Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH2:28]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCCc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCc2ccccc2)C3)nc1
Temperature: 75 °C
Yield: 29 %

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Part E, 112.9 mg, 0.40 mmol), K2CO3 (110.1 mg, 0.80 mmol), and phenethyl bromide (82 uL 0.60 mmol) in DMF (2.0 mL). Heat at 70-80° C. overnight. Remove DMF azeotropically with xylenes. Purify by flash chromatography, eluting with 75:19:6 EtOAc/CH2Cl2/2.0 M NH3 in MeOH and then with 60:30:10 EtOAc/hexanes/2.0 M NH3 in MeOH. Purify by reverse phase chromatography, eluting with 0-99% 0.1% TFA/acetonitrile and 0.1% TFA/water to give the title compound (44.9 mg, 27% from Step D): MS ES+ 284.0 (M−H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=9.85 min, 100% purity; Anal. Calcd for C24H25N3O2.0.1H2O.0.1MeOH: C, 73.75; H, 6.57; N, 10.71. Found: C, 73.45; H, 6.62; N, 10.72.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[O-:18][C:19]#[N:20].[Na+].C(O)(=O)C(C1C=CC=CC=1)O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:19]([NH2:20])=[O:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: N#C[O-]
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Agent: O=C(O)C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC1=Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A suspension of 10 g of 10-methoxyiminostilbene in 200 ml toluene was treated with 20 g of sodium cyanate and 39 g of mandelic acid and was heated to reflux for about 10 hrs. The reaction mixture was cooled to room temperature and charged with sodium hydroxide solution and maintained for 19 hrs. The resulting suspension was filtered, washed with water and dried to give 10 g of 10-methoxy carbamazepine.
Reaction SMILES: [OH-].[NH4+].[CH3:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1[NH2:6].[NH4+].[C:13](=S)([S-:15])N.ClC(OCC)=O>O.C(=S)=S>[CH3:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1[N:6]=[C:13]=[S:15]
Reactant: NC(=S)[S-]
Reactant: Cc1cccc(C)c1N
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: S=C=S
Solvent: O
Product: Cc1cccc(C)c1N=C=S
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 55.2 %

Procedure:
745 grams (9.8 moles) of carbon disulfide and 1230 milliliters (ml) of concentrated ammonium hydroxide was added to a 5 liter, 3-neck flask fitted with a mechanical stirrer, teflon clad thermocouple, and an additional funnel. The contents of the flask were cooled to 0° C. by use of an ice bath. Then with rapid stirring, 1,008 grams of 2,6-dimethylaniline was added drop wise to the contents of the flask. The temperature was maintained below 10° C. by controlling the rate of addition. It is preferable to maintain the temperature in the range of about 10° C. to avoid a run away reaction (which run away begins to occur at a temperature of about 30° C. and is accompanied by a loss of ammonium (NH3) and carbon disulfide (CS2) gas). The addition took approximately 45 minutes. The reaction mixture (orange-red in color) was allowed to stir for an additional four hours, during which time a dithiocarbamate salt crystalized. The salt crystals were collected by suction filtration using a Buchner funnel, and were allowed to suck dry on the aspirator. The crystaline salt was placed in a 12-L flask fitted with a mechanical stir, thermo couple, and an addition funnel, and 5 liters of water with 2-propanol (water to propanol ratio of which ranged between 1:1 and 3:1 by volume, respectively) was added. Ethyl chloroformate (890.8 grams; 8.21 moles) was added dropwise to the stirred slurry at a rate such that the temperature did not rise above 40° C.; a cooling bath was used to help control the temperature. The addition funnel was replaced by a condenser, and the reaction mixture was heated to between 60° and 70° C. and maintained at this temperature for 1 hour. The reaction mixture was cooled to ambient temperature and then 1 liter of water was added. The layers were separated, and the bottom layer (2,6-dimethylphenylisothiocyanate) was washed with 200 ml of water and then dryed over anhydrous sodium sulfate. Distillation under vaccuum (125° Centigrade at about 3 torr.) gave 949 grams (55.2% yield on total theoretical basis by weight) of 2,6-dimethylphenylisothiocyanate. The intermediate product is filtered to remove any solid by-product prior to use in next step. The product was used directly in the next step of the synthesis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([S:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:29]1C=CC=C[CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([S:17][C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[C:11]([CH2:13][C:14]([O:16][CH2:29][CH3:30])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: c1ccccc1
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)sc1Sc1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.0 g of 2-p-chlorophenyl-5-p-chlorophenylthio-4-thiazoleacetic acid were added 10 ml of benzene and 2.0 ml of thionyl chloride, and the mixture was refluxed for 30 minutes. The solvent and the excess thionyl chloride were distilled off under reduced pressure. To the residue was added 20 ml of ethanol and stirred at room temperature for 1 hour and then the solvent was distilled off under reduced pressure. Recrystallization of the residue from ethanol gave 0.8 g of the title compound, melting at 103°-104° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[F:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43](O)=[O:44])[CH:38]=[CH:39][C:40]=1[CH3:41].Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:43](=[O:44])[CH2:42][C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[C:35]([F:34])[CH:36]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: Cc1ccc(CC(=O)O)cc1F
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1ccc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1F
Reaction time: 0.17 h
Yield: 72.7 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotraiazole (0.4 g, 2.6 mmol) and 3-fluoro-4-methylphenylacetic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-fluoro-4-methyl-phenyl)-acetamide (0.7 g, 70%) as a white solid: mp 148-150° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.06 min. (98%); 1H NMR (DMSO-d6) δ 2.04-2.07 (m, 1H), 2.20 (s, 3H), 2.52-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.52 (s, 2H), 4.70 (d, J=5.7 Hz, 2H), 5.12-5.18 (dd, J=5.1 and 12.7 Hz, 1H), 6.99-7.07 (dd, J=11.2 and 14.7 hz, 2H), 7.21 (t, J=8.0 Hz, 1H), 7.63-7.76 (dd, J=3.3 and 7.5 Hz, 1H), 7.77-7.83 (dd, J=7.6 and 11.9 Hz, 2H), 8.65 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 13.74 (13.78), 21.95, 30.90, 37.84, 41.41, 48.83, 115.31, 115.60, 121.89, 124.84 (124.87), 127.12, 131.02 (131.28), 131.51, 133.20, 134.66, 135.87 (135.97), 139.09, 158.77 (161.98), 166.90, 167.42, 169.78, 170.26, 172.73; Anal. Calcd. for C23H20N3O5F: C, 63.15; H, 4.61; N, 9.61; F, 4.34. Found: C, 62.78; H, 4.45; N, 9.32; F, 4.47.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1F)=O.[NH2:13][NH2:14]>O>[CH3:11][O:10][C:7]1[CH:6]=[C:5]2[C:4]([C:2]([CH3:1])=[N:13][NH:14]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(C)n[nH]c2c1
Temperature: 25 °C

Procedure:
2-fluoro-4-methoxyacetophenone (5.0 g) was treated with hydrazine (75 ml) under argon and the mixture was heated to reflux for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (200 ml) then extracted three times with ethyl acetate (50 ml). The combined extracts were dried over sodium sulphate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:3, v/v) to yield the title compound (4.05 g).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Cl:12][C:13]1[CH:14]=[C:15](/[CH:19]=[CH:20]/[C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:21](=[O:22])/[CH:20]=[CH:19]/[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Agent: Cl
Product: O=C(/C=C/c1cccc(Cl)c1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(3-chlorophenyl)propenoic acid; the compound was purified by chromatography on silica gel using amrnmoniated methanol/chloroform mixtures as the eluent; MS (ES+) 291, 293 (MH+).
Reaction SMILES: [C:1]1([N:7]2[C:15]([NH2:16])=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]1([N:7]2[C:15]([N:16]=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1c2ccccc2nn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C(=Nc1c2ccccc2nn1-c1ccccc1)c1ccccc1
Yield: 107.1 %

Procedure:
To a solution of 2-phenyl-2H-indazol-3-amine (300 mg, 1.4 mmol; Shirtcliff, Laura D.; Rivers, Jazmin; Haley, Michael M, Journal of Organic Chemistry (2006), 71(17), 6619-6622) in CH2Cl2 (16 ml) was added benzaldehyde (730 μl, 7.2 mmol; [100-52-7]), acetic acid (220 ul, 4.3 mmol) and sodium triacetoxyborohydride (912 mg, 4.3 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was heated under reflux conditions for 64 h, poured onto ice water/aqueous NaHCO3 solution 1/1 and extracted two times with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure, the resulting yellow oil was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (470 mg, 1.5 mmol; quant.) as yellow solid. MS: m/e=298.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][NH:16][C:15](=[N:19]N)[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21](N)[CH3:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:21][CH3:22])[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN=c1cc(-c2c[nH]nc2-c2cccc(Cl)c2)cc[nH]1
Reactant: CCN
Solvent: CCO
Product: CCNc1cc(-c2c[nH]nc2-c2cccc(Cl)c2)ccn1
Yield: 46 %

Procedure:
A solution of the bromopyridine compound prepared in step 3 of Example A-219 (300 mg, 0.9 mmol) in ethylamine (3.5 ml) and ethanol (5 ml) as heated at 150° C. in a sealed tube for 9 hours. The solvent was removed in vacuo and the residue chromatographed on silica gel with 70 ethyl acetate/30 toluene to give 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-ethyl-2-pyridinamine (125 mg, 46%) as a solid, m.p. 186-187° C.
Reaction SMILES: Cl[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([O:18][C:19]2[C:20]([CH3:28])=[N:21][N:22]([CH2:25][CH2:26][OH:27])[C:23]=2[CH3:24])[CH:17]=1)[C:13]#[N:14].N1C=CN=C1.O>CN(C)C=O>[Si:2]([O:27][CH2:26][CH2:25][N:22]1[C:23]([CH3:24])=[C:19]([O:18][C:16]2[CH:15]=[C:12]([CH:11]=[C:10]([Cl:9])[CH:17]=2)[C:13]#[N:14])[C:20]([CH3:28])=[N:21]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: Cc1nn(CCO)c(C)c1Oc1cc(Cl)cc(C#N)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(CCO[Si](C)(C)C(C)(C)C)c(C)c1Oc1cc(Cl)cc(C#N)c1
Reaction time: 72 h
Yield: 82.1 %

Procedure:
Chloro-t-butyldimethylsilane (2.78 g, 18.5 mmol) was added in one portion to a stirred solution of the pyrazole of Example 114 (4.89 g, 16.8 mmol) and imidazole (1.48 g, 21.8 mmol) in N,N-dimethylformamide (30 ml) at room temperature under nitrogen. The reaction was stirred for 3 days and water (200 ml) was added. The aqueous phase was extracted with diethyl ether (3×200 ml) and the combined organic phases were washed with water (2×50 ml) and brine (2×50 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane to provide the title compound (5.60 g) as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:13]Br>C(OCC)C.O.[Cl-].[Al+3].[Cl-].[Cl-]>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH2:2][Br:13])=[CH:5][CH:6]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1ccc(C(C)=O)cc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1ccc(C(=O)CBr)cc1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a stirred solution of 1,4-diacetylbenzene (5.3 g, 32.7 mmol), aluminum chloride (0.05 g, 0.38 mmol) in diethylether (50 ml) was added bromine (5.3 g, 32.7 mmol) dropwise over 20 minutes. The mixture was stirred for 30 minutes, and diluted with water. The whole was concentrated to remove diethylether, and the aqueous suspension was filtered to give 7.0 g of white solid. The compound was used for next reaction without purification.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][CH:16]=[C:15]([CH2:18][OH:19])[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][CH:16]=[C:15]([CH:18]=[O:19])[CH:14]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCc1c[nH]c(-c2ccc(C3CCCCC3)cc2)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1c[nH]c(-c2ccc(C3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
To a solution (35 mL) of [5-(4-cyclohexylphenyl)-1H-pyrrol-3-yl]methanol (1.00 g) in acetonitrile were added tetra-n-propylammonium perruthenate (115 mg), N-methylmorpholine N-oxide (0.60 g) and molecular sieves 4A powder (1.15 g) under ice-cooling. The mixture was stirred at room temperature for 1.5 hr, and the reaction mixture was suspended in ethyl acetate, and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as crystals (yield 0.53 g, 53%).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:8]([N:5]1[C:4](=[O:6])[CH:3]=[CH:2][C:1]1=[O:7])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1C=CC(=O)N1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1C=CC(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Maleimide (20.0 g, 206 mmol) and trityl chloride (57.4 g, 206 mmol) were mixed together in 200 ml of chloroform and triethylamine (31.3, 309 mmol) was added dropwise to the reaction over a period of 20 minutes. After stirring for one hour at room temperature, the reaction was washed with 10% aqueous hydrogen chloride (HCl) solution and dried over magnesium sulfate (MgSO4). The crude product was slurried in 20 ml of ethylacetate. A total of 18.4 g of a solid material was filtered and dried (60% yield). 1H NMR (CDCl3): 7.31 (m, 15H, aromatics), 6.25 (s, 2H, vinyl).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:29])=[O:28])=[CH:25][CH:26]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:8]2=[N:9][CH:10]=1)=[O:4].[Mn]([O-])(=O)(=O)=[O:40].[K+]>CO.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:29])(=[O:40])=[O:28])=[CH:25][CH:26]=3)=[CH:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[N:11]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)=O)nc1)n2S(=O)(=O)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)nc1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfinyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (301 mg, 0.55 mmol) in methanol (30 ml) was added a solution of potassium permanganate (88 mg, 0.55 mmol) in water (30 ml). The reaction mixture was stirred at 25° C. for 1 h. The suspension was filtered through a short silica gel pad and then washed with ethyl acetate (3×30 mL). The filtrate was concentrated and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (2×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (230 mg, 72%): LC/MS m/e calcd for C28H27N3O6S2 [M+H]+ 566.67, observed 565.9.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[N:3]=1.[Br:15]Br.O.[OH-].[K+]>C(O)(=O)C>[Br:15][C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:5]=1[NH2:7]
Reactant: BrBr
Reactant: Cc1cc(N)n(-c2ccccc2C)n1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1-n1nc(C)c(Br)c1N
Reaction time: 0.5 h

Procedure:
To a solution of 3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate F, 7.78 g, 41.7 mmol) in acetic acid (90 mL) was added a solution of bromine (6.64 g, 41.6 mmol) in acetic acid (10 mL). The reaction mixture was stirred for 30 min. Water was added to the reaction mixture, and the mixture was basified using a cold KOH solution (1 N). The white solid, 4-bromo-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine, was collected and used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:21]Br>C(#N)C>[Br:21][C:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[N:9]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc2cnn(-c3ccc(C)cc3)c2c1
Solvent: CC#N
Product: COC(=O)c1ccc2c(Br)nn(-c3ccc(C)cc3)c2c1
Reaction time: 60 h
Yield: 74.2 %

Procedure:
Methyl 1-(4-methylphenyl)-1H-indazole-6-carboxylate (2.7075 g, 10.17 mmol) was dissolved in acetonitrile (102 ml) at 25° C. under Ar. Bromine (1.886 ml, 36.60 mmol) was added. The reaction mixture was allowed to stir for 60 h. The reaction was stopped, quenched by addition of saturated aqueous sodium bicarbonate (40 mL), and the mixture extracted with ethyl acetate (3×35 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×25 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 330 g column) on a CombiFlash Rf purification system eluting with ethyl acetate-hexanes (0-5%). The title compound (2.8006 g, 7.55 mmol, 74.2% yield) was recovered as a white solid. LC-MS [M+1]=346.1.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].Cl[CH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[O:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([O:12][CH2:14][C:15]3[CH:32]=[CH:31][CH:30]=[C:17]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)[CH:16]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: N#Cc1nc2ccc(O)cc2o1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1nc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Temperature: 0 °C

Procedure:
To 2-cyano-6-hydroxybenzoxazole (11.87 mmoles) and 2-((3-chloromethylphenoxy)methyl)quinoline (11.87 mmoles) in dimethylsulfoxide (20 ml) is added powdered sodium hydroxide (0.475 q). After one week the reaction mixture is poured into ice water and the resulting precipitate collected and purified by HPLC to give 2-cyano-6-(3-(quinolin-2-ylmethyloxy)benzyloxy)-benzoxazole which is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1.Cl([O-])(=O)(=O)=O.C[S+](C)C1C=CC=CC=1>N1C=CC=CC=1>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: C[S+](C)c1ccccc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Yield: 58.3 %

Procedure:
In 10 ml of pyridine were dissolved 0.39 g of 5-fluorouracil and 0.42 g of 2,3-dihydrofuran. To the solution were added 72 mg of dimethylphenylsulfonium perchlorate and the mixture was reacted for 5 hours at 130° C. After the reaction, pyridine was distilled off under reduced pressure and 20 ml of water were added to the residue. The aqueous solution was treated with caustic soda to have a pH value of 10-11 and then washed with 20 ml of chloroform. The aqueous alkaline solution was treated while cold with diluted hydrochloric acid to adjust the pH value of the solution to 3.5 and then extracted three times with 20 ml of chloroform. The chloroform extract was dried and then the chloroform was distilled off. The residue was recrystallized from ethanol to obtain 0.35 g of 1-(2-tetrahydrofuryl)-5-fluorouracil. The yield was 58.3%.