+H)+.
Reaction SMILES: [CH2:1](N(CC)C1C=C(C=C(C)N=1)C(O)=O)C.Cl[C:17]1[CH:18]=[C:19]([CH:23]=[C:24](Cl)[N:25]=1)[C:20]([OH:22])=[O:21].[CH2:27]([NH:31][CH3:32])[CH:28]([CH3:30])[CH3:29]>>[CH2:27]([N:31]([CH3:32])[C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:1])[N:25]=1)[C:20]([OH:22])=[O:21])[CH:28]([CH3:30])[CH3:29]
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Reactant: CNCC(C)C
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Product: Cc1cc(C(=O)O)cc(N(C)CC(C)C)n1

Procedure:
The title compound is prepared in analogy to 2-diethylamino-6-methyl-isonicotinic acid starting from 2,6-dichloro-isonicotinic acid and N-isobutyl-N-methylamine; LC-MS: tR=0.50*min, [M+1]+=223.28.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:2][C:3]([NH:5][C:6]2[CH:26]=[CH:25][C:9]3[N:10]=[C:11]([NH:14][C@H:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][CH2:17][CH2:16]4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:30][CH2:29]1
Reactant: CN1CCNCC1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)COC(N[C@@H]2CCCc4ccccc42)=N3)CC1
Yield: 100 %

Procedure:
Prepared from the above described 2-chloro-N-{2-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amino]-4H-benzo[d][1,3]oxazin-6-yl}-acetamide (150 mg, 0.406 mmol, HPLC 1.185 min) and N-methylpiperazine (901 ul, 8.1 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (176 mg, 100%, HPLC 0.503 min), MS (ISP) m/e=434.4 [(M+H)+].
Reaction SMILES: [Si:1]([C:8]1C(C)=[C:16]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=[CH:15]2)[C:9]=1[CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=[O:28])C=1Cl.S([O-])([O-])(=O)=S.[Na+].[Na+].C[C:42]([CH3:44])=[O:43]>>[Si:1]([C:8]1[C:44]([CH:42]=[O:43])=[C:16]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=[CH:15]2)[C:9]=1[CH:19]=[O:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)=O
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Cc1c2cccccc-2c(C)c1[Si](C)(C)C(C)(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)c1c(C=O)c2cccccc-2c1C=O
Reaction time: 1 h
Yield: 89 %

Procedure:
90 mg of 40 (0.33 mmol) was dissolved in 5 ml of acetone at room temperature. To this solution was added 359 mg of DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) (1.58 mmol) in one portion. The reaction mixture immediately turned color from blue to red as it was stirred in the dark for 1 hour. When all reactant was gone the reaction mixture was stirred with 15 ml of saturated sodium thiosulfate solution to remove unreacted DDQ for 2 min and then 15 ml of saturated sodium bicarbonate was added, and then it was stirred for 2 min to remove acidic DDQH2. The reaction mixture was then extracted with chloroform (5×40 ml). The combined bottom red organic phases were subsequently washed with 15 ml of saturated NaCl solution, dried over anhydrous MgSO4, filtered and evaporated. The red residue was then purified by column chromatography using 7:3 hexane:ethylacetate to provide 88.4 mg of bis-aldehyde 32 in 89% yield as red crystals. 1H NMR δ 10.59 (s, 2H), 10.12 (dd, 2H, J=10), 8.11 (tt, 1H, J=10), 7.94 (t, 1H, J=10), 1.05 (s, 9H), 0.61 (s, 6H); 13C NMR δ 190.28, 162.4, 144.9, 142.75, 140.94, 134.14, 132.73, 27.06, 17.99, 0.98; LRMS (LC/MS-ESI, MeOH) m/e 299 (MH+)
Reaction SMILES: [F:1][C:2]1([F:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.IN1C(=O)[CH2:18][CH2:17][C:16]1=O.F.FC1C=C2C(CCCC32SCCS3)=CC=1.S([O-])([O-])(=[O:40])=S.[Na+].[Na+]>ClCCl.N1C=CC=CC=1>[F:13][C:2]1([F:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C@H:5]([CH:17]([CH3:18])[CH3:16])[C:4](=[O:40])[CH2:3]1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc2c(c1)C(F)(F)CCC2
Reactant: O=S([O-])([O-])=S
Agent: F
Agent: Fc1ccc2c(c1)C1(CCC2)SCCS1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@@H]1C(=O)CC(F)(F)c2cc(F)ccc21
Temperature: -50 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
1,1,7-Trifluoro-1,2,3,4-tetrahydronaphthalene (52): A solution of N-iodosuccinimide (32.3 g, 144.0 mmol) in dichloromethane (260 mL) was cooled to −78° C. in a plastic round bottom flask. A 70% solution of hydrogen fluoride in pyridine (18 mL) followed by a dichloromethane solution (20 mL) of dithiolane 61 (8.65 g, 36.0 mmol) were added dropwise. Upon completion of addition the reaction was warmed to −50° C. and stirred at this temperature for 3 h. The reaction was then poured into ice cold saturated sodium bicarbonate (200 mL) followed by a saturated solution of sodium thiosulfate (150 mL). The colored reaction became colorless and biphasic. The organic phase was separated, dried (sodium sulfate) and concentrated to give a yellow oil. The product was purified by silica gel chromatography with a gradient heptanes/ethyl acetate eluent system on an ISCO companion system to give the desired product as a yellow oil (3.11 g, 16.7 mmol, 46% yield). 1H NMR (400 MHz, CDCl3) δ: 7.34 (d, J=8 Hz, 1H), 7.07 (m, 1H), 7.05 (m, 1H), 2.80 (brs, 2H), 2.26 (m, 2H), 1.99 (m, 2H); 19F NMR (400 MHz, CDCl3) δ: −91.7 (s, 2H), −122.8 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1(C)[C@@H](/C=C\C(=O)OC2C=CC=CC=2)[C@H:3]1C(O)=O.[CH3:20][C:21]1([CH3:54])[C@@H:23](/[CH:24]=[CH:25]\[C:26](=[O:34])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:22]1[C:35]([O:37][C@H:38](C#N)[C:39]1[CH:44]=C[CH:42]=[C:41]([O:45]C2C=CC=CC=2)[CH:40]=1)=[O:36].CC1(C)C(/C=C\C(=O)OC2C=CC=CC=2)C1C([O-])=O>>[CH3:20][C:21]1([CH3:54])[C@@H:23](/[CH:24]=[CH:25]\[C:26](=[O:34])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:22]1[C:35]([O:37][CH:38]1[CH2:42][C:41](=[O:45])[C:40]([CH2:3][CH:2]=[CH2:1])=[C:39]1[CH3:44])=[O:36]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)Oc1ccccc1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)Oc1ccccc1
Agent: CC1(C)C(/C=C\C(=O)Oc2ccccc2)C1C(=O)[O-]
Product: C=CCC1=C(C)C(OC(=O)[C@@H]2[C@H](/C=C\C(=O)Oc3ccccc3)C2(C)C)CC1=O
Yield: 189.6 %

Procedure:
Using the procedure of Example 2, 1.5 g of (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-phenoxy-1-propenyl]-cyclopropane-carboxylic acid and 1 g of (S) 3-(2-propenyl)-1-hydroxy-2-methyl-4-oxo-cyclopent-2-en-1-yl were reacted to obtain 1.6 g of (1S) 2-methyl-4-oxo-3-(2-propenyl)-2-cyclopenten-1-yl (1R, cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-phenoxy-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+66°±2.5 (c=0.5% in benzene).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:30]1([CH3:39])[C:31]([C:36](Cl)=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=1>C(Cl)Cl>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:21]([C:20]3[CH:24]=[CH:25][C:17]([F:16])=[CH:18][CH:19]=3)=[O:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:36](=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH3:39])[CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2ccccc21
Reactant: Cc1ccccc1C(=O)Cl
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCn1c2ccc(C(=O)c3ccc(F)cc3)cc2c2cc(C(=O)c3ccccc3C)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-ethylcarbazol (8.0 g) in CH2Cl2 (200 mL) is added 4-fluorobenzoyl chloride (6.5 g) and AlCl3 (5.6 g) at 0° C. After stirring overnight at room temperature, 2-toluoyl chloride (6.5 g) and AlCl3 (6.0 g) are further added at 0° C. and the mixture is stirred at room temperature overnight. The reaction mixture is poured into ice-water, and the crude product is extracted twice with CH2Cl2. The combined organic layer is washed with H2O and brine, dried over MgSO4, and concentrated to give the residue, which is used for the next step without further purification. The structure of the product, which is obtained as a beige solid, is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 1.52 (t, 3H), 2.35 (s, 3H), 4.46 (q, 2H), 7.20 (t, 2H), 7.27-7.46 (m, 4H), 7.50 (t, 2H), 7.86 (d, 1H), 7.88 (d, 1H), 8.02 (d, 1H), 8.07 (d, 1H), 8.54 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: Cl.Cl.Cl.[N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]=1[S:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][S:29][C:30]1[C:35]([NH:36][C:37](=[O:40])[CH2:38]Br)=[C:34]([S:41][CH3:42])[CH:33]=[C:32]([CH3:43])[N:31]=1>C(#N)C.O>[N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]=1[S:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:38][C:37]([NH:36][C:35]2[C:30]([S:29][CH3:28])=[N:31][C:32]([CH3:43])=[CH:33][C:34]=2[S:41][CH3:42])=[O:40])[CH2:18][CH2:17]1
Reactant: c1ccc2[nH]c(SCCN3CCNCC3)nc2c1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
1-[2-(Benzimidazol-2-ylthio)ethyl]piperazine trihydrochloride 1.0 g (2.69 mmol) was suspended in acetonitrile (30 mL), and potassium carbonate 1.45 g (10.49 mmol) was added to the suspension. Water (8 mL) was added dropwise to the mixture under stirring at room temperature until the entirety of the suspension assumed a homogeneous solution. Subsequently, N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-bromoacetamide 810 mg (2.52 mmol) was gradually added to the mixture, and the mixture was stirred for 2.5 hours at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with chloroform (100 mL×3). The organic layer was washed with saturated brine (50 mL), followed by drying over sodium sulfate anhydrate and concentrating under reduced pressure. The residue was purified through silica gel column chromatography (eluent: chloroform:saturated ammonia in methanol=20:1). The thus-obtained oily product was crystallized from ethanol-diethyl ether, thereby yielding 1.16 g of 2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide (yield: 88%) as a colorless crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](F)(F)F.[Al+3].[Cl-:14].[Cl-:15].[Cl-].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)([Cl:15])[Cl:14]
Reactant: [Cl-]
Reactant: FC(F)(F)c1ccc(Cl)cc1Cl
Reactant: Fc1ccccc1
Agent: [Al+3]
Product: Fc1ccc(C(Cl)(Cl)c2ccc(Cl)cc2Cl)cc1

Procedure:
From 2,4-dichlorobenzotrifluoride (215 mg, 1 mmol), AlCl3 (400 mg, 3 mmol) and fluorobenzene (96 mg, 1 mmol), light yellow oil (382 mg, 118% crude).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][O:18][C:19]([CH2:21][CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)=[O:20]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:27]([C:26]2[CH:30]=[CH:31][C:23]([CH2:22][CH2:21][C:19]([O:18][CH3:17])=[O:20])=[CH:24][CH:25]=2)[OH:28])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: COC(=O)CCc1ccc(C(=O)O)cc1
Product: COC(=O)CCc1ccc(C(O)=C2C(=O)N(C(C)=O)c3ccc(C(C)=O)cc32)cc1

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-(2-methoxycarbonyl-ethyl)-benzoic acid
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:12]=2[N:11]=1.[CH3:22][C:23]([CH3:27])([CH3:26])[CH2:24][NH2:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:22][C:23]([CH3:27])([CH3:26])[CH2:24][NH:25][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[NH:14][C:10]([NH:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:11][C:12]=2[CH:18]=1)=[O:20]
Reactant: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Reactant: CC(C)(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)CNC(=O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1

Procedure:
Prepared analogously to example 3c from 2-(2,6-dichloro-phenylamino)-1H-benzimidazole-5-carboxylic acid, 2,2-dimethyl-propylamine, TEA and TBTU in DMF.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:10][C:11]1([CH3:19])[O:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[O:12]1.[CH2:20](OC(OCC)OCC)C>C(O)C>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][CH:20]=[C:14]2[C:15](=[O:17])[O:16][C:11]([CH3:19])([CH3:10])[O:12][C:13]2=[O:18])=[CH:3][CH:4]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(N)cn1
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cn1
Temperature: 5 °C
Yield: 95 %

Procedure:
A double jacketed flask was charged with 5-amino-2-methoxypyridine (500 g, 1 eq.), 2,2-dimethyl-1,3-dioxane-4,6-dione (697 g, 1.2 eq.), triethylorthoformate (740 mL, 1.1 eq.) and ethanol (4 L). The mixture was heated to reflux for one hour. The dark suspension obtained was cooled to 5° C. and the mixture was filtered. The product was washed with ethanol (1 L) and dried on a rotary evaporator to obtain a purple solid (1058 g; 95% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:16])=[C:4](NC(=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.[CH:17](=O)/[CH:18]=[CH:19]/[CH3:20].[OH-].[NH4+:23]>Cl.O1CCOCC1>[Br:1][C:2]1[C:3]([F:16])=[C:4]2[C:5]([CH:17]=[CH:18][C:19]([CH3:20])=[N:23]2)=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: C/C=C/C=O
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1F
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc2ccc(Br)c(F)c2n1
Temperature: 106 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
A solution of tert-butyl 3-bromo-2-fluorophenylcarbamate (6.0 g, 20.7 mmol) in 4N HCl (30 mL) in dioxane was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in 6 N HCl (100 mL) and (E)-but-2-enal (2.96 ml, 36.2 mmol) was added dropwise at 106° C. The reaction was stirred at 106° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was basified with ammonium hydroxide to about pH 12, extracted with DCM (2×100 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 7-bromo-8-fluoro-2-methylquinoline (2.99 g, 60.2%) as a solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][O:17][C:11]=3[CH:10]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.O>[CH3:25][S:26]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][O:17][C:11]=3[CH:10]=2)[CH2:3]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCN(CCc2ccc3c(c2)OCO3)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCN(CCc2ccc3c(c2)OCO3)C1

Procedure:
(S)-3-Hydroxy-1-(3,4-methylenedioxyphenethyl)pyrrolidine (281 mg, 1.19 mmol) was dissolved in dichloromethane (8 ml). Triethylamine (162 mg, 1.60 mmol) and methanesulfonyl chloride (183 mg, 1.60 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred at 0° C. for 1 hour. The reaction liquid was distributed in dichloromethane and water. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with a solvent mixture of dichloromethane and methanol (50:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-3-methanesulfonyloxy-1-(3,4-methylenedioxyphenethyl) pyrrolidine in the form of a light yellow oil (359 mg, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[CH3:17][C:18]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([C:20]1[O:21][CH:22]=[CH:23][N:24]=1)[CH3:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:31]([C:28]2[CH:27]=[CH:26][C:25]([C:18]([CH3:19])([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)[CH3:17])=[CH:30][CH:29]=2)(=[O:32])=[O:33])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Reactant: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1ncco1
Product: CC(C)(c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2)cc1)c1ncco1

Procedure:
The title compound was prepared from (2-Amino-5-chloro-phenyl)-pyridin-3-yl-methanone and 4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following the general procedure described for the preparation of N-aryl-benzenesulfonamides. MS: m/z 482 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[H-].[Na+].O>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][O:24][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCc2ccc(F)cc2)CC1
Reaction time: 3.5 h
Yield: 96.2 %

Procedure:
To a solution of 0.75 g (6.02 mmol) of 4-fluorobenzylbromide and 0.58 g (2.7 mmol) of 1-t-butoxycarbonyl-4-hydroxymethylpiperidine in 5 mL of THF was added 0.136 g (5.4 mmol) of NaH in 3 portions over 30 min. After 3.5 h, 50 mL of H2O was added to the reaction mixture and it was extracted with ethyl acetate. The combined organic fractions were washed with sat'd Nacl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl aceate, 4:1) to give 0.84 g of the title compound.