Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([N:23]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24]2)[CH:17]=[CH:18][C:19]=1[N+:20]([O-])=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Zn].C(O)(=O)C>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([N:23]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24]2)[CH:17]=[CH:18][C:19]=1[NH2:20])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(-n2cc(F)c(F)c2)cc1OCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1ccc(-n2cc(F)c(F)c2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
To a mixture of zinc (33.7 g), THF (40 mL) and acetic acid (80 mL) was added dropwise a mixture of 1-[3-(benzyloxy)-4-nitrophenyl]-3,4-difluoro-1H-pyrrole (8.52 g), THF (80 mL) and acetic acid (40 mL) at 0° C., and the mixture was stirred at 0° C. for 15 min. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), and recrystallized from hexane/ethyl acetate to give the title compound (7.53 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[O:29])[C:21](=[O:28])[N:22]2[CH3:27].Cl>ClCCl>[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]([OH:29])([C:8]1[C:9]([OH:11])=[CH:10][C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=1)[C:21](=[O:28])[N:22]2[CH3:27]
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: CN1C(=O)C(=O)c2c(Br)cccc21
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: ClCCl
Product: CN1C(=O)C(O)(c2cc3c(cc2O)OCCO3)c2c(Br)cccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a stirred solution of 2,3-dihydro-1,4-benzodioxin-6-ol (36.0 g, 230 mmol) in dichloromethane (1000 mL) was added isopropylmagnesium chloride (120 mL, 2.0 M solution in tetrahydrofuran, 240 mmol) at 0° C. The mixture was allowed to stir at 0° C. for 1 h and 4-bromo-1-methyl-1H-indole-2,3-dione (48.0 g, 200 mmol) was added. The reaction mixture was stirred at ambient temperature for 22 h and 5% w/v hydrochloric acid was added at 0° C. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was triturated in methanol and washed with diethyl ether to afford 4-bromo-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-one (63.4 g, 80%): 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1H), 7.21-7.13 (m, 2H), 7.01-6.93 (m, 2H), 6.45 (s, 1H), 6.03 (s, 1H), 4.17-4.10 (m, 4H), 3.08 (s, 3H); MS (ES+) m/z 373.8 (M−17), 375.8 (M−17).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].C1(=O)OC(=O)C=C1.[C:17]([OH:25])(=[O:24])[C@H:18]([CH2:20][C:21]([OH:23])=[O:22])O>>[C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[C:17]([O-:25])(=[O:24])/[CH:18]=[CH:20]/[C:21]([O-:23])=[O:22]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: O=C(O)CC(O)C(=O)O
Agent: O=C1C=CC(=O)O1
Product: O=C([O-])/C=C/C(=O)[O-]

Procedure:
Malic acid is used as an acidulant and taste enhancer in the beverage and food industry. Racemic malic acid is synthesized petrochemically from maleic anhydride whereas enantiometrically pure L-malic acid (used in pharmaceutical production) is produced from fumarate by hydration with fumarase.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([O:13][C:14]([N:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:32][CH3:33])=[C:21]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:22]=2)[CH:17]1[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1)=[O:15])[CH3:12].C([O-])(=O)C.[K+]>ClCCl.O>[CH2:11]([O:13][C:14]([N:16]1[CH:25]=[C:24]([CH:3]=[O:4])[C:23]2[C:18](=[CH:19][C:20]([O:32][CH3:33])=[C:21]([O:26][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[CH:22]=2)[CH:17]1[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)N1C=Cc2cc(OC3CCCC3)c(OC)cc2C1Cc1cccc(OC)c1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1C=C(C=O)c2cc(OC3CCCC3)c(OC)cc2C1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
To anhydrous N,N-dimethylformamide (0.151 mL, 1.95 mmol) at 0° C. was added phosphorus oxychloride (0.079 mL, 0.85 mmol) dropwise. The mixture was warmed to room temperature and stirred for 30 minutes. The mixture was cooled in an ice-bath, 6-cyclopentyloxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (350 mg, 0.78 mmol) in dichloromethane (2 mL) was added dropwise. After addition was complete, the mixture was heated on an oil bath for 4 hrs at 80° C. The mixture was cooled to 0° C. and a solution of potassium acetate (228 mg, 2.32 mmol) in water (2 mL) was added slowly. The mixture was then heated at 80° C. for 20 minutes. The mixture was cooled, poured into water and diluted with dichloromethane (60 mL). The organic layer was washed water (2×20 mL), saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 6-cyclopentyloxy-4-formyl-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (386 mg, 99% yield) as a yellow oil. The crude product was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:12]([OH:14])=[O:13])[CH2:3]1.[C:15]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:3]1
Reactant: O=C1C[C@H](C(=O)O)Cc2ccccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC(=O)c2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To the stirred solution of (R)-4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (5.0 g, 26.3 mmol), K2CO3 (10.90 g, 79 mmol) and methyl iodide (6.58 mL, 105 mmol) was added in DMF (50 mL) and stirred for overnight at 25° C. Water was added (130 mL) and extracted with ethyl acetate (2×30 mL). The organic phase was washed with aq. Sodium bicarbonate solution (2×20 mL), dried over Na2SO4 and filtered. The clear organic phase was evaporated in vacuo to get pure title compound (4.5 g) m/z 204.09.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14]COC)=[CH:12][CH:11]=[C:10]([C:18]2([OH:24])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([C:18]2([OH:24])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(C2(O)CCOCC2)nc1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1ccc(C2(O)CCOCC2)nc1Cc1ccccc1
Yield: 73.8 %

Procedure:
A mixed solution of 377 mg of 2-benzyl-6-(4-hydroxytetrahydro-4H-pyran-4-yl)-3-methoxymethyloxypyridine, 2 ml of dichloromethane and 2 ml of trifluoroacetic acid was stirred at room temperature overnight. The reaction solution was neutralized by an aqueous sodium bicarbonate solution, and ethyl acetate was added thereto. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 60% ethyl acetate/hexane, to give 241 mg of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1.CO>ClCCl.[Fe](Cl)(Cl)Cl>[CH3:22][O:21][C:17]1[CH:18]=[CH:19][C:20]2[C:6]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:15]=2[CH:16]=1
Reactant: COc1cccc(-c2ccccc2-c2cccc(OC)c2)c1
Agent: Cl[Fe](Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c3ccc(OC)cc3c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 56.5 h
Yield: 70.5 %

Procedure:
Into a flask, 2 g of 1,2-bis(3-methoxyphenyl)benzene was put, and allowed to dissolve in 100 ml of dichloromethane under nitrogen atmosphere. In the solution, 3.25 g of iron(III) chloride was added, and the solution was stirred at room temperature for 56.5 hours. Methanol was added to terminate the reaction, and then the solution was washed by water. The organic layer was purified by silica gel column chromatography, and then recrystallized in a toluene/heptane mixed solvent, and thus 1.4 g of 2,7-dimethoxytriphenylene was obtained. Obtained 2,7-dimethoxytriphenylene was converted to 2,7-dihydroxytriphenylene by boron tribromide, and allowed to react with trifluoromethanesulfonyl chloride, and converted to 2,7-bis(trifluoromethanesulfonyloxy)triphenylene. The product was allowed react with bis(pinacolate)diboron, and thus 2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)triphenylene was synthesized.
Reaction SMILES: [F:1][CH2:2][C:3]([NH:6][C:7]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[C:9](=[C:10](I)[CH:11]=[CH:12][CH:13]=2)[N:8]=1)([CH3:5])[CH3:4].[CH3:20][C@@H:21]1[C:25]2[NH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28][C:24]=2[C:23](=[O:38])[NH:22]1>>[F:1][CH2:2][C:3]([NH:6][C:7]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[C:9](=[C:10]([C:27]3[NH:26][C:25]4[C@@H:21]([CH3:20])[NH:22][C:23](=[O:38])[C:24]=4[CH:28]=3)[CH:11]=[CH:12][CH:13]=2)[N:8]=1)([CH3:5])[CH3:4]
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: Cn1c(NC(C)(C)CF)nc2c(I)cccc2c1=O
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(NC(C)(C)CF)nc34)[nH]c21
Yield: 34 %

Procedure:
This compound (77 mg, 34% yield) as a brown solid was prepared according to the procedure described for Example 448, using 24(1-fluoro-2-methylpropan-2-yl)amino)-8-iodo-3-methylquinazolin-4(3H)-one (712) (221 mg, 0.59 mmol) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705) (193 mg, 0.74 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.63 (1H, br.), 7.94 (1H, d, J=7.4 Hz), 7.80 (1H, d, J=6.8 Hz), 7.60 (1H, br.), 7.22 (1H, t, J=7.1 Hz), 6.52 (1H, s), 6.02 (1H, s), 4.74 (1H, s), 4.62 (1H, s), 4.51 (1H, m), 3.51 (3H, s), 1.45 (6H, s), 1.38 (3H, d, J=5.9 Hz). m/z (ESI, +ve) 383.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH:11](OCC)OCC>ClC1C=CC=CC=1>[Br:1][C:2]1[C:3]2[S:9][CH:10]=[CH:11][C:4]=2[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(CSc1ccc(Cl)cc1Br)OCC
Solvent: Clc1ccccc1
Product: Clc1cc(Br)c2sccc2c1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
In a round-bottomed flask fitted with a reflux condenser and addition funnel, a mixture of chlorobenzene (11 mL) and polyphosphoric acid (7 g) was heated to reflux. A solution of 2-bromo-1-[(2,2-diethoxyethyl)thio]-4-chlorobenzene in chlorobenzene (10 mL) was added dropwise via addition funnel then the mixture was refluxed overnight. The viscous mixture was decanted while hot. Additional chlorobenzene (25 mL) was added to the flask, stirred at 120° C. for 15 minutes, then decanted. The remaining viscous mixture in the flask was treated with toluene (50 mL), water (25 mL), and saturated Na2CO3 (aq) (10 mL). The resulting layers were separated, and the aqueous phase was extracted with toluene. The toluene and chlorobenzene fractions were combined, washed with saturated Na2CO3 (aq), then saturated NaCl (aq), dried over Na2SO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 0-10% EtOAc/hexanes to afford the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J=1.5 Hz, 1H); 7.59 (d, J=5.5 Hz, 1H); 7.53 (d, J=1.5 Hz, 1H); 7.39 (d, J=5.5 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14](=[O:16])[NH:13][C:12]=3[CH:17]=2)=[CH:4][CH2:3]1>CO.[Pd]>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14](=[O:16])[NH:13][C:12]=3[CH:17]=2)[CH2:4][CH2:3]1
Reactant: O=C1CC=C(c2ccc3oc(=O)[nH]c3c2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1CCC(c2ccc3oc(=O)[nH]c3c2)CC1

Procedure:
To a Parr hydrogenation flask was added a solution of 5-(4-oxo-cyclohex-1-enyl)-3H-benzooxazol-2-one (as prepared in the previous step, 180 mg, 0.79 mmol) in MeOH (10 mL) followed by 5% Pd/C (Aldrich, ˜100 mg). The reaction was charged with 40 psi H2 gas for 10 hours at room temperature. The catalyst was removed by passing the reaction solution through a pad of Celite. MeOH was added to washed the Celite column three times. The combined organic layers were concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)([F:4])[F:3].C(N(CC)CC)C.[NH2:20][C:21]1[CH:22]=[C:23]([C:27]#[CH:28])[CH:24]=[CH:25][CH:26]=1>CCOCC.[Pd].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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([F:4])([F:3])[O:5][C:6]1[CH:7]=[C:8]([C:28]#[C:27][C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)[NH2:20])[CH:9]=[CH:10][CH:11]=1
Reactant: C#Cc1cccc(N)c1
Reactant: FC(F)(F)Oc1cccc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Nc1cccc(C#Cc2cccc(OC(F)(F)F)c2)c1
Temperature: 65 °C
Yield: 85.7 %

Procedure:
A multinecked flask as described in Example 1 was charged with 5.0 g (0.021 mol) of m-bromophenyl trifluoromethyl ether, 50 ml of dried, degassed triethylamine, 2.43 g (0.212 mol) of 3-aminophenylacetylene, 0.048 g (0.68 mmol) of bis(triphenylphosphine) palladium II chloride, 0.148 g (0.564 mmol) of triphenylphosphine, and 0.03 g (0.157 mmol) of cuprous iodide. The reaction mixture was heated at 65° C. for 20 hours at which point gas chromotography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 75 ml of ether. Filtration of the insoluble triethylamine hydrobromide salt by-product followed by concentration of the filtrate gave the crude product as a viscous orange-colored liquid. Short path distillation of the crude product under reduced pressure gave 5.1 g (0.018 mol, 86% yield) of the purified product as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]([F:12])[C:7]=1[O:8][CH:9]([F:11])[F:10].[CH2:14]([Si:21]1(C2C=CC=CC=2)[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:14]([Si@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]([O:13][C:4]2[CH:3]=[C:2]([F:1])[C:7]([O:8][CH:9]([F:11])[F:10])=[C:6]([F:12])[CH:5]=2)=[O:28])[CH2:25][CH2:26]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Oc1cc(F)c(OC(F)F)c(F)c1
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Product: CCCCCCC[Si@H]1CC[C@H](C(=O)Oc2cc(F)c(OC(F)F)c(F)c2)CC1

Procedure:
The general procedure of Example 3 was repeated using 3,5-difluoro-4-difluoromethoxyphenol and 4-n-heptyl-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[O-:12][CH2:13][CH3:14].[Na+].C(O)C>CN(C)C=O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([O:12][CH2:13][CH3:14])[N:10]=1
Reactant: CC[O-]
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOc1nc(Cl)ccc1C(N)=O
Temperature: 15 °C
Reaction time: 0.67 h
Yield: 95 %

Procedure:
Refer to synthesis of D46 for preparation of 2,6-dichloro-nicotinamide (1). Freshly prepared sodium ethoxide solution in ethanol (12.1 mL of 2.17 M, 26.2 mmol) was slowly added over 10 min to a solution of 1 (5.01 g, 26.2 mmol) in dimethylformamide (30 mL) at 15° C. [Note: a water bath was used to maintain reaction temperature around 14-16° C.; sodium ethoxide was prepared from reaction of Na solid (1.50 g, 65.2 mmol) with anhydrous EtOH (30.0 mL)]. Upon completion of sodium ethoxide addition, the reaction was stirred for 40 min at 14-16° C. [Note: An aliquout (0.3 mL) of reaction was concentrated. A 1H NMR of aliquout recorded in d6-DMSO showed ˜98% conversion to desired 2]. The reaction was poured into water (500 mL) and extracted with EtOAc (3×400 mL). All organics were combined, dried over Na2SO4, filtered and concentrated to give the title compound as a light gray solid (5.20 g, 95% purity as established by 1H NMR). The title compound was carried forward without further purification. 1H NMR 400 MHz (d6-DMSO) δ 8.16 (d, J=8.2 Hz, 1H), 7.76 (br s, 1H), 7.57 (br s, 1H), 7.17 (d, J=7.8 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([CH:27]([CH:29]4[CH2:31][CH2:30]4)O)=[N:25][N:26]=[C:18]1[C:17](=[O:32])[NH:16]3)=[O:12])[CH2:6][CH2:5]2.ClCCl.C(N(S(F)(F)[F:42])CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([CH:27]([CH:29]4[CH2:31][CH2:30]4)[F:42])=[N:25][N:26]=[C:18]1[C:17](=[O:32])[NH:16]3)=[O:12])[CH2:6][CH2:5]2
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1nnc(C(O)C3CC3)n12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1nnc(C(F)C3CC3)n12
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A mixed solution of 60 mg of 7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-1-[cyclopropyl(hydroxy)methyl]-8-methyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one and 3 mL of dichloromethane was cooled to −70° C., and 100 μL of N,N-diethylaminosulfur trifluoride was added thereto, followed by slowly warming to −20° C. over 4 hours. The reaction liquid was returned to room temperature and stirred overnight. To the mixed liquid were added a saturated aqueous sodium hydrogen carbonate solution and chloroform, followed by extraction with chloroform, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 97/3). To the obtained solid was added 4 mL of methanol, followed by warming and washing. The precipitate was collected by filtration and dried under reduced pressure to obtain 31 mg of 7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-1-[cyclopropyl(fluoro)methyl]-8-methyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=2[O:27][CH2:28][O:29][CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:22][C:21]=2[O:27][CH2:28][O:29][CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCc1ccccn1
Reactant: COCOc1cc(O)ccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1cc(OCc2ccccn2)ccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Reaction time: 0.33 h
Yield: 89 %

Procedure:
Methyl 3-cyclohexyl-2-[4-hydroxy-2-(methoxymethoxy)phenyl]-1H-indole-6-carboxylate was dissolved in DMF (0.17 M) and Cs2CO3 (1.05 eq) was added. The mixture was stirred for 20 min, then 2-bromomethylpyridine (1.05 eq) was added and the suspension was stirred at RT. After 4 h Cs2CO3 (0.3 eq) was added and the mixture was stirred overnight. Since the reaction was incomplete the mixture was warmed for 30 min to 35° C. The mixture was diluted with EtOAc and extracted with 1N aqueous HCl, sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. The product was obtained as a beige amorphous solid (89%). (ES+) m/z 501 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[OH:16][S:17](O)(=[O:19])=[O:18]>O>[OH:1][C:2]1[C:3]([S:17]([OH:19])(=[O:18])=[O:16])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:7][CH:6]=2
Reactant: O=S(=O)(O)c1ccc2ccc(O)cc2c1
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=S(=O)(O)c1ccc2cc(S(=O)(=O)O)c(O)cc2c1
Temperature: 115 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
7-Hydroxynaphthalene-2-sulfonic acid (250 g, 1.16 mol) was added in portions to a mixture of concentrated H2SO4 (950 g) and water (50 g). The mixture was stirred at 110-120° C. for 3 hours, cooled to room temperature, added to a mixture of ice and water (5000 ml) and the product precipitated by the addition of sodium chloride. The slurry was warmed to 90° C. to dissolve the product, stirred for 1 hour at this temperature and then allowed to cool. The product was filtered off and the damp product dissolved in water (3000 ml) at pH 10 by the addition of concentrated sodium hydroxide solution. The solution was then filtered to remove a small amount of insoluble material. The pH of the filtrate was lowered to 7 with concentrated HCl and the product precipitated by the addition sodium chloride. The product was filtered off and dried in a vacuum oven to give 117 g of a cream coloured solid (68% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[NH2:1][C:2]1[C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: Nc1ncc(Br)nc1Br
Product: Nc1ncc(Br)nc1N1CCOCC1

Procedure:
2-Amino-3,5-dibromopyrazine is reacted with morpholine at 130° C. under pressure yielding 2-amino-3-morpholino-5-bromopyrazine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[Br:24]N1C(=O)CCC1=O>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:24])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2cccc(Oc3ccc(F)cc3)c2c1O
Product: COC(=O)c1nc(Br)c2cccc(Oc3ccc(F)cc3)c2c1O

Procedure:
The title compound was synthesized from 5-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester and N-bromosuccinimide in analogy to example 18e; MS-(+)-ion: M+1, 79Br/81Br=392.4 and 394.3.