Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].Cl.[CH2:32](N(CC)CC)C>>[CH3:32][CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][NH:16][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: Cc1cc(Cl)c(C(N)=O)cc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCCCNC
Agent: Cl
Product: CCCCCCCCCCCCC(C)CNc1cc(C)c([N+](=O)[O-])cc1C(N)=O
Temperature: 0 °C

Procedure:
A mixture of 19.2 grams 2-chloro-4-methyl-5-nitrobenzamide, 21.4 grams methyltetradecylamine and 46.0 ml triethylamine was heated on a steam bath for 20 hours. The mixture was poured into about 200 ml ice water and made acid with concentrated HCl to a pH of 2-3. The mixture was filtered, washed with water and vacuum dried. The crude material was recrystallized from ethanol to give 30 grams product. m.p. = 117°-119°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)ncc2Cl)CC1
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (0.475 g, 2.6 mmol) in dry DMF (8.5 mL) was added tert-butyl piperazine-1-carboxylate (0.51 g, 2.7 mmol) followed by DIEA (0.51 mL, 3.1 mmol) at 0° C., and the mixture was stirred for 1 h. LCMS showed the reaction was completed. The reaction was diluted with water (100 mL), and the white solid was filtered. The residue was washed with water and dried to give the title compound (445 mg, 51%) as a white solid. MS (ES+) C13H18Cl2N4O2 requires: 332. found: 333 [M+H]+
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([NH:17][CH3:18])=[CH:10][CH:9]=3.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:19](=[O:21])[CH3:20])[C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([NH:17][CH3:18])=[CH:10][CH:9]=3
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccc2c(c1)Sc1cc(NC)ccc1N2
Solvent: c1ccncc1
Product: CNc1ccc2c(c1)Sc1cc(NC)ccc1N2C(C)=O
Temperature: 120 °C
Yield: 53 %

Procedure:
The 3,7-dimethylamino-10H-phenothiazine obtained in Synthesis 1 was placed in a 250 cm3 round bottom flask and acetic anhydride ((H3CCO)2O, 40 cm3) and pyridine (10 cm3) were added, and the resulting solution was heated at 120° C. for 18 hours with stirring. The reaction mixture was cooled to room temperature and then poured carefully into ice-water while stirring to give a light brown solid, which was filtered using a standard Buchner funnel apparatus with a water aspirator, washed once with water (100 cm3), and dried in an oven at 60° C. for 3 hours to yield the title compound (MW 327.45, 4.63 g, 14.1 mmol, yield 53%), which was recrystallised from ethanol by dissolving it in hot ethanol (100 cm3), adding activated charcoal (1 g), filtering to remove the charcoal, cooling the solution to 5° C. using an ice-water bath so that a precipitate formed (colourless crystals), and filtering using a standard Buchner filter with a water aspirator in order to collect the crystals. The crystals where then dried in an oven at 60° C. for 3 hours.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12](CO)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.CS(Cl)(=O)=O.[C-]#N.[Na+]>C(Cl)Cl.O.CN(C=O)C>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:7][C:6]#[N:3])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: COc1cc(CO)cc(C(F)(F)F)c1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(CC#N)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (2.04 ml) was added to a solution of the product of step (ii) (3.02 g) in DCM (30 ml) and cooled to 0° C. before adding methane sulfonyl chloride (1.13 ml). The reaction mixture was stirred for 2 h at RT. The reaction mixture was diluted with water, extracted with DCM then dried (MgSO4) and evaporated under reduced pressure to give an oil. The oil was dissolved in DMF (20 ml), sodium cyanide (1.07 g) was added and stirred at 100° C. for 2 h. The reaction mixture was diluted with water, extracted with ether, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent ether) to give the subtitle compound (1.9 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][C:13](=[CH2:15])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.B1C2CCCC1CCC2.[OH2:25].[Na+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][CH:13]([CH2:15][OH:25])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: C=C1CC(c2ncc3c(Cl)nccn23)C1
Reactant: O
Agent: B1C2CCCC1CCC2
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC1CC(c2ncc3c(Cl)nccn23)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 8-chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazine (4.48 g, 20.4 mmol) in anh THF (255 mL) at −78° C. under Ar, 9-BBN (61.2 mL, 0.5M in THF, 30.6 mmol) was added dropwise over 8 min (a suspension). The cooling bath was replaced with ice-H2O and the reaction was allowed to warm slowly to rt. After being stirred for 17 h, H2O (100 mL,) was added followed by, after ˜5 min, NaBO3.H2O(12.2 g, 122.3 mmol) added in one lot. The reaction was stirred at rt for 5 h and then filtered through Celite. The Celite and residual solids were washed with DCM and EtOAc. The filtrate was concentrated under reduced pressure to yield an aq solution, which was saturated with NaCl and extracted with EtOAc (3×). The extracts were dried (Na2SO4) and concentrated under reduced pressure to yield a light yellow oil which was purified by flash chromatography on SiO2 (9:1 DCM:MeOH) to afford the title compound as a light yellow oil; HPLC: tR (mass-directed HPLC, polar7 min) 2.52 min; MS (ES+): 238.0. The addition may be carried out at 0° C. Suspension quickly clears up after the exchange of cooling baths. The final product contained 1,5-cis-octanediol derived from 9-BBN. Based on 1H NMR estimated roughly to be 66% target material and 33% of the byproduct. The crude product was taken onto next step crude, stereoselectivity of the product was 4-5:1 as judged by 1H NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH2:11][CH2:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][C:7]=1SC.O[O:18][S:19]([O-:21])=O.[K+].[CH3:23]O>O>[F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH2:11][CH2:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[S:19]([CH3:23])(=[O:21])=[O:18]
Reactant: O=S([O-])OO
Reactant: CSc1ccc(C(=O)CCC(C)=O)cc1F
Reactant: CO
Agent: [K+]
Solvent: O
Product: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)c(F)c1
Reaction time: 5 h
Yield: 66 %

Procedure:
To a stirred solution of 3-fluoro-4-(methylthio)benzaldehyde (3.04 g, 17.9 mmol) in ethanol (12 mL) was added methyl vinyl ketone (1.3 mL, 15.5 mmol), 3-benzyl-5-(2-hydroxyethyl)4-methylthiazolium chloride (0.84 g, 3.1 mmol), and Et3N (4.32 mL, 31 mmol) at room temperature. After stirring for 2 hours, volatiles were removed by evaporation. The residue was taken up with ethyl acetate (200 mL), and washed with water (120 mL), dil. aqueous HCl (120 mL), water (120 mL), brine (120 mL), dried over MgSO4, and concentrated in vacuo. The resulting crude residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/2) to provide 1-[3-fluoro-4-(methylthio)phenyl]pentane-1,4-dione (2.7 g, 73% yield). To a stirred suspension of 1-[3-fluoro-4-(methylthio)phenyl]pentane-1,4-dione (2.7 g, 11.25 mmol) in methanol (50 mL) was added Oxone (14.14 g, 23 mmol) in water (50 mL) at room temperature. After stirring for 5 hours, the mixture was diluted with water. The whole was extracted with CH2Cl2 (50 mL×4), the combined organic layer washed with brine, dried over MgSO4, and evaporated in vacuo to give the subtitle compound (2.8 g, 66% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[CH:16]=O)(=[O:10])=[O:9].ClCCl.B(F)(F)F.CCOCC.[CH2:31]([SH:35])[CH2:32][CH2:33][SH:34]>O>[Cl:1][C:2]1[C:3]([CH3:18])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[CH:16]1[S:35][CH2:31][CH2:32][CH2:33][S:34]1)(=[O:10])=[O:9]
Reactant: SCCCS
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C=O)c1Cl
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccsc2C2SCCCS2)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-formylthiophene-3-sulfonamide described in Production Example 1-3 (4.9 g, 16 mmol) and dichloromethane (100 mL) was successively added boron trifluoride diethyl etherate (8.1 mL, 64 mmol) and 1,3-propanedithiol (1.9 mL, 19 mmol) under ice cooling, followed by stirring at room temperature for 90 minutes. Water was added under ice cooling to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with brine, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-(1,3-dithian-2-yl)thiophene-3-sulfonamide as a crude product. To a mixture of crude N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-(1,3-dithian-2-yl)thiophene-3-sulfonamide and tetrahydrofuran (50 mL) was added dropwise n-butyl lithium (9.7 mL, 16 mmol, 1.6 M n-hexane solution) at −78° C., followed by stirring for 20 minutes at an internal temperature of −35° C. The reaction mixture was cooled to −78° C., and 5-(chloromethyl)-6-methyl-1,3-dihydro-2-benzofuran described in Production Example 1-6 (960 mg, 5.3 mmol) was added at that temperature and stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C., and a mixture of acetic acid (0.90 mL, 16 mmol) and tetrahydrofuran (7 mL) was added at that temperature. The reaction mixture was gradually returned to room temperature, water and an aqueous citric acid solution were added at that temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=4:1) to give the title compound (1.6 g, 54% yield).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:52])([F:51])[C:17]1[CH:18]=[C:19]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:20][N:21]([C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1)[C@H:22]1[CH2:28][CH2:27][CH2:26][NH:25][C:24]2[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:31]([CH3:33])=[CH:32][C:23]1=2.[CH2:53]([N:60]1[CH2:65][CH2:64][C:63](=O)[CH2:62][CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.C(O)(=O)C>C(#N)C.ClCCl>[CH2:53]([N:60]1[CH2:65][CH2:64][CH:63]([N:25]2[CH2:26][CH2:27][CH2:28][C@H:22]([N:21]([CH2:20][C:19]3[CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=[C:17]([C:16]([F:51])([F:15])[F:52])[CH:18]=3)[C:38]3[N:39]=[N:40][N:41]([CH3:43])[N:42]=3)[C:23]3[CH:32]=[C:31]([CH3:33])[C:30]([C:34]([F:35])([F:36])[F:37])=[CH:29][C:24]2=3)[CH2:62][CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2c(cc1C(F)(F)F)N(C1CCN(Cc3ccccc3)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 24 h
Yield: 26.6 %

Procedure:
Add sodium triacetoxyborohydride (0.153 g, 0.724 mmol) portionwise to a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.200 g, 0.362 mmol), 1-benzyl-piperidin-4-one (0.206 g, 1.09 mmol) and glacial acetic acid (1 mL) in acetonitrile (10 mL) at room temperature under an atmosphere of nitrogen and stir for 24 h. Quench the reaction with saturated sodium bicarbonate (5 mL) and dilute with dichloromethane (15 mL). Separate the layers and wash the organic layer with saturated sodium bicarbonate and brine (20 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as an off-white solid (0.070 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 1.63-2.13 (m, 8H), 2.34 (s, 3H), 2.82-3.0 (m, 3H), 3.10-3.22 (m, 1H), 3.33-3.41 (m, 1H), 3.50 (s, 2H), 4.09-4.13 (m, 1H), 4.14 (s, 3H), 4.74-4.97 (m, 2H), 5.34-5.49 (m, 1H), 6.89 (s, 1H), 7.32 (s, 1H), 7.41 (s, 5H), 7.60 (s, 2H), 7.71 (s, 1H); ESI MS m/z 726 [C35H36F9N7+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)(Cl)=O.[F:28][C:29]1[CH:35]=[C:34]([CH3:36])[C:33]([OH:37])=[CH:32][C:30]=1[NH2:31]>CN(C=O)C.C(O)(C)C>[F:28][C:29]1[CH:35]=[C:34]([CH3:36])[C:33]([OH:37])=[CH:32][C:30]=1[NH:31][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCCCN1CCOCC1
Yield: 27.3 %

Procedure:
A mixture of 6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (370 mg, 1.16 mmol), thionyl chloride (5 ml) and DMF (3 drops) was heated at reflux for 2 hours and allowed to cool. The excess thionyl chloride was removed by evaporation and the residue was azeotroped with toluene. A solution of 2-fluoro-5-hydroxy-4-methylaniline (220 mg, 1.56 mmol) in isopropanol (10 ml) was added to the solid residue and the mixture was heated at reflux for 2 hours and then allowed to cool. The resulting precipitate was collected by filtration, washed with methylene chloride and dried. The impure solid product was treated with aqueous sodium hydrogen carbonate, to give a suspension and the product was recollected by filtration and purified by column chromatography eluting with methylene chloride/methanol (9/1) to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (140 mg, 27%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:24])[N:14]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C:15]3=[N:16][C:17]=2[CH:18]=1.[F:25][C:26]([F:31])([F:30])[CH2:27][CH:28]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:24])[N:14]3[CH2:23][CH2:22][N:21]([CH2:28][CH2:27][C:26]([F:31])([F:30])[F:25])[CH2:20][CH2:19][C:15]3=[N:16][C:17]=2[CH:18]=1
Reactant: O=c1c2ccc(C#Cc3ccccn3)cc2nc2n1CCNCC2
Reactant: O=CCC(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1c2ccc(C#Cc3ccccn3)cc2nc2n1CCN(CCC(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-(2-(pyridin-2-yl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one (150 mg, 0.48 mmol), 3,3,3-trifluoropropanal (80 mg, 0.72 mmol), and sodium cyanoborohydride (60 mg, 0.96 mmol) in MeOH (10 mL) was added acetic acid (29 mg, 0.48 mmol). The mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with saturated sodium carbonate solution (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the desired product. The product was then converted to the corresponding 2HCl salt. MS (ESI): 413 (MH+); 1H NMR (300 MHz, CD3OD) δ 8.94-8.92 (d, J=5.82 Hz, 1H), 8.72-8.66 (t, J=7.98 Hz, 1H), 8.39-8.34 (t, J=9.00 Hz, 2H), 8.15-8.10 (t, J=7.83 Hz, 1H), 8.07 (s, 1H), 7.91-7.88 (d, J=8.22 Hz, 1H), 4.84-4.80 (m, 3H), 3.81-3.71 (m, 5H), 3.66-3.54 (m, 2H), 3.03-2.94 (m, 2H). mGluR5 PAM EC50: ++. Fold shift at 10 μM: +++.
Reaction SMILES: ClCC([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=O.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[NH:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[CH:5]=[CH:6]1
Reactant: O=C(CCl)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2[nH]ccc2c1
Reaction time: 16 h

Procedure:
A stirred solution of 2-chloro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone (12.5 g) in TFA at room temperature is treated with triethylsilane (72 mL, 7 eq.), stirred for 16 h, diluted with EtOAc and saturated sodium carbonate to pH 8. The phases are separated and the organic phase is dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, 10% EtOAc in ether as eluent) to give the title pyrrolo[2,3-b]pyridine compound, identified by NMR and mass spectral analyses.
Reaction SMILES: N1C=CC=CC=1.[OH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1.[C:18](Cl)(=[O:29])[O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.O>ClCCl>[C:18](=[O:29])([O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:13]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Nc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
Adapting a known procedure (P. Pasetto, et al., Anal. Chim. Acta, 2005, 542(1), 66-75), 8.03 mL of anhydrous pyridine (7.84 g, 99.3 mmol; 1.5 eq.) was added at a temperature of about 0° C. (ice bath) to a suspension of 10.00 g N-(4-hydroxyphenyl)acetamide (1) (paracetamol (INN), acetaminophen (USAN) (66.2 mmol; 1.0 eq.) in 300 mL of anhydrous dichloromethane (DCM). The reaction mixture was stirred at the same temperature for about 10 minutes. To this mixture, a solution of 13.97 g (69.5 mmol; 1.05 eq.) of commercially available 4-nitrophenyl carbonochloridate (2) in 20 mL of anhydrous DCM was then added dropwise and the reaction mixture was stirred with gradual warming to room temperature for overnight. Fifty (50) mL of water were added to the reaction mixture. A solid precipitated out of solution. The solid was filtered off and washed successively with diethylether (Et2O) (2×50 mL) and hexane (4×50 mL) to afford 9.92 g (47% yield) of the target compound 3 as a colorless solid after drying in high vacuum. The initial filtrate (DCM and water) was washed with a saturated aqueous solution of sodium chloride (NaCl/brine). The organic layer was dried using anhydrous sodium sulfate (Na2SO4) to afford an additional 7.0 g (33% yield) of the target compound 3. Rf-value: 0.35 (ethyl acetate/hexane=1:1). 1H NMR (DMSO-d6, 300 MHz): δ=10.09 (s, 1H), 8.34 (d, J=9.3 Hz, 2H), 7.68 (d, J=9.3 Hz, 2H), 7.64 (d, J=9.0 Hz, 2H), 7.31 (d, J=8.7 Hz, 2H), 2.05 (s, 3H) ppm. LC/MS (ESI): m/z=317.2 [M+H]+. The analytical data corresponded to the analytical data given in the literature.
Reaction SMILES: [CH3:1][N:2]1[C:15]([CH3:17])([CH3:16])[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:29][C:19]([F:18])([F:28])[C:20]1[N:21]=[CH:22][C:23]([CH2:26][CH2:27][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[C:15]([CH3:17])([CH3:16])[CH2:14][C:5]2=3)=[CH:24][CH:25]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C(C)(C)C3
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CC(C)(C)N(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,3,3,8-tetramethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([O:16]C)=[O:15])=[CH:13][C:8]=3[O:7][C:6]=2[CH:18]=1.C1COCC1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:8]=3[O:7][C:6]=2[CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)oc1cc(Br)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)oc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To a mixture of methyl 3-bromo-dibenzofuran-7-carboxylate (3.2 g, 10.5 mmol) in 2:1 THF:methanol (90 ml) was added 2.5N NaOH (60 ml). After stirring at room temperature for 1 hour, the reaction was complete. Nearly all the THF:methanol was evaporated off and then the mixture was adjusted to pH=1 with concentrated HCl and extracted with ethyl acetate. Drying (MgSO4) and evaporation yielded 3.1 g (100%) of the title compounds which was used in the next reaction without purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:13]=2)O1.Br[C:22]1[N:27]=[C:26]([NH2:28])[CH:25]=[CH:24][CH:23]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:12]2[CH:13]=[C:9]([C:22]3[N:27]=[C:26]([NH2:28])[CH:25]=[CH:24][CH:23]=3)[CH:10]=[N:11]2)[CH:15]=1
Reactant: CC1(C)OB(c2cnn(-c3cccnc3)c2)OC1(C)C
Reactant: Nc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Nc1cccc(-c2cnn(-c3cccnc3)c2)n1
Temperature: 75 °C

Procedure:
Under argon, 3.17 g (11.7 mmol) of 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]pyridine, 2.02 g (11.7 mmol) of 6-bromopyridine-2-amine and 945 mg (817 μmol) of tetrakis(triphenylphosphine)palladium were added to a mixture, degassed by means of argon, of 23.3 ml of 2 M sodium carbonate solution in water and 63.3 ml of acetonitrile. The reaction mixture was heated to 75° C. for 18 hours, diluted with acetonitrile after cooling, dried over MgSO4, filtered and concentrated. The crude product thus obtained was purified by chromatography (acetonitrile/acetone).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:8]([C:6]1[CH:5]=[CH:4][C:3]([F:10])=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)[CH3:9]
Reactant: OB(O)c1ccccc1
Reactant: CCc1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1ccc(F)c(-c2ccccc2)c1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
To a degassed mixture of Intermediate 228.1 (104 mg, 0.512 mmol), phenylboronic acid (94 mg, 0.768 mmol) and Na2CO3 (217 mg, 2.05 mmol) in 4 mL DME/H2O (3:1) was added Pd(PPh3)4 (59 mg, 0.051 mmol). The mixture was stirred at 150° C. for 5 min in a microwave oven, then was diluted with EtOAc, washed with water and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (100% hexanes) to afford Intermediate 228.2.