Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][CH2:2][CH3:3].C(I)C.[CH2:7]([N:9]1[C:17]2[C:12](=[CH:13]C=[CH:15][CH:16]=2)[C:11]([CH3:18])=[CH:10]1)[CH3:8].[OH-].[Na+]>CN(C)C=O.O.C(OCC)C>[CH2:7]([N:9]1[C:17]2[C:12](=[CH:13][C:3]([CH:2]=[O:1])=[CH:15][CH:16]=2)[C:11]([CH3:18])=[CH:10]1)[CH3:8]
Reactant: CC[O-]
Reactant: CCn1cc(C)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCn1cc(C)c2cc(C=O)ccc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Into a 2000 milliliter 3 neck flask equipped with a magnetic stirring bar, a thermometer and a nitrogen inlet tube are introduced 400 milliliters anhydrous dimethylformamide, 220 milliliters anhydrous ethylether and 29.36 grams (0.22 moles) 3-methylindolyl (available from Aldrich Chemical Company). After the contents of this flask are thoroughly combined, about 64.84 grams (0.26 moles) thallous ethoxide are added to the solution, and the flask thereafter heated to 40° C with stirring for about 60 minutes during which time the reaction mixture takes on a metallic appearance. At the end of this interval, 41.33 grams (0.26 moles) ethyliodide is introduced into the flask whereupon precipitation of orange colored particulates takes place. The reaction mass is heated to a temperature of about 50° - 5° C with constant agitation for an additional 3 hours, cooled and the solids separated from the reaction mass by filtration. The filtrate is diluted with water and separates into 2 distinct phases; the ether phase being set aside and the aqueous phase being extracted several times with chloroform. All organic layers are then recombined and extracted several times with water to remove residual traces of dimethylformamide. The ether phase is now dried over anhydrous magnesium sulfate and evaporated to an oily residue. This residue is distilled at 80° C (0.2 mm) and the fraction collected at this temperature analyzed and found to be N-ethyl-3-methylindole. Into a 3 neck 250 milliliter round bottom flask equipped with a nitrogen inlet tube, a magnetic stirring bar and a thermometer are placed 17.47 milliliters dimethyformamide. The flask and its contents are cooled in an ice bath and 21.29 milliliters of POC13 added by dropwise addition. The flask is now transferred to a room temperature oil bath and 36.6 grams (0.23 moles) N-ethyl-3-methylindole in 25 milliliters dimethylformamide added by dropwise addition. The reaction of these materials is highly exothermic and the temperature of the bath is maintained at 40° C during the combination of these materials and the reaction allowed to proceed for an additional 3 hours at this temperature. At the end of this period, the reaction mixture is poured into about 1 liter of water with stirring, and the resulting solution titrated with sodiumhydroxide until slightly basic (approximately 7 milliliters base added to this solution). An oily residue product which forms is extracted with chloroform, the chloroform evaporated and the product purified by vacuum distillation; yield is approximately 50 percent.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14]/[CH:15]=[CH:16]/[CH2:17][Cl:18])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7].[ClH:37].[CH3:38][C:39]1([CH3:45])[CH2:44][O:43][CH2:42][CH2:41][NH:40]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[ClH:18].[ClH:37].[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14]/[CH:15]=[CH:16]/[CH2:17][N:40]2[CH2:41][CH2:42][O:43][CH2:44][C:39]2([CH3:45])[CH3:38])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CN(C/C=C/CCl)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: CC1(C)COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C[C@@H]2CN(C/C=C/CN3CCOCC3(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reaction time: 6 h
Yield: 64 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(E)-4-chloro-2-butenyl]-2-(3,4-dimethylbenzyl)piperazine (450 mg), 3,3-dimethylmorpholine hydrochloride (130 mg) and powdered potassium carbonate (350 mg) in dry acetonitrile (5 ml) was heated at reflux temperature for 3 hours. Additional potassium carbonate (350 mg) and 3,3-dimethylmorpholine hydrochloride (130 mg) were added and then the resulting mixture was further heated at reflux temperature. After 6 hours, the reaction mixture was cooled and then filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (50:1). The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(E)-4-(3,3-dimethylmorpholino)-2-butenyl]piperazine dihydrochloride (370 mg).
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH3:29][C@H:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:38]([NH:37][C@@H:30]([CH3:29])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: C[C@H](N=C=O)c1ccccc1
Reactant: Fc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: C[C@H](NC(=O)N1CC(OC(c2ccc(F)cc2)c2ccccc2C(F)(F)F)C1)c1ccccc1

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]azetidine hydrochloride (162) (150 mg, 0.42 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (2.62 mmol/g; 475 mg, 1.26 mmol), molecular sieves and (S)-α-methylbenzyl isocyanate (60 μL, 0.42 mmol). The resultant mixture was shaken at ambient temperature for 16 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (24 mL), then evaporated to afford the desired product as a colourless glass which gave a white solid on scratching (136 mg, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:10]2[C:11]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=3)[CH2:7][CH2:8][C:9]2=[O:14])=[CH:19][CH:18]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CCc3cc([N+](=O)[O-])ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 2.60 mmol), 4-methoxybenzyl chloride (388 μL, 2.86 mmol) and potassium carbonate (1.08 g, 7.80 mmol) in 10 mL DMF was stirred at room temperature overnight. After this time, the mixture was poured into 20 mL H2O then extracted with 2×50 mL CH2Cl2. The organic layer was separated, washed with brine and concentrated to give a yellow solid which was subjected to flash chromatography on silica gel using 1% MeOH/CH2Cl2 to give an off-white solid (605 mg, 74.5%). 1H-NMR (DMSO-d6) δ: 8.15 (d, J=2.7 Hz, 1H), 8.02 (dd, J=2.7, 9.0 Hz, 1H), 7.15 (dd, J=3.0, 9.0 Hz, 1H), 6.88-6.85 (m, 4H), 5.14 (s, 2H), 3.70 (s, 3H), 3.11-3.06 (m, 2H), 2.80-2.75 (m, 2H).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].C(N(CC)CC)C.C([O:16][C:17](=[O:31])[C:18](=O)[CH2:19][S:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)C>C(Cl)Cl.CO>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[S:20][C:19]1[CH:18]([C:17]([OH:31])=[O:16])[O:5][C:2](=[O:6])[C:3]=1[OH:4]
Reactant: CCOC(=O)C(=O)CSc1nc2ccccc2s1
Reactant: O=CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: O=C1OC(C(=O)O)C(Sc2nc3ccccc3s2)=C1O

Procedure:
To a solution of glyoxylic acid monohydrate (98 mg, 1.03 mmol) in 6 mL methylenechloride/methanol (5:1) was added triethylamine (418 μL, 3.0 mmol) and stirred vigorously. 3-(benzothiazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (281 mg, 1.06 mmol) in 6 mL methylenechloride/methanol (5:1) was added dropwise over a period of 3 hours and the reaction was stirred overnight (15 hrs) at room temperature. The reaction mixture was then neutralized with NaH2PO4 and washed with ethylacetate. The resulting very polar product remained in the aqueous layer and was purified by reverse-phase HPLC. The pure fractions were pooled and concentrated under reduced pressure. Upon evaporation of solvent, 3-(benzothiazol-2-ylsulfanyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid precipitated out (70 mg) as a white solid which was filtered and washed with water. The filtrate was collected and lyophilized to afford a pale yellow solid which was determined to be the triethylamine salt of the desired product. 1H-NMR (MeOD, 300 MHz) δ (ppm): 7.92-7.87 (m, 2H), 7.51-7.38 (m, 2H), 5.68 (s, 1H). MS (ESI) m/z: 310 (M+H+).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.C1(C)C=CC=CC=1.[NH2:30][C:31]1[C:32]2[C:57]([CH3:64])([C:58]([NH:60][NH:61][CH:62]=O)=O)[C:56](=[O:65])[NH:55][C:33]=2[N:34]=[C:35]([C:37]2[C:45]3[C:40](=[N:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][C:48]([F:54])([F:53])[C:49]([F:52])([F:51])[F:50])[N:38]=2)[N:36]=1>C1COCC1>[NH2:30][C:31]1[C:32]2[C:57]([CH3:64])([C:58]3[S:10][CH:62]=[N:61][N:60]=3)[C:56](=[O:65])[NH:55][C:33]=2[N:34]=[C:35]([C:37]2[C:45]3[C:40](=[N:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][C:48]([F:54])([F:53])[C:49]([F:52])([F:51])[F:50])[N:38]=2)[N:36]=1
Reactant: CC1(C(=O)NNC=O)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(c2nncs2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 100 °C

Procedure:
Lawesson's reagent (133 mg, 0.328 mmol) was added to a toluene (5 mL) solution of the intermediate from Step B (170 mg, 0.298 mmol). THF (0.5 mL) was added to improve solubility and the reaction was heated to 100° C. for 1 hour in a screw cap vial. The reaction was then cooled and concentrated in vacuo. The crude product was purified by silica gel column chromatography using a hexanes/EtOAc gradient to give the title compound. Chiral separation using SFC on a Chiralcel OD column provided both enantiomers of the title compound. 1H NMR (600 MHz, CD3OD): δ 9.45 (s, 1H); 9.04 (dd, J=7.8, 1.2 Hz, 1H); 8.60 (dd, J=4.2, 1.2 Hz, 1H); 7.36 (dd, J=7.8, 4.2 Hz, 1H); 4.94 (t, J=8.4 Hz, 2H); 4.56 (bs, 2H), 3.01-2.92 (m, 2H); 1.98 (s, 3H). m/z=511.95 (M+H).
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([C:23]([CH:26]=[CH2:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[Al](I)(I)[I:29].I>>[C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([C:23]([CH2:26][CH2:27][I:29])([F:24])[F:25])([F:21])[F:22])([F:18])[F:19])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: I[Al](I)I
Reactant: C=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: I
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI

Procedure:
The same process as in Example 1 was conducted except that 41 g of CF3(CF2)7CH═CH2, 12 g of CaSO4/C (25/75 mass %) instead of AlI3, and 12 g of hydrogen iodide gas were used. CF3(CF2)7CH2CH2I was produced at a conversion rate of 60% and at a selectivity of 100%.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:14][N:15]=[C:16]2[C:20](=O)[O:19][C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:17]2)[CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:2][CH2:3][CH3:4].O.[NH3:29].Cl>CC(C)=O>[CH2:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([N:14]2[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:17][C:16]([C:20]([NH2:29])=[O:19])=[N:15]2)[CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:2][CH2:3][CH3:4]
Reactant: N
Reactant: CCCCOCc1cc(NN=C2N=C(c3ccccc3)OC2=O)ccc1Cl
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCCCOCc1cc(-n2nc(C(N)=O)nc2-c2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
In 10 ml of acetone, 1.157 g (3 mmol) of 4-[(3-butoxymethyl-4-chlorophenyl)hydrazono]-2-phenyl-2-oxazolin-5-one synthesized in the similar way to Synthesis Examples 1-3 was suspended, the suspension being then added with 0.6 ml of concentrated ammonia water and stirred at room temperature for 30 minutes. The resulting solution was made acid by adding 0.6 ml of concentrated hydrochloric acid and further stirred at 50° C. for 30 minutes. Acetone was distilled off and the residue was extracted by adding benzene and water. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvents were distilled off to obtain a crude product. This crude product was purified by silica gel chromatography using hexane/ethyl acetate (1/2, v/v) as developing solvent and further recrystallized to obtain 1.087 g (94.2% yield) of 1-(3-butoxymethyl-4-chlorophenyl)-5-phenyl-1H-1,2,4-triazole-3-carboxamide (m.p. 96°-98° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:34][NH:35][O:36][CH3:37].Cl.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([N:35]([O:36][CH3:37])[CH3:34])=[O:9]
Reactant: CNOC
Reactant: COc1ncc(Br)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ncc(Br)cc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of 5-bromo-2-methoxynicotinic acid (15.0 g, 64.65 mmol) in anhydrous DMF (150 mL), HOBT (9.0 g, 66.61 mmol) and EDCI (25.0 g, 130.41 mmol) were added. The reaction mixture was stirred at room temperature for 2 hour. And then MeNHOMe.HCl (20.0 g, 205.04 mmol) and Et3N (60 mL, 415.06 mmol) was added to the mixture. The mixture was stirred at 20° C. overnight. The reaction mixture was concentrated in vacuo. Then H2O was added, and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified using column chromatography (eluted with petroleum ether:EtOAc=2:1) to provide 5-bromo-N,2-dimethoxy-N-methylnicotinamide (16.5 g, yield: 92%). 1H-NMR (CDCl3, 400 MHz) δ 8.23 (d, J=2.4 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 3.95 (s, 3H), 3.53 (s, 3H), 3.33 (s, 3H). MS (M+H)+: 275/277.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.B(F)(F)F.CCOCC.[OH:20][N:21]=[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:38]3[C:37]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[N:36][CH:35]=[N:34][C:33]=3[N:32](COCC[Si](C)(C)C)[CH:31]=2)[CH:25]=1)[NH2:23].O>O1CCCC1>[N:39]1([C:37]2[C:38]3[C:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([C:22]5[N:23]=[CH:1][O:20][N:21]=5)[CH:25]=4)=[CH:31][NH:32][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1
Reactant: CCOC(OCC)OCC
Reactant: C[Si](C)(C)CCOCn1cc(-c2cccc(C(N)=NO)c2)c2c(N3CCOCC3)ncnc21
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1cc(-c2ncon2)cc(-c2c[nH]c3ncnc(N4CCOCC4)c23)c1
Temperature: 40 °C

Procedure:
Triethyl orthoformate (760 mg, 5.1 mol) and boron trifluoride diethyl etherate (370 mg, 2.6 mol) were added to a 0° C. solution of N′-hydroxy-3-[4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzenecarboximidamide (C35) (600 mg, 1.3 mmol) in tetrahydrofuran (25 mL). The reaction mixture was heated at 40° C. for 18 hours, then poured into water (50 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated. Purification via preparative reversed phase high-performance liquid chromatography (Column: Phenomenex Gemini C18, 8 μm; Mobile phase A: aqueous ammonia, pH 10; Mobile phase B: acetonitrile; Gradient: 30% to 50% B) provided the product as a yellow solid. Yield: 62 mg, 0.18 mmol, 14%. LCMS m/z 349.0 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.40 (s, 1H), 8.24 (br s, 1H), 7.98 (br d, J=7.5 Hz, 1H), 7.82 (br d, J=7.3 Hz, 1H), 7.63-7.70 (m, 2H), 3.39-3.45 (m, 4H), 3.13-3.20 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8](C#C[Si](C)(C)C)[C:7]([NH:16][C:17](=O)[CH3:18])=[N:6][CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[CH:18]=[CH:17][NH:16][C:7]2=[N:6][CH:5]=1)=[O:20]
Reactant: COC(=O)c1cnc(NC(C)=O)c(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cnc2[nH]ccc2c1
Temperature: 80 °C
Yield: 79.1 %

Procedure:
To a stirred solution of 6-acetylamino-5-trimethylsilanylethynyl-nicotinic acid methyl ester (24.4 mmol theoretical from previous step) in tetrahydrofuran (15 mL) was added tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 100 mL, 100 mmol) at 25° C. The mixture was heated at reflux at 80° C. for 2 h and then cooled to 25° C. The resulting mixture was extracted with ethyl acetate, washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to afford 1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (3.4 g, 79% over two steps) as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 4.01 (s, 3H), 6.71 (d, J=3.6 Hz, 1H), 7.53 (d, J=3.6 Hz, 1H), 8.77 (s, 1H), 9.04 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)[N:6]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCCl>[Br:14][CH2:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([Cl:1])[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2csc(Cl)n2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1nc(-c2cccc(CBr)c2)cs1
Reaction time: 3 h

Procedure:
600 mg of 2-chloro-4-(3-tolyl)thiazole was dissolved in a mixture of 8 ml of carbon tetrachloride and 2 ml of 1,2-dichloroethane. N-bromosuccinimide (511 mg) and 3 mg of benzoyl peroxide were added, and the mixture refluxed with stirring for 3 hours. After cooling, the precipitate was separated from the reaction mixture by filtration. It was washed with an aqueous solution of sodium hydrogen carbonate, and the solvent was evaporated under reduced pressure to give 4-(3-bromomethylphenyl)-2-chlorothiazole as a pale yellow oil.
Reaction SMILES: NN1CCCC1.[CH3:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][C:19]([F:22])([F:21])[F:20])[CH:16]=2)[NH:11][C:10](=O)[CH:9]=1.P(Cl)(Cl)([Cl:26])=O>O>[Cl:26][C:10]1[CH:9]=[C:8]([CH3:7])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][C:19]([F:22])([F:21])[F:20])[CH:16]=2)[N:11]=1
Reactant: Cc1cc(=O)[nH]c2ccc(OC(F)(F)F)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: NN1CCCC1
Solvent: O
Product: Cc1cc(Cl)nc2ccc(OC(F)(F)F)cc12
Temperature: 105 °C
Reaction time: 2.5 h

Procedure:
4-(Trifluoromethoxy)aniline (10 mL) was added dropwise to ethyl acetoacetate (44 mL) at 160° C., and the mixture was stirred at the same temperature for 1 h. The mixture was left stand for cooling to room temperature and crystallized with hexane to obtain 3-oxo-N-(4-(trifluoromethoxy)phenyl)butane amide (6.5 g). (2) To concentrated sulfuric acid (32.5 mL) was added 3-oxo-N-(4-(trifluoromethoxy)phenyl)butane amide (6.5 g), and the mixture was stirred at 95° C. for 3 h. The reaction solution was added dropwise to water with ice cooling, and the precipitated crystals were collected by filtration. The resulting crystals were suspended in water, the suspension was made basic with aqueous ammonia, and the precipitated crystals were collected by filtration to obtain 4-methyl-6-(trifluoromethoxy)quinoline-2(1H)-one (1.87 g). (3) A mixture of 4-methyl-6-(trifluoromethoxy)quinoline-2(1H)-one (1.87 g) and phosphorus oxychloride (19 mL) was stirred at 105° C. for 2.5 h. The reaction solution was added dropwise to water with ice cooling, and the precipitated crystals were collected by filtration to obtain 2-chloro-4-methyl-6-trifluoromethoxyquinoline (1.98 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Cl:11][CH2:12][C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:1]([NH:4][CH2:5][C:6]1[S:7][C:8]([C:13](=[O:14])[CH2:12][Cl:11])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cccs1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)NCc1ccc(C(=O)CCl)s1

Procedure:
To a solution of 5.0 g of 2-acetylaminomethylthiophene and 4.4 g of chloroacetylchloride in 100 ml of dichloromethane is added a small portion of 8.6 g of anhydrous aluminum chloride at room temperature, and the mixture is refluxed with stirring for an hour and poured into ice-cold water. The precipitated crystals are collected by filtration to give 2-acetylaminomethyl-5-chloroacetylthiophene, melting at 146°-148° C.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1>>[CH3:18][N:4]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[C:2]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cccnc1
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(-c2cccnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 19) was reacted with pyridine-3-yl-boronic acid to give the title compound as colorless foam. MS: 500.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[C:23]([CH2:27][CH:28]=O)([CH3:26])([CH3:25])[CH3:24].C1CCN2C(=NCCC2)CC1>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]([NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[CH:28][CH2:27][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)CC=O
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=CCC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 94.4 %

Procedure:
N-(Benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (2 g, 6.0 mmol, 1.0 equiv) was dissolved in dry THF (20 mL). tert-Butylacetaldehyde (0.758 mL, 6.0 mmol, 1.0 equiv) and DBU (0.903 mL, 6.0 mmol, 1.0 equiv) were added and the reaction mixture was stirred for 16 h. The solution was diluted with 100 mL of CH2Cl2 and washed with 1×50 mL water, and 1×50 mL brine. The organic layer was dried over Na2SO4, decanted and concentrated in vacuo to provide 2-benzyloxycarbonylamino-5,5-dimethyl-hex-2-enoic acid methyl ester as a thick oil (1.73 g, 94%) which was used without further purification; MS: 306 (M+1).
Reaction SMILES: NC1C=C(C2SC3C=CC=CC=3N=2)C([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=CC=1.[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[S:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)=[N+]=[N-]>>[NH2:25][C:28]1[CH:33]=[CH:32][C:31]([O:11][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8])=[CH:30][C:29]=1[C:34]1[S:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1
Reactant: [N-]=[N+]=Nc1ccccc1-c1nc2ccccc2s1
Reactant: Nc1ccc(OS(=O)(=O)C(F)(F)F)c(-c2nc3ccccc3s2)c1
Product: Nc1ccc(OS(=O)(=O)C(F)(F)F)cc1-c1nc2ccccc2s1

Procedure:
This compound was prepared in a similar way to the compound of Example XIV from 2-(2-azidophenyl)benzothiazole (Found: M+ 374. C14H9F3N2O3S2 requires MW 374).