Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1[S:21][C:22]([CH3:29])=[CH:23][C:24]=1[S:25](Cl)(=[O:27])=[O:26]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:25]([C:24]2[CH:23]=[C:22]([CH3:29])[S:21][C:20]=2[CH3:19])(=[O:27])=[O:26])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)s1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: Cc1cc(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)c(C)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was reacted with 2,5-dimethylthiophene-3-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): 17.39 (dd, J=1.8 & 10.2 Hz, 1H), 7.24-7.16 (br m, 2H), 7.13 (dd, J=9.0 & 17.4 Hz, 1H), 6.77 (d, J=9.6 Hz, 1H), 5.98 (dt, J=2.4, 8.7 & 17.4 Hz, 1H), 5.55 (br s, 1H), 2.33 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:31][N:30]([C:32]3[N:36]([CH3:37])[N:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[C:33]=3[Cl:41])[CH2:29][CH2:28][C:4]=2[N:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:27])=[CH:11][N:12]3[S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:7]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:52][C:53]1([CH3:59])[CH2:58][CH2:57][CH2:56][NH:55][CH2:54]1>ClCCl.[Cl-].[Na+].O.C(O)(C)C>[Cl:41][C:33]1[C:34]([CH:38]([CH3:40])[CH3:39])=[N:35][N:36]([CH3:37])[C:32]=1[N:30]1[CH2:29][CH2:28][C:4]2[N:5]=[C:6]([C:8]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:9]=3[C:10]([CH3:27])=[CH:11][N:12]4[S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=3)(=[O:18])=[O:19])[N:7]=[C:2]([N:55]3[CH2:56][CH2:57][CH2:58][C:53]([CH3:59])([CH3:52])[CH2:54]3)[C:3]=2[CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(Cl)c5c(n4)CCN(c4c(Cl)c(C(C)C)nn4C)C5)cccc32)cc1
Reactant: CC1(C)CCCNC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCCC(C)(C)C6)n4)CN(c4c(Cl)c(C(C)C)nn4C)CC5)cccc32)cc1
Temperature: 120 °C

Procedure:
Isopropanol (2.2 mL) was added to 4-chloro-6-(4-chloro-3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (85 mg, 0.139 mmol) in a microwave vial. Then diisopropylethylamine (0.1 mL, 0.573 mmol) was added followed by the HCl salt of 3,3-dimethylpiperidine (25 mg, 0.167 mmol). The vessel was sealed and heated via microwave irradiation at 120° C. for 2.5 h then cooled to room temperature and diluted with dichloromethane and brine. The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified via silica gel flash chromatography (25-55% ethyl acetate/heptanes) to provide 6-(4-chloro-3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-(3,3-dimethylpiperidin-1-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 686.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.N1(C2CCCCCCCCCC2)CCCNCCCCC[CH2:15]1.CI.O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: C1CCCCCC(N2CCCCCCNCCC2)CCCC1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
To a stirred solution of 4-bromo-2-nitrobenzoic acid (3.81 g, 15 mmol) in DMF (30 mL) at 0° C. was added 1,8-diazabicycloundecane (DBU; 10.3 mL, 75 mmol) followed by MeI (4.67 mL, 75 mmol). The mixture was stirred for 15 min at 0° C., then was allowed to warm to rt and was stirred overnight. The mixture was poured into water and extracted with EtOAc (2×). The combined organic extracts were washed with water (2×), dried (MgSO4), and concentrated. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 90%). To a solution of the nitrobenzoate (3.52 g, 13.5 mmol) in 1:1 EtOAc/DCM (30 mL) at rt was added SnCl2.2H2O (15.27 g, 67 mmol). After 18 h, the mixture was concentrated, diluted with satd. aq. NaHCO3, and extracted with DCM (3×). The combined organic layers were dried (MgSO4) and concentrated to provide the desired aminobenzoate as a white solid (2.89 g, 93%). 1H NMR (400 MHz, CDCl3): 7.70 (d, J=8.6, 1H), 6.84 (d, J=1.9, 1H), 6.75 (dd, J=8.6, 1.9, 1H), 5.78 (br s, 2H), 3.86 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]2[N:9]=[C:10]([C:12]3[C:17]([CH3:18])=[CH:16][C:15](OS(C(F)(F)F)(=O)=O)=[CH:14][C:13]=3[CH3:27])[NH:11][C:7]=2[CH:6]=1)=[O:4].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CCCCCCC.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]>[CH3:1][O:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]2[N:9]=[C:10]([C:12]3[C:13]([CH3:27])=[CH:14][C:15]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:16][C:17]=3[CH3:18])[NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2nc(-c3c(C)cc(OS(=O)(=O)C(F)(F)F)cc3C)[nH]c2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc(-c3c(C)cc(N4CCOCC4)cc3C)[nH]c2c1
Temperature: 80 °C

Procedure:
To a stirred solution of 2.4 g of 2-(2,6-Dimethyl-4-trifluoromethanesulfonyloxy-phenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester in 6 ml of toluene was added 4 ml of morpholine, 280 mg of Pd2(dba)3, 400 mg of P(biphenyl)t-Bu2 and 2.0 g of K3PO4. The reaction vessel sealed and heated at 80° C. overnight. The reaction was cooled to room temperature and diluted with water and heptane. The resulting precipitates were collected by filtration, washed with water and dried to afford the title compound. LCMS retention T=1.14 min, m/z=366.2, Method 10.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[N:31]=[C:32]=[O:33]>ClCCl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[NH:31][C:32]([NH:10][C:9]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1)=[O:33]
Reactant: COc1ccc(N)cc1OC1CCCC1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)Nc2c(Cl)cccc2Cl)cc1OC1CCCC1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A stirred solution of 3-cyclopentyloxy-4-methoxyaniline (1 g) and triethylamine (0.69 mL) in dry dichloromethane (20 mL) is treated dropwise at 0°-5° C. with a solution of 2,6-dichlorophenyl isocyanate (0.9 g) in dry dichloromethane (10 mL). The resulting mixture is stirred for 30 minutes at this temperature and then for 6 hours at room temperature. The precipitate which forms is collected and stirred with isopropanol (50 mL), with ice cooling. The resulting solid is collected and dried, to give N-(2,6-dichlorophenyl)-N'-(3-cyclopentyloxy-4-methoxyphenyl)urea (1.06 g), m.p. 203°-204° C. [Elemental analysis: C,57.2; H,5.0; N,7.0; Cl,18.2%; calculated: C,57.7; H,5.1; N,7.1; Cl,18.0%].
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]([O:11]C)=[CH:8][C:9]#[N:10])=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC(C(OC)(OC)CC#[N:28])=CC=1.Cl.NO.C[O-].[Na+]>CO>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:11][N:10]=[C:9]([NH2:28])[CH:8]=2)=[CH:3][CH:2]=1
Reactant: COC(CC#N)(OC)c1ccc(-c2ccccc2)cc1
Reactant: COC(=CC#N)c1ccc(-c2ccccc2)cc1
Agent: C[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: Nc1cc(-c2ccc(-c3ccccc3)cc2)on1

Procedure:
3-(4-Biphenylyl)-3-methoxyacrylonitrile plus 3-(4-biphenylyl)-3,3-dimethoxypropionitrile (2.9 grams as a mixture from example 6), hydroxylamine hydrochloride (4.7 grams), and sodium methoxide (11.9 grams) were mixed in 500 ml. of methanol and refluxed for 48 hours. After the methanol was evaporated, water was added and the product, separated by filtration, yielded 1.2 grams. NMR confirmed the identity of the product.
Reaction SMILES: F[C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34].C(=O)(O)[O-]>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:32][S:33]([C:36]1[CH:41]=[C:40]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[CH:2][C:3]([C:22]4[S:26][C:25]([C:27]5([OH:31])[CH2:30][CH2:29][CH2:28]5)=[N:24][CH:23]=4)=[C:4]3[CH:10]=2)[CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)ccnc3[nH]2)c1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 107C) (150 mg, 0.272 mmol) and 3-methylsulfonyl phenylboronic acid (54.4 mg, 0.272 mmol) in N,N-dimethylformamide (2.04 mL) was added saturated aqueous bicarbonate solution (680 μL) followed by bis(triphenylphosphine) palladium dichloride (13.37 mg, 0.019 mmol). The mixture was heated to 70° C. for 3 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane, to give the title compound. A solution of the residue in methanol (2.0 mL) and 2N sodium hydroxide solution (700 μL) was heated by microwave irradiation (Biotage, Initiator) to 120° C. for 30 minutes. The reaction was cooled to room temperature, and the pH adjusted to ˜3 with 10% aqueous HCl solution. The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.60 (s, 1H), 8.58 (s, 1H), 8.53 (s, 1H), 8.37 (d, J=7.93 Hz, 1H), 8.28 (d, J=5.04 Hz, 1H), 7.88 (d, J=6.71 Hz, 1H), 7.75 (t, J=7.78 Hz, 3H), 7.51 (s, 1H), 7.32 (d, J=5.04 Hz, 1H), 3.32 (s, 3H), 2.64-2.55 (m, 2H), 2.45-2.35 (m, 2H), 2.05-1.92 (m, 2H); MS ESI(+) m/z 426.7 [M+H]+.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([CH3:11])[CH:5]=1.[N:12]([O-])=O.[Na+].[O-]S(S([O-])=O)=O.[Na+].[Na+].[OH-].[Na+]>Cl.O.C(OCC)C>[ClH:1].[NH:8]([C:7]1[CH:9]=[CH:10][C:4]([O:3][CH3:2])=[CH:5][C:6]=1[CH3:11])[NH2:12]
Reactant: COc1ccc(N)c(C)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(NN)c(C)c1
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
33 g (0.19 mol) 4-methoxy-2-methylaniline hydrochloride was suspended in 100 ml (6M) hydrochloric acid under argon atmosphere. The mixture was cooled to +5° C. and a solution of 13.1 g (0.19 mol) NaNO2 in 35 ml water was added dropwise at such rate that the temperature was kept below +5° C. After the addition was completed the solution was stirred for 30 min at +5° C. 101.7 g (0.58 mol) Na2S2O4 was dissolved in 500 ml wager at +5° C. and the solution was poured into the reaction mixture and stirred for 30 min. 250 ml diethyl ether was added and made basic with NaOH (10M) until pH 9. The phases were separated and the water phase extracted with diethyl ether. The combined organic phases were washed with NaCl(aq) and dried with Na2SO4. The ether phase was filtered through celite. A saturated solution of HCl(g) in ether was added to the solution containing the product and the hydrochloride salt of the hydrazine precipitated. The crystals were collected on a suction filter and washed with diethyl ether and chloroform. 29.5 g (82%) of the product was isolated.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9]([Mg]Br)[CH3:10]>C1COCC1>[CH2:9]([CH:7]([C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1)[OH:8])[CH3:10]
Reactant: Cc1ccc(C=O)s1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc(C)s1
Temperature: -78 °C

Procedure:
5-Methyl-2-thiophenecarboxaldehyde (10.0 g) is dissolved in THF and cooled to -78° C. To that solution is added ethyl magnesium bromide (1M in hexane; 80 cc) dropwise over several minutes. The cooling bath is removed and the reaction allowed to equilbrate to room temperature. The reaction is quenched by adding a saturated solution of NH4Cl. The reaction is extracted with ether, dried and evaporated to yield the title product as an almost colorless oil.
Reaction SMILES: [CH:1](=[N:5][OH:6])[CH2:2][CH2:3][CH3:4].[CH3:7]/[C:8](/[C:11]([CH3:13])=O)=[N:9]\[OH:10]>CCOCC>[CH3:13][C:11]1[N+:5]([O-:6])=[C:1]([CH2:2][CH2:3][CH3:4])[N:9]([OH:10])[C:8]=1[CH3:7]
Reactant: CC(=O)/C(C)=N/O
Reactant: CCCC=NO
Solvent: CCOCC
Product: CCCc1n(O)c(C)c(C)[n+]1[O-]
Reaction time: 48 h

Procedure:
A mixture of butyraldoxime (8.7 g., 0.1 mole) and diacetyl monoxime (10.1 g., 0.1 mole) was warmed to obtain a homogeneous solution. After standing for 2 days at room-temperature, the mixture was heated on the steam-bath for 3 hr., and then diluted with ether (500 ml), the tan solid separated was removed by filtration (16.7 g.) and recrystallised from ethanol (95%) having a melting point 174°-175°C
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=CC=CC=1C=O.COC1C=C(C=CC=1)O[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O:39][CH3:40])=[O:38].CO/C=C(\C1C=CC=CC=1OC1C=CC=C(OC2C=CC=CC=2)C=1)/C(OC)=O.[H-].[Na+].C(OC)=O.C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.OC1C=C(C=CC=1)OC1C=CC=CC=1/C(=C\OC)/C(OC)=O>>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccccc1Oc1cccc(OC)c1
Reactant: Oc1cccc(Oc2ccccc2)c1
Agent: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(O)c1
Agent: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Solvent: COS(=O)(=O)OC
Solvent: COC=O
Product: COC(=O)Cc1ccccc1Oc1cccc(Oc2ccccc2)c1

Procedure:
Methyl 2-(3-phenoxyphenoxy)phenylacetate was prepared from 3-phenoxyphenol and 2-bromobenzaldehyde by the steps described in Example 1 for the preparation of methyl 2-(3-methoxyphenoxy)phenylacetate. This was the converted into (E)-methyl 3-methoxy-2-[2-(3-phenoxyphenoxy)phenyl]propenoate [1H n.m.r (250 MHz) 3.61 (3H, s), 3.78 (3H, s), 6.68-7.35 (13H, m), 7.48 (1H, s) ppm] using sodium hydride and methyl formate, and then potassium carbonate and dimethyl sulphate, using the procedure described in Example 1 for the preparation of (E)-methyl 2-[2-(3-hydroxyphenoxy)phenyl]-3-methoxypropenoate, except that just 2 equivalents of sodium hydride were used in this case.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.C([O-])(=O)C.[Na+].[Br:16]Br.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>CO>[Br:16][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[N:10][CH:9]=1
Reactant: Clc1nccn2ccnc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: CO
Product: Clc1nccn2c(Br)cnc12
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) suspension of 8-chloroimidazo[1,2-a]pyrazine (18.6 g, 0.12 mol) and sodium acetate (29.8 g, 0.36 mol) in methanol (125 ml, pre-saturated with solid potassium bromide) was treated with bromine (6.5 ml, 0.13 mol) added dropwise over 5 min. After stirring for 10 min thin-layer chromatography indicated no starting material. Solid sodium sulphite (15.3 g, 0.12 mol) was then added to the slurry and stirring continued for 10 min. The mixture was then treated with saturated aqueous sodium hydrogencarbonate (650 ml) added in portions. This mixture was extracted with dichloromethane (2×350 ml). The organics were combined, dried over anhydrous magnesium sulphate, filtered and concentrated to afford 3-bromo-8-chloroimidazo[1,2-a]pyrazine as a cream-coloured solid: δH (400 MHz, CDCl3) 7.82 (1H, d, J 4.5), 7.83 (1H, s), 8.05 (1H, d, J 4.6). This solid was suspended in 1:1 dichloromethane/methanol (160 ml) and treated with solid sodium methoxide (9.8 g, 0.18 mol). The resulting mixture was then stirred at 40° C. for 2 h. The reaction was cooled, diluted with water (750 ml) then extracted with dichloromethane (600 ml). The organics were dried over anhydrous magnesium sulphate, filtered and concentrated to give 3-bromo-8-methoxyimidazo[1,2-a]pyrazine as a white solid (24.5 g, 89% over 2 steps): δH (360 MHz, DMSO) 4.06 (3H, s), 7.57 (1H, d, J 4.5), 7.81 (1H, s), 8.03 (1H, d, J 4.5).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH:17]=O.C(O)(C(F)(F)F)=O>>[F:13][C:14]1[CH:15]=[C:16]([CH:17]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1F
Yield: 81.9 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (5.4 g, 33.5 mmol), 3,4-difluorobenzaldehyde (5.0 g, 1.05 equiv.) and TFA (5.2 mL, 2 equiv.) to give the title compound (7.8 g, 82%) as white crystals. MP: 151° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1Cn1c(C)nc2c(Br)cc(N3CCOCC3)cc21
Temperature: 90 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
To the mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.7 g, 2.364 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added in 1-(bromomethyl)-2-methylbenzene (0.525 g, 2.84 mmol) and potassium carbonate (0.980 g, 7.09 mmol). The resulting reaction mixture was stirred at 90° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜90% EtOAc in Hexane) to give the product as solid (0.726 g, 77%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.43 (s, 3H) 2.54 (s, 3H) 3.00-3.14 (m, 4H) 3.78-3.90 (m, 4H) 5.22 (s, 2H) 6.44 (d, J=7.83 Hz, 1H) 6.53 (d, J=2.02 Hz, 1H) 7.02-7.12 (m, 1H) 7.15 (d, J=2.02 Hz, 1H) 7.18-7.27 (m, 2H); MS (ES+) m/e 400.0 [M+H]+.
Reaction SMILES: [O:1]1[C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[CH:3]=[CH:2]1.CCCC[Sn](O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC.C(#N)C.[I:41]I>CCOC(C)=O.C1(C)C=CC=CC=1.CC(C)=O>[I:41][C@@H:3]1[C@@H:4]([OH:5])[C@H:6]([OH:7])[C@H:8]2[CH2:9][O:10][C@@H:2]1[O:1]2
Reactant: OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Reactant: II
Agent: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CC(C)=O
Product: O[C@H]1[C@H](O)[C@H]2CO[C@H](O2)[C@@H]1I
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
The de-acetylated syrupy D-glucal IntA1 from step 1 (53.7 g, based on quantitative yield, 367 mmol) is treated with bis(tributyltin)oxide (175 g, 150 mL, 294 mmol, 0.8 eq) and activated powdered 3A molecular sieves [150 g] in refluxing dry Acetonitrile [3.5 L] for 16 hours. Next morning, the mixture is cooled to 5° C. under N2 and I2 [140 g, 551 mmol] is added in one portion. The dark brown mixture is stirred for 15 minutes @ 5° C., then for 3 hours at room temperature. TLC (either 1/1:toluene/Acetone or 100% EtOAc) showed the complete conversion of D-glucal (Rf 0.14) into iodo derivative (Rf 0.45). The mixture was filtered through Celite and concentrated. To this residue is added saturated aqueous sodium thiosulfate (200 mL) and hexanes (200 mL). The biphasic mixture is vigorously mixed for 16 hours. The aqueous phase is then continuously extracted with DCM (1.5 Lt.) for 24 hours (till no product was detected in the aqueous layer). The organic extract is dried over Na2SO4 and concentrated. To the residue was added 500 mL acetone. The yellow insoluble material was filtered and discarded. The acetone solution was evaporated to dryness. The residue was treated with EtOAc to separate the desired iodo-1,6-anhydro derivative, IntA2 as a white solid. Yield: 76 g. TLC IntA2 Rf=0.7, SiO2, 100% Ethyl Acetate.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:15][C:16](=O)[CH2:17][C:18](=O)[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:15][C:16]1[CH:17]=[C:18]([CH3:19])[N:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:2]2[N:1]=1
Reactant: COC(=O)c1c(N)[nH]c2ccccc12
Reactant: CC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: COC(=O)c1c2ccccc2n2c(C)cc(C)nc12
Yield: 75.6 %

Procedure:
A stirred solution of methyl 2-aminoindole-3-carboxylate (I. Forbes et al, J. Chem. Soc. Perkin I, 1992, 275) (0.25 g, 0.0013 mole) in xylene (5 ml) was treated with 2,4-pentanedione (0.13 g, 0.0013 mole) and a few crystals of 4-toluenesulphonic acid and heated under reflux for 2 h. The mixture was concentrated in vacuo and the residue dissolved in chloroform (20 ml), washed with water (2×20 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound as a brown solid (0.25 g, 75%).