Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[CH:8][CH:7]=1.Cl>CO.O>[O:17]=[C:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C:9]1[CH:10]=[CH:11][C:6]([C:5]([OH:18])=[O:4])=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(N2CCCC2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(N2CCCC2=O)cc1
Reaction time: 1 h
Yield: 66.5 %

Procedure:
A mixture of pyrrolidin-2-one (500 mg, 5.9 mmol), 4-bromo benzoic acid methyl ester (1.5 g, 6.97 mmol), Pd2(dba)3 (135 mg, 0.14 mmol), xantphos (256 mg, 0.44 mmol) and cesium carbonate (2.7 g, 8.28 mmol) in dioxane (2 mL) in a sealed tube was subjected to reaction in a microwave reactor (time: 20 min, temp: 105° C., power: zero). The reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to afford the residue. The residue obtained was purified by column chromatography (using 60-120 silica gel and 50% ethyl acetate in hexane as eluent) to afford 485 mg (37.89% Yield) of 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester. NaOH (295 mg, 7.4 mmol) was added to a stirred mixture of 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (485 mg, 2.2 mmol) in a mixture of MeOH (5 mL) and H2O (5 mL), stirring was continued at 60° C. for 1 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get the residue, which was acidified with 10% aqueous HCl solution, the precipitate was collected to afford 300 mg (66% Yield) of 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:13])[CH:8]=2)[N:3]=[CH:2][CH:11]=1
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2nccc(Cl)c2c1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
2,4-Dichloroquinoline (2.5 g, 12.6 mmol) was dissolved in anhydrous toluene (20 ml), a suspension of sodium methoxide (2.5 g, 46.3 mmol) in anhydrous toluene (20 ml) was added and the mixture was heated under reflux for 16 hours. After cooling to room temperature the suspension was filtered, the filter cake washed once with toluene (50 ml), the combined filtrates were evaporated under reduced pressure to dryness to yield 2.1 g (10.8 mmol, 86%) of a red solid. MS (ES) m/z=193.1 [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)[C:5]#[N:6].[ClH:19].N([O-])=O.[Na+].[S:24](=[O:26])=[O:25]>O>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)=[C:2]([S:24]([Cl:19])(=[O:26])=[O:25])[CH:3]=1)#[N:6]
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2N)c1
Reactant: O=S=O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)Cl)c1
Temperature: 0 °C
Yield: 86.1 %

Procedure:
Compound 22 (12.00 g, 50.36 mmol) was added to H2O (50.0 mL) and concentrated HCl (100 mL) at room temperature. The reaction mixture was then stirred in an ice bath. Sodium nitrite (10.434 g, 151.1 mmol) in H2O (50 mL) was added to the reaction mixture dropwise at 0° C. The reaction mixture was allowed to stir in the ice bath for an hour. In a separate flask, sulfur dioxide was bubbled through acetic acid (430 mL) for 45 min. Cupric chloride dihydrate (4.305 g, 25.2 mmol) was then added to this sulfur dioxide saturated solution, and stirred for an additional 30 min. This saturated sulfur dioxide solution was then stirred in an ice bath for an additional five min. The reaction mixture containing compound 22 was then added dropwise to the cupric chloride solution. After the addition was complete, the solution was stirred for an additional hour and then poured slowly onto an ice water slurry and stirred for an hour. The resulting precipitate was then filtered and the yellow solid was rinsed with water to afford compound 23 (13.944 g, 86.1% yield). 1H NMR (500 MHz, DMSO-d6): δ 8.06 (d, J=2 Hz, 1H), 7.71 (dd, J1=8 Hz, J2=2 Hz, 1H), 6.85 (s, 1H), 6.81 (d, J=9 Hz, 1H), 6.66 (s, 2H), 2.26 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7]([CH2:18][CH2:19][CH2:20][NH:21][C:22](OCCC)=O)([OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)CCC>[CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7]([CH2:18][CH2:19][CH2:20][NH:21][CH3:22])([OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCOC(=O)NCCCC1(O)c2ccccc2CCc2c(C)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CNCCCC1(O)c2ccccc2CCc2c(C)cccc21

Procedure:
12.5 g. of 1-methyl-10,11-dihydro-5-(3-methylcarbethoxyaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene, 14 g. of potassium hydroxide and 120 ml. of n-butanol are boiled at reflux for 17 hours under nitrogen and with strong stirring. The butanol is removed by distillation under reduced pressure. The residue is taken up in ether and washed with water. 1-Methyl-10,11-dihydro-5-(3-methylaminopropyl)-5-hydroxy-5H-dibenzo[a,d] cycloheptene is obtained as a thick oil by evaporation of the ether.
Reaction SMILES: Cl[CH:2]([C:4]1[C:5]([NH:12][CH3:13])=[N:6][C:7]([S:10][CH3:11])=[N:8][CH:9]=1)[CH3:3].[I-].[Na+].[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(N(C(C)C)C(C)C)C>C(#N)C.O>[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][CH:2]([C:4]1[C:5]([NH:12][CH3:13])=[N:6][C:7]([S:10][CH3:11])=[N:8][CH:9]=1)[CH3:3]
Reactant: Nc1ccccc1Br
Reactant: CNc1nc(SC)ncc1C(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1nc(SC)ncc1C(C)Nc1ccccc1Br
Reaction time: 16 h
Yield: 38.9 %

Procedure:
0.25 g of the product from Example 11b, supra, and 34 mg sodium iodide in 10 mL acetonitrile were stirred for 15 min at RT. The resulting suspension was added drop-wise at RT to a mixture of 0.21 g 2-bromoaniline (Aldrich) and 0.33 g N-ethyl-di-isopropyl amine (Aldrich) in 5 mL acetonitrile. Stirring was continued for 16 hrs and the mixture was diluted with 20 mL water and extracted with dichloromethane. Chromatography on silica (eluent CHCl3) yielded 158 mg of the title product.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[NH:4]1.C(N(CC)CC)C.[C:24](=[S:26])=[S:25].[CH3:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>CO.CS(C)=O>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[N:4]1[C:24]([S:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH3:32])=[CH:30][CH:29]=1)=[S:25]
Reactant: C[C@@H]1N[C@H](CO)Cc2c1[nH]c1ccccc21
Reactant: Cc1ccc(CCl)cc1
Reactant: S=C=S
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CS(C)=O
Product: Cc1ccc(CSC(=S)N2[C@H](CO)Cc3c([nH]c4ccccc34)[C@@H]2C)cc1
Yield: 79.8 %

Procedure:
In the same manner as described in Example 34 by using (1S, 3S)-3-hydroxymethyl-1-methyl-1,2,3,4-tetrahydro-β-carboline (1.08 g), triethylamine (1.01 g), CS2 (0.76 g), 4-methylbenzyl chloride (1.4 g) and dimethylsulfoxide (10 ml), there is prepared the title compound (1.58 g, 80%) as white powder, [α]D20 +63.2° (c=0.5, methanol); NMR (CDCl3, δ): 2.31 (s, 3H, ##STR18## 4.66 (s, 2H, ##STR19## Mass m/e: 396 (M+), 258 (M+ -- ##STR20##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:31]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:34]5[CH:33]=[N:32][O:31][CH:35]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: OB(O)c1cnoc1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cnoc5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 16-4), isoxazol-4-boronic acid (73 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and potassium carbonate (163 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (127 mg, 44%) as an orange solid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][N:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1)=[O:4].[N:29]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][C@H:30]1[C:39](O)=[O:40].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:19][N:18]([CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:39]([C@@H:30]2[CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:38][N:29]2[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:40])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)[CH3:20]
Reactant: CN(C)Cc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)Cc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Yield: 57 %

Procedure:
tert-Butyl 3-{N-[(1R)-2-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared according to the procedure described in Preparation V, (2R)-2-amino-1-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-3-(4-chlorophenyl)propan-1-one (0.34 g, 0.85 mmol), Boc-L-Tic-OH (Peptech Corp.) (0.26 g, 0.93 mmol), EDC (0.2 g, 1.0 mmol), HOBT (used in place of HOAT) (Bachem) (0.14 g, 0.93 mmol) and CH2Cl2 (4 mL). The crude compound was purified on a Biotage 40S column (CH2Cl2/MeOH 95:5) to give tert-butyl 3-{N-[(1R)-2-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate as a white foam (0.32 g). MS m/z: 660 (M+H). Calc'd for C37H46ClN5O4: 660.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].C1COCC1.C([N-]C(C)C)(C)C.[Li+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCCCCCC.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1ccccc1OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccccc1)c1ccccc1OC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 34.9 %

Procedure:
A 500 mL round-bottom flask is charged with methyl 2-(2-methoxyphenyl)acetate (8.496 g, 47 mmol, 1 eq) and THF (200 mL). The homogeneous mixture is cooled to 0° C. in an ice bath. Lithium diisopropyl amide (23.5 mL of a 2.0M solution in heptane/THF) is added, maintaining a temperature less than 3° C. The reaction is stirred 45 minutes at this reduced temperature. Benzyl bromide (5.6 mL, 47 mmol, 1 eq) is added dropwise. The reaction is allowed to gradually warm to room temperature and is stirred for 18 hours. The reaction is quenched with 1N HCl and extracted 3 times with equal portions of EtOAc. The combined extracts are washed with H2O and brine, dried over Na2SO4, filtered, and concentrated. The residue is purified over silica to afford 4.433 g (35%) of the desired compound. ESI+MS 293 (M+Na).
Reaction SMILES: [OH-:1].[Na+].[NH:3]([CH2:7][CH2:8][OH:9])[CH2:4][CH2:5][OH:6].[O:10]=O.[Na][Na]>[Cu].O>[NH:3]([CH2:7][C:8]([OH:10])=[O:9])[CH2:4][C:5]([OH:1])=[O:6]
Reactant: OCCNCCO
Reactant: O=O
Reactant: [OH-]
Agent: [Cu]
Agent: [Na+]
Agent: [Na][Na]
Solvent: O
Product: O=C(O)CNCC(=O)O
Temperature: 90 °C
Yield: 95 %

Procedure:
183 g. of 97% sodium hydroxide; 300 g. of demineralized water; 163.2 g. of 98% diethanolamine; 64 g. of Copper-Raney with a humidity level of 30%, which really means using 44.8 g. of net-weight catalyst in the test, and finally 40 further g. of demineralized water, to break down all the previous reagents, are all stirred into a stainless steel autoclave reactor (AISI 316) with a 1 liter capacity, and in the above-mentioned order. Then, and while still stirring, the heating process is started until 170° C. is reached and the pressure inside the reactor is 18 Kg/cm2. At this stage, the reactor is brought into contact with a shot of oxygen previously set at 18 Kg/cm2 so as to have the same pressure and making sure that the pressure is kept constant during the course of the process, the oxygen consumed being continually replaced. The suspension is continuously stirred for 3.5 hours. When this time has elapsed, the reaction is concluded, and it is cooled to 90° C. and filtered with suction with Buchner and Kitasato, regaining the humidity weight of 71.0 g. of the copper catalyst, this being kept for successive reuse after regeneration. The reaction solution, once analyzed by chromotography, provides a 95% yield of free iminodiacetic acid in the form of disodium salt, and this can be easily isolated and purified either by crystalization at 85° C. at pH 22, or electrochemically using one of the electrodialysis processes mentioned before. The purification yield is quantitative (100%) using the isolation procedure and purification by electrodialysis.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1>>[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=S(=O)(O)Cl
Product: Cc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
A round bottom flask was charged with chlorosulfonic acid (170 mL, 2.57 mol) at 0° C. and 4-methyl benzoic acid (50 g, 0.37 mol) was added portion wise. The reaction mixture was heated at 130° C. for 5 h. The reaction mixture was then poured over ice and stirred for 10 minutes. The solids formed were filtered, washed with cold water and dried to afford 4-methyl-3-(chlorosulfonyl)benzoic acid as a white powder. This compound (80 g, 0.34 mol) was then charged into a round bottom flask containing sodium sulfite (200 g, 2.05 mol) and water (80 mL) portion wise. Aqueous sodium hydroxide (6 N) was then added dropwise till the pH of the reaction mixture reaches 10 and the reaction was stirred overnight. The reaction was then made acidic (pH 2) by addition of 2N HCl. The solids formed were filtered and dried to get 4-methyl-3-sulfinobenzoic acid as a white solid. This compound (55 g, 0.275 mol) was charged into a round bottom flask containing potassium carbonate (75.8 g, 0.55 mol) and N,N-dimethylformamide (450 mL). Methyl iodide (68.1 mL, 1.10 mol) was added slowly and the reaction was stirred for 4 hours. The reaction mixture was then diluted with water and extracted with EtOAc. The solvents were removed under reduced pressure to get the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]([CH3:21])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C[C:23]([O-:26])([CH3:25])C.[K+].[OH2:28]>C(O)CO.O1CCOCC1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:3]2[C:2]([O:28][CH2:25][CH2:23][OH:26])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9][CH:10]1[CH3:21])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[O-]
Reactant: O
Reactant: CC1CN(c2nccnc2Cl)CCN1C(=O)OC(C)(C)C
Agent: [K+]
Solvent: OCCO
Solvent: C1COCCO1
Product: CC1CN(c2nccnc2OCCO)CCN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a mixture of tert-butyl 4-(3-chloropyrazin-2-yl)-2-methylpiperazine-1-carboxylate (3.0 g, 9.6 mmol; from Step 2) in ethylene glycol (10 mL) and dioxane (30 mL) was added t-BuOK (1.18 g, 10.6 mmol). The resulting mixture was stirred at 90° C., under N2, overnight. Water (10 mL) was added to the light brown reaction mixture and extracted with dichloromethane (3×20 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography using toluene/EtOAc (2:3) as eluent to furnish 3.19 g (98%) of the title compound. HPLC purity: 99%. MS m/z 339 (M+H)+. HRMS m/z calcd for C16H26N4O4(M)+ 338.1954, found 338.1953.
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O)([O-:10])=[O:9].[NH2:19]/[C:20](/[CH3:29])=[CH:21]\[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23]>C1C=CC=CC=1.C(O)(C)C.N1CCCCC1>[C:27]([CH2:26][CH2:25][O:24][C:22]([C:21]1[CH:13]([C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N+:8]([O-:10])=[O:9])[C:2]([C:1]([OH:7])=[O:6])=[C:3]([CH3:5])[NH:19][C:20]=1[CH3:29])=[O:23])#[N:28]
Reactant: CC(=O)CC(=O)[O-]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: C/C(N)=C/C(=O)OCCC#N
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC1=C(C(=O)O)C(c2ccccc2[N+](=O)[O-])C(C(=O)OCCC#N)=C(C)N1
Yield: 77.1 %

Procedure:
9.7 g of 2-nitratoethyl acetoacetate, 7.6 g of 2-nitrobenzaldehyde and 0.2 g of piperidine in 40 ml of benzene were heated at reflux under azeotropic dehydration conditions for 3 hours. The mixture was treated in a manner similar to that of Referential Example 1, there was obtained the residue, to which was added 7.7 g of 2-cyanoethyl 3-aminocrotonate. The mixture was taken up in 40 ml of isopropyl alcohol and heated at reflux for 3 hours. The isopropyl alcohol was evaporated under reduced pressure, and the residue was applied to a silica gel column chromatography (eluent: dichromomethane) and recrystallized from a mixture of dichromethane and diethyl ether to give 14.3 g of 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-cyanoethyl) ester 5-(2-nitratoethyl) ester.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:18]=[C:17]([O:19][CH2:20][O:21][CH3:22])[CH:16]=[C:15]([O:23][CH2:24][O:25][CH3:26])[C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Si](C=[N+]=[N-])(C)C.CCCCCC.C(O)(=O)C>CO>[CH3:27][O:13][C:12](=[O:14])[C:11]1[C:15]([O:23][CH2:24][O:25][CH3:26])=[CH:16][C:17]([O:19][CH2:20][O:21][CH3:22])=[CH:18][C:10]=1[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COCOc1cc(COCc2ccccc2)c(C(=O)O)c(OCOC)c1
Solvent: CO
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COCOc1cc(COCc2ccccc2)c(C(=O)OC)c(OCOC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
The above-obtained 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)benzoic acid (20 mg, 0.054 mmol) was dissolved in methanol (2 mL) and the obtained solution was added with 2.0 mol/L trimethylsilyldiazomethane-hexane solution (0.30 mL, 0.60 mmol), followed by stirring at a room temperature for 1 hour. The reaction mixture was added with acetic acid (0.050 mL) and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=100/1) to obtain 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)benzoic acid methyl ester (12 mg, 57%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10](=O)[CH2:11][C:12]([O:14]CC)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]([C:21]1[CH:31]=[CH:30][C:24]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)=[N+:19]=[N-:20].[O-]CC.[Na+].O>C(O)C>[CH2:28]([NH:27][C:25]([C:24]1[CH:30]=[CH:31][C:21]([N:18]2[C:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:11]([C:12]([OH:14])=[O:13])[N:20]=[N:19]2)=[CH:22][CH:23]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)CC(=O)CCCc1ccccc1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 10.5 h
Yield: 92.6 %

Procedure:
Ethyl 6-phenyl-3-oxohexanoate (1.11 g, 4.73 mmol, 1.25 eq.) obtained in Example 100a) and 4-azido-N-ethylbenzamide (0.719 g, 3.78 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (357 mg, 4.73 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 10.5 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (1.32 g, 3.50 mmol, 92.6%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:37][CH2:38][O:39][CH3:40])=[C:14]([NH:16][C:17]2[C:18]([NH:27][S:28]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)(=[O:30])=[O:29])=[N:19][C:20]3[C:25]([N:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([N:34]1[CH2:35][CH2:36][CH:31]([S:28]([NH:27][C:18]2[C:17]([NH:16][C:14]3[CH:15]=[C:10]([O:9][CH3:8])[CH:11]=[CH:12][C:13]=3[CH2:37][CH2:38][O:39][CH3:40])=[N:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)(=[O:30])=[O:29])[CH2:32][CH2:33]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COCCc1ccc(OC)cc1Nc1nc2ccccc2nc1NS(=O)(=O)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1ccc(OC)cc1Nc1nc2ccccc2nc1NS(=O)(=O)C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
Acetic anhydride (21 mg; 0.2 mmol; 1.2 eq) is added to a suspension of N-(3-{[5-methoxy-2-(2-methoxyethyl)phenyl]amino}quinoxalin-2-yl)piperidine-4-sulfonamide (100 mg; 0.17 mmol; 1 eq) in DCM (10 mL), followed by Et3N (0.06 mL; 0.43 mmol; 2.5 eq) and the reaction mixture is stirred at room temperature for 2 h. The solution is diluted to 30 mL with DCM, washed successively with 0.1 M HCl and brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. The residue is recrystallised from a mixture of DCM/n-pentane to afford 59 mg (67%) of the title compound as a pale yellow solid. 1H NMR (DMSO-d6) δ 12.25 (s, 1H), 9.15 (s, 1H), 7.95-7.81 (m, 2H), 7.50-7.44 (m, 1H), 7.37-7.26 (m, 2H), 7.22 (d, J=8.4 Hz, 1H), 6.71 (dd, J=8.4, 2.6 Hz, 1H), 4.53 (br d, J=12.8 Hz, 1H), 3.97 (br d, J=13.3 Hz, 1H), 3.78 (s, 3H), 3.60-3.36 (m, 3H), 3.25 (s, 3H), 3.10 (br t, J=12.0 Hz, 1H), 2.78 (t, J=6.0 Hz, 2H), 2.58 (br t, J=12.7 Hz, 1H), 2.19 (br d, J=12.7 Hz, 2H), 2.02 (s, 3H), 1.80-1.50 (m, 2H). HPLC (max plot) 99%; Rt 3.85 min. UPLC/MS (ES+) 512.2, (ES−) 512.3.