Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:43]1[CH:48]=[CH:47][C:46]([C:49]#[N:50])=[CH:45][N:44]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:43]4[CH:48]=[CH:47][C:46]([C:49]#[N:50])=[CH:45][N:44]=4)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(Oc2ccc(C#N)cn2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
A mixture of 59 mg (0.1 mMol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate, 120 mg of 2-chloro-5-cyanopyridine and 65 mg (0.2 mMol) of cesium carbonate in 0.5 mL of dimethyl formamide was stirred at rt for 5 h. The mixture was diluted with ethyl acetate and extracted with water. Evaporation of the solvent and chromatography on silica gel (1:1 ethyl acetate-hexanes) gave the title compound (16 mg). 1H NMR: 0.88(6H,dd), 1.55-1.8(3H,m), 2.8-3.2(7h,m), 3.65(2H,m), 3.8(2H,m), 3.95(1H,m), 5.0(2H,m), 5.6(1H,d), 6.05(2H,s), 6.82(1H,d), 6.95(1H,d), 7.0(2H,d), 7.1-7.4(4H,m), 7.9(1H,d), 8.4(1H,bs). MS: 695(M+H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Temperature: 0 °C
Yield: 83.4 %

Procedure:
4-(6-Nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (83 g, 0.269 mol) in methanol (1.3 L) plus Raney Nickel (15 g, 50% slurry in water) were placed in a Parr shaker and hydrogenated at 50 psi of hydrogen for 5 h. The reaction mixture was filtered through a pad of celite and concentrated to a brown solid. This material was triturated with diethyl ether (120 mL) for 4 h. Heptane was added and the mixture was cooled to 0° C. for 45 min. The solid was collected by filtration and dried to afford the product 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester as a tan solid (62.46 g, 83%). mp 130–132° C. MS (ESI); M++1: Calc'd, 279.2, Found 279. Anal. Calc'd for C14H22N4O3: C, 60.41; H, 7.97; N, 20.13. Found; C, 60.45; H, 7.60; N, 19.87.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:12]N1C(=O)CCC1=O>ClCCl>[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Br:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C=O)c(N)c1
Solvent: ClCCl
Product: COc1cc(N)c(C=O)cc1Br
Yield: 54.7 %

Procedure:
To a stirred solution of 2-amino-4-methoxybenzaldehyde (6 g, 39.7 mmol) in dichloromethane (100 mL) was added N-bromosuccinimide (7 g, 39.7 mmol). LCMS monitored the reaction until the starting material consumed completely. The reaction mixture was diluted with dichloromethane and water. The separated organic layer was dried sodium sulfate, filtered and concentrated to give the title compound (5 g, 56%) as a yellow solid. MS (ES+) C8H8BrNO2 requires: 229, 231. found: 230, 232 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH:16]([CH3:26])[CH2:17][NH:18]C(=O)OC(C)(C)C)[N:12]2[CH:27]=[CH:28][N:29]=[C:11]2[CH:10]=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH:16]([CH3:26])[CH2:17][NH2:18])[N:12]2[CH:27]=[CH:28][N:29]=[C:11]2[CH:10]=1
Reactant: CC(CNC(=O)OC(C)(C)C)Nc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(CN)Nc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 138.8 %

Procedure:
tert-Butyl (2-{[7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]amino}propyl)carbamate (Example 36A) (700 mg, 1.6 mmol) is dissolved in dichloromethane (20 ml), and trifluoroacetic acid (2.5 ml, 32 mmol) is added. The resulting solution is stirred at RT for 1 h, concentrated in a rotary evaporator and dried on the vacuum line. 1 g of the product is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.II.[Mg].[CH:13]([O-])([O-])[O:14]CC.S(=O)(=O)(O)O>C(OCC)C>[F:9][C:5]1[CH:4]=[CH:3][C:2]([CH:13]=[O:14])=[CH:7][C:6]=1[CH3:8]
Reactant: Cc1cc(Br)ccc1F
Reactant: CCOC([O-])[O-]
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: Cc1cc(C=O)ccc1F
Reaction time: 8 h

Procedure:
A solution of 5-bromo-2-fluorotoluene (6 g) in ethyl ether (10 ml) and a catalytic amount of iodine were added to a suspension of magnesium (960 mg) in ethyl ether (10 ml) under nitrogen atmosphere and the whole was refluxed for 30 minutes. After cooling, a solution of ethyl orthoformate (5.4 g) in ethyl ether (20 ml) was added to the mixture and the whole was stirred overnight. Sulfuric acid (10%, 20 ml) was added to the mixture and the organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel with a mixture of hexane and ethyl acetate (10:1) as eluent to give 4-fluoro-3-methylbenzaldehyde as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[N:4]([CH2:8][C:9](=O)[CH3:10])[N:3]=1.O.[NH2:13][NH2:14].C(O)(=O)C(O)=O>CC(O)C.O>[CH3:10][C:9]1[CH2:8][N:4]([NH:3][C:2](=[O:6])[CH3:1])[C:5](=[O:7])[NH:13][N:14]=1
Reactant: CC(=O)Cn1nc(C)oc1=O
Reactant: NN
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: O
Product: CC(=O)NN1CC(C)=NNC1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.9 %

Procedure:
To a solution of 5-methyl-3-(2-oxo-propyl)-3H-1,3,4-oxadiazol-2-one (2.052 g, 13.14 mmol) in a mixture of 2-propanol (12 mL) and water (0.3 mL) is added hydrazine monohydrate (0.96 mL, 19.8 mmol). The mixture is stirred at rt under N2 for 15 h, and then heated to reflux for 7 h. A solution of oxalic acid (0.363 g, 4.032 mmol) in 2-propanol (6 mL) is added to the warm reaction solution. The resulting precipitate is removed by filtration through a coarse porosity sintered glass funnel, and the filtrate is concentrated in vacuo to approximately 10 mL in total volume. The concentrated solution is chilled to −12° C., and the resulting crystals are collected by filtration and dried to afford N-(6-methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-acetamide (1.562 g, 70%). MS: 171 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.10 (br s, 1H), 7.57 (br s, 1H), 4.20 (s, 2H), 2.04 (s, 3H), 1.95 (s, 3H); 1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1), 9.74 (s, 1), 4.04 (s, 2), 1.84 (s, 6).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[C:8](=[O:19])[NH:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:6]>S(=O)(=O)(O)O>[CH2:5]([C:7]1[C:8](=[O:19])[NH:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([N+:1]([O-:4])=[O:2])[CH:13]=1)[CH3:6]
Reactant: CCC1=C(c2ccc(F)cc2)CNC1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCC1=C(c2ccc(F)c([N+](=O)[O-])c2)CNC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Nitric acid (70%, 14 mL, 0.22 mol) is added dropwise to a solution of 3-ethyl-4-(4-fluorophenyl)-1,5-dihydro -2H-pyrrol-2-one (37.6 g, 0.18 mol) in concentrated sulfuric acid (140 mL) while the temperature is maintained at 0°-5° C. The mixture is stirred for 2 hr at 0° C., and then is poured onto 2500 g of ice. The resulting precipitate is collected by filtration, and washed with water until the washes are neutral. Recrystallization of the solid from ethanol followed by drying under vacuum at 50° C. for 24 hr provides the title compound.
Reaction SMILES: [F:1][CH2:2][C@@H:3]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH2:4][C:5](OCC1C=CC=CC=1)=[O:6].[H-].C([Al+]CC(C)C)C(C)C>CCOCC>[F:1][CH2:2][C@@H:3]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH2:4][CH:5]=[O:6]
Reactant: O=C(C[C@@H](CF)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: O=CC[C@@H](CF)N1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (S)-benzyl 4-fluoro-3-(1,3-dioxoisoindolin-2-yl)butanoate (compound 7-4, 0.5 mmol) in dry ether (5 mL) was added dropwise to diisobutylaluminum hydride (1.0 M in toluene, 1.5 mmol) at −78° C. The reaction was stirred at −78° C. for approximately 30 min as monitored by LC/MS. After completion, the reaction was quenched by adding water (10 mL) at −78° C. Extracted with ethyl acetate, washed with water (×3), brine (×2), dried over sodium sulfate, filtered and concentrated. The crude product, compound 7-5, was used in the next reaction step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:11]C(=O)C(C)(C)C)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[NH2:11]
Reactant: CC(C)(C)C(=O)Nc1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of N-(3-fluoro-4-nitro-phenyl)-2,2-dimethyl-propionamide (87.0 g, 0.36 mol) in CH2Cl2 (400 mL) and 6N hydrochloric acid (800 mL) was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with 1000 mL of ethyl acetate and potassium carbonate (500.0 g) was added portion wise. The aqueous solution was separated and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed by evaporation under reduced pressure; the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to afford 3-fluoro-4-nitroaniline (56.0 g, 99%). 1H NMR (300 MHz, CDCl3) δ 8.07 (t, J=8.7 Hz, 1 H), 7.86 (dd, J=2.1, 13.2 Hz 1 H), 7.59 (brs, 2 H), 7.22 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.C(N(CC)CC)C>CS(C)=O>[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:21]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:22])=[CH:31][CH:30]=1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Reactant: COCCOc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCCOc1ccc(NC(=O)N2CCC(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1
Temperature: 25 °C
Yield: 22.9 %

Procedure:
A mixture of 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (18 mg, 0.0536 mmol), as prepared in Example 3a, 4-(2-methoxy-ethoxy)-phenylamine (8.9 mg, 0.0533 mmol), as prepared in the previous step, and triethylamine (14 μL, 0.1 mmol) was stirred in DMSO (0.5 mL) at 50° C. overnight. The reaction was then cooled to RT, partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a brown solid (5.7 mg, 23%). 1H NMR (300 MHz, CDCl3) δ 9.16 (s, 1H), 7.28-7.25 (m, 4H), 6.89 (m, 2H), 6.33 (br s, NH), 4.29-4.24 (m, 2H), 4.12-4.07 (m, 8H), 3.74 (m, 2H), 3.59 (m, 1H), 3.45 (s, 3H), 3.17 (m, 2H), 2.22-2.08 (m, 2H), 2.05-1.97 (m, 2H); LC/MS (ESI): calcd mass 466.2, found 467.4 [M+1]+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:10](=[O:22])[CH2:9]1)[CH3:7]>>[CH2:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([F:21])[CH:18]=[CH:19][C:20]=2[S:2]([Cl:1])(=[O:5])=[O:3])[C:10](=[O:22])[CH2:9]1)[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CCN1CCN(Cc2cccc(F)c2)C(=O)C1
Product: CCN1CCN(Cc2cc(F)ccc2S(=O)(=O)Cl)C(=O)C1

Procedure:
Chlorosulphonic acid (2 mL) was added to 4-ethyl-1-(3-fluorobenzyl)-piperazin-2-one (Intermediate 175, 0.59 g) with stirring and cooling in ice. The cooling was removed and the solution was stirred at room temperature for 4 hours before being carefully added to a mixture of ethyl acetate, ice and sodium bicarbonate. The organic layer was dried (Na2SO4) and filtered and the filtrate was concentrated in vacuo to give 2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluoro-benzenesulfonyl chloride (0.37 g) as a colourless gum.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][NH2:17])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>ClCCl>[CH2:22]([NH:24][C:25]([NH:17][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[S:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]=2)[CH:9]=1)=[O:26])[CH3:23]
Reactant: CCN=C=O
Reactant: CC(C)c1nnc2ccc(Sc3ccccc3CN)cn12
Solvent: ClCCl
Product: CCNC(=O)NCc1ccccc1Sc1ccc2nnc(C(C)C)n2c1
Reaction time: 0.33 h
Yield: 93.3 %

Procedure:
To a solution of 2-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylsulfanyl)-benzylamine (200.0 mg, 0.671 mmol) in dichloromethane (6.71 mL) under nitrogen at ambient temperature was added ethyl isocyanate (53.0 μL, 0.67 mmol). The reaction was stirred for 20 minutes, then the solvent was removed in vacuo. The residue was recrystallized from ethyl acetate to give the title compound (231 mg, 94%). MS (M+1)=370.5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:13][C:14](=O)[CH3:15])[CH:7]=1)[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:14]=2[CH3:15])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(SCC(C)=O)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 2, using the following starting materials: [3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:13]3)O)=[N:4][CH:5]=[CH:6][N:7]=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:13]3)[N:30]2[C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]2=[O:31])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC(c1ccc2ncc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(c1ccc2ncc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A flask containing crude (3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methanol (153 mg, ˜0.44 mmol) was flashed with Ar and charged with phthalimide (71 mg, 0.48 mmol) and triphenylphosphine (130 mg, 0.48 mmol) and anh. THF (10 mL). DIAD (0.1 mL, 0.48 mmol) was added slowly dropwise at rt and then the reaction was stirred at rt for 16 h. The reaction was concentrated under reduced pressure and purified by flash chromatography (silica gel, 5% EtOAc in DCM to 10%) affording 2-[(3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methyl]-1H-isoindole-1,3(2H)-dione compound as a creamy solid. To stirred solution of the crude 2-[(3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methyl]-1H-isoindole-1,3(2H)-dione (147 mg, 0.31 mmol) in anh. EtOH (12 mL) and anh. DCM (2 mL) under Ar was added anh. hydrazine (0.03 mL, 0.9 mmol). The reaction mixture was stirred at rt for 22 h. The 1:1 mixture of the product and a partially cleaved phthalimide was concentrated under reduced pressure at rt and dried under high vacuum overnight. The light yellow, solid residue was dissolved in anh. i-PrOH (6 mL) and anh. CHCl3 (3 mL) and heated under Ar at 50° C. for 16 h. Later the reaction was cooled to rt, evaporated to dryness and triturated with DCM. The DCM aliquots were filtered through a pad of Celite affording the title compound as a light yellow solid; 1H NMR (400 MHz, CD3OD/CDCl3) δ 9.37 (s, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.23 (d, J=6.8 Hz, 2H), 8.12 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.88 (dd, J=0.8 Hz, 8.8 Hz, 1H), 7.62-7.52 (m, 3H), 5.81 (s, 1H). MS (ES+): m/z 348.0 (40) [MH+]; HPLC: tR=2.08 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]\[CH2:4][CH3:5].CN(C)C.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>CCOCC>[S:12]([O:6][CH2:1]/[CH:2]=[CH:3]\[CH2:4][CH3:5])([CH3:11])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC/C=C\CO
Agent: CN(C)C
Solvent: CCOCC
Product: CC/C=C\COS(C)(=O)=O
Yield: 83.3 %

Procedure:
Z-2-Penten-1-ol (5.0 g, 58.1 mmol), trimethylamine (6.45 g, 63.9 mmol), methanesulfonylchloride (7.0 g, 61.1 mmol) and ether (30 ml) were allowed to react at ambient temperature for 1 hour. After the completion of the reaction, the insoluble matter was removed and washed with water. The washed substance was dried over sodium sulfate. The solvent was distilled off to obtain 7.95 g of Z-1-mesyloxy-2-pentene as pale yellow oily material (83.4%). This material was added to a mixture of 3,8-dimethyl-5-hydroxycarbostyril (7.0 g, 37.0 mmol), potassium carbonate (10.2 g, 74.0 mmol) and dimethylformamide (210 ml), and allowed to react at 70° C. for 1 hour. The reaction mixture was condensed under reduced pressure, and the residue was poured into water to obtain 7.36 g of the title compound as a brown solid (77.3%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10]Br.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH2:19][C:20]([CH3:22])=[O:21].O>CC(CC)=O>[C:20]([C:19]1([C:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C:4]2[C:3](=[CH:8][CH:7]=[C:6]([F:9])[CH:5]=2)[CH2:2]1)(=[O:21])[CH3:22]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: Fc1ccc(CBr)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(=O)C1(C(=O)OC(C)(C)C)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 10 g of 1,2-bis-(bromomethyl)-4-fluoro-benzene in 200 ml of methylethylketone were added 29.4 g of potassium carbonate followed by 6.7 g of tert-butyl acetoacetate. The mixture was stirred for 16 h at ambient temperature. 200 ml of water were added. The phases were separated and the aqueous phase was extracted once with 100 ml of methylethylketone. The combined organic phases were washed once with 100 ml of water. The solvent was evaporated and to the resulting oil were added 20 ml of methanol. After 1 h stirring at ambient temperature the product was filtered off, washed with 2×5 ml of methanol and dried. Yield: 6.2 g. Melt.p. 73° C. 1HNMR: δ=1.48 ppm (s, 9H); 2.25 ppm (s, 3H); 3.44 ppm (AB, 2H); 3.47 (AB, 2H); 6.87 ppm (m, 2H); 7.12 ppm (dd, 1H)
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:21]=CC(C=O)=[CH:16][C:15]=2[F:22])=[CH:9][C:8]=1[C:23]([F:26])([F:25])[F:24]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:3]([C:2]1[CH:1]=[CH:21][C:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[C:8]([C:23]([F:25])([F:26])[F:24])[CH:9]=2)=[C:15]([F:22])[CH:16]=1)=[CH2:4]
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (6.73 g, 18.83 mmol) in anhydrous THF (20 mL) was added dropwise n-butyllithium (11.77 mL, 18.83 mmol) under −78° C. over 30 min. It was stirred for 1 h, then was added by 4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3-fluorobenzaldehyde (5.0 g, 15.69 mmol). It was warmed slowly to room temperature and stirred for overnight at room temperature. Purification via a flash column chromatography then afforded the title compound (4.0 g, 80% yield). LCMS: rt=5.7 min, [M+H+]=316
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:16]=[N:15][C:14]3[C:9](=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][CH:13]=3)[N:8]=2)[CH:4]=[N:3]1.Br[C:27]1[CH:28]=[C:29]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[F:44])(=[O:36])=[O:35])[CH:30]=[N:31][CH:32]=1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>[F:44][C:38]1[CH:39]=[C:40]([F:43])[CH:41]=[CH:42][C:37]=1[S:34]([NH:33][C:29]1[CH:30]=[N:31][CH:32]=[C:27]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:15]=[CH:16][C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[N:8]3)[CH:28]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Nc1cncc(Br)c1)c1ccc(F)cc1F
Reactant: Cn1cc(-c2cnc3ccc(B4OC(C)(C)C(C)(C)O4)cc3n2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccc(F)cc5F)c4)cc3n2)cn1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
A mixture of 2-(1-methyl-1H-pyrazol-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline (9.22 mmol), N-(5-bromo-3-pyridinyl)-2,4-difluorobenzenesulfonamide (8.13 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.404 mmol) in 2M aqueous sodium carbonate (40 mL) and 1,4-dioxane (40 mL) was heated at 100° C. for 1 h. Upon cooling, the reaction mixture separated into two layers (aqueous and organic). The organic layer was partitioned between ethyl acetate (50 mL) and water (25 mL). The two aqueous layers were then combined and the pH was adjusted to ˜7 with 2N aqueous HCl. A solid precipitated and was filtered away from the solution. The solid was dried in vacuo and then desiccated over P2O5 to afford the title product (2.5 g, 64%). MS(ES)+ m/e 479 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9][C:10]([F:13])([F:12])[F:11])[C:5]([Cl:14])=[C:4]([Cl:15])[C:3]=1[CH3:16].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:15][C:4]1[C:5]([Cl:14])=[C:6]([S:9][C:10]([F:12])([F:11])[F:13])[C:7]([Cl:8])=[C:2]([Cl:1])[C:3]=1[CH2:16][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)c(Cl)c(SC(F)(F)F)c(Cl)c1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)Sc1c(Cl)c(Cl)c(CBr)c(Cl)c1Cl
Yield: 48.7 %

Procedure:
A mixture of 2,3,5,6-tetrachloro-4-trifluoromethylthiotoluene (13.46 g, 0.041 mol) and N-bromosuccinimide (7.26 g, 0.041 mol) in carbon tetrachloride (34 ml) was stirred and heated at reflux for 21 hours. After cooling the mixture was filtered and the filtrate washed with aqueous sodium hydroxide solution (5%, 2×100 ml), water (100 ml), dried over anhydrous magnesium sulphate and evaporated to dryness. Recrystallization of the residue gave 2,3,5,6-tetrachloro-4-trifluoromethylthiobenzyl bromide (8.17 g) m.p. 117°-118.5° C. as a white crystalline solid. By proceeding in a similar manner but by replacing 2,3,5,6-tetrachloro-4-trifluoromethylthiotoluene with the following starting material there was prepared: 2-bromo-4-trifluoromethylbenzyl bromide as a mobile yellow oil from 2-bromo-4-trifluoromethyltoluene.