Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].O.[C:16]1([OH:24])[CH:23]=[C:21]([CH3:22])[CH:20]=[C:18]([OH:19])[CH:17]=1.C([O-])(O)=O.[Na+].O>ClCCl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([O:19][C:18]1[CH:20]=[C:21]([CH3:22])[CH:23]=[C:16]([OH:24])[CH:17]=1)(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: Cc1cc(O)cc(O)c1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.8 %

Procedure:
To a stirred solution of 2-methylsulfonylbenzenesulphonyl chloride (3.63 g, 14.2 mmol) and orcinol monohydrate (2.02 g, 14.2 mmol) in dichloromethane (50 mL) was added saturated NaHCO3 aqueous solution (30 mL) dropwise in 30 min. After stirred vigorously at room temperature for 3 days, water was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over Na2SO4, filtered, and concentrated to half of the volume (˜60 mL). Hexanes (30-40 mL) were added to initiate crystallization. After standing overnight, the mixture was filtered, and the solid was rinsed with small amount of diethyl ether and dichloromethane to give the title compound as a pale pink solid (2.18 g, 44.8%). 1H NMR (CDCl3) δ 8.43 (dd, 1H, J=1.3, 7.9 Hz), 8.11 (dd, 1H, J=1.3, 7.9 Hz), 7.87 (td, 1H, J=1.4, 7.7 Hz), 7.73 (td, 1H, J=1.4, 7.7 Hz), 6.58 (s, 1H), 6.55 (s, 1H), 6.51 (s, 1H), 3.45 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[C:13](=[O:16])([O-])[O-:14].[Na+].[Na+]>COCCOC.O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:6]3[CH:11]=[CH:10][C:9]([C:13]([OH:14])=[O:16])=[CH:8][CH:7]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Brc1ccc(-n2cncn2)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(-n3cncn3)cc2)cc1
Yield: 184.5 %

Procedure:
4-(1,2,4-Triazol-1-yl)bromobenzene (340 mg, 1.5 mmol), 4-carboxylic acid benzene boronic acid (250 mg, 1.5 mmol), sodium carbonate (650 mg, 4 eq), tetrakis (triphenylphosphine)palladium(0) (50 mg) in DME (25 ml) and water (25 ml) was heated under argon at reflux for 24 h, cooled, evaporated to dryness under reduced pressure, partitioned between saturated aqueous sodium carbonate solution (50 ml) and ethyl acetate (50 ml), the aqueous extracts acidified with conc. HCl and dried in vacuo to afford the title compound as a pale yellow crystalline solid (367 mg, 92%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13](Br)=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:19]#[N:20]>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:19]#[N:20])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]C#N
Reactant: Cc1cc(Br)sc1C(=O)NCc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(C#N)sc1C(=O)NCc1ccccc1
Temperature: 150 °C
Reaction time: 7 h
Yield: 37.6 %

Procedure:
A mixture of N-benzyl-5-bromo-3-methylthiophene-2-carboxamide (1.00 g, 3.22 mmol) and copper cyanide (0.72 g, 8.06 mmol) in anhydrous N,N-dimethylformamide (15 mL) was stirred under nitrogen atmosphere at 150° C. for 7 h. The mixture was allowed to cool to ambient temperature, and partitioned between ethyl acetate (150 mL) and 14% aqueous ammonium hydroxide (100 mL). The organic layer was washed with 14% aqueous ammonium hydroxide (75 mL), water (75 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (0-25% ethyl acetate in hexanes) to afford the title compound as a colorless solid (0.31 g, 37%): 1H NMR (300 MHz, CDCl3) δ 7.41-7.29 (m, 6H), 6.13 (br s, 1H), 4.61 (d, J=5.7 Hz, 2H), 2.50 (s, 3H); MS (ES+) m/z 257.2 (M+1), 279.2 (M+23).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]1[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[C:39]2[C:38](=[O:40])[N:37]([CH3:41])[C:36](=[O:42])[N:35]([CH3:43])[C:34]=2[N:33]=[CH:32]1)[OH:24])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:44](=[S:46])=[S:45].[CH3:47]I>O1CCCC1.O.C(OCC)(=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]1[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[C:39]2[C:38](=[O:40])[N:37]([CH3:41])[C:36](=[O:42])[N:35]([CH3:43])[C:34]=2[N:33]=[CH:32]1)[O:24][C:44]([S:46][CH3:47])=[S:45])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: S=C=S
Reactant: Cn1c(=O)c2c(ncn2-c2ccccc2C(O)C2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)n(C)c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSC(=S)OC(c1ccccc1-n1cnc2c1c(=O)n(C)c(=O)n2C)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% oleaginous) was added to a solution of 2-[[2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-yl)-phenyl]hydroxymethyl]piperazine-1,4-dicarboxylic acid di-tert-butyl ester (low polarity) (0.214 g) in tetrahydrofuran (10 ml) at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 20 minutes. The temperature of the mixture was returned to 0° C., carbon disulfide (0.045 ml) was added thereto, and the mixture was stirred for 1 hour. Then, methyl iodide (0.047 ml) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hours. The reaction mixture was poured into 50 ml of ethyl acetate and 20 ml of water, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to give 0.175 g of the title compound from the elution fraction of hexane-ethyl acetate (3:7).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([CH2:8][NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[O:11])#[N:7].C(N(C(C)C)CC)(C)C>ClCCl>[C:6]([CH2:8][NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:24][CH:23]=1)(=[O:20])=[O:21])=[O:11])#[N:7]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (0.140 mL, 1.81 mmol) was added dropwise to a stirred solution of trans-N-cyanomethyl-2-(4-hydroxymethylbenzenesulfonylmethyl)-cyclohexanecarboxamide (0.576 g, 1.645 mmol) and diisopropylethylamine (0.344 mL, 1.97 mmol) in dichloromethane (5 mL) chilled to 5° C. The ice bath was removed and the reaction was allowed to proceed with stirring overnight. The reaction was not complete, so additional diisopropylethylamine (0.172 ml, 1.0 mmol) was added, followed by additional methanesulfonyl chloride (0.070 mL, 0.90 mmol). The reaction was allowed to stir an additional hour at ambient temperature. Dichloromethane (100 mL) was added and the solution was washed with water, 1N HCl, and then saturated aqueous sodium bicarbonate. The organic layer was dried with magnesium sulfate, filtered, and concentrated by rotary evaporation to yield trans-methanesulfonic acid 4-[2-(cyanomethyl-carbamoyl)-cyclohexylmethanesulfonyl]-benzyl ester as a white solid.
Reaction SMILES: [O-][CH2:2]C.[Na+].[Na].S(O)(O)(=O)=O.[C:11]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)(=[NH:13])[NH2:12].C([CH:29]([CH2:35][C:36]([O-:38])=O)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=O>C(O)C>[CH2:20]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[C:36]([OH:38])[C:35]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:2][N:13]=2)[CH2:15][CH2:16]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Reactant: CC[O-]
Reactant: CCOC(=O)C(C=O)CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Cc1cnc(N2CCN(Cc3ccccc3)CC2)nc1O
Reaction time: 0.25 h
Yield: 41 %

Procedure:
Added to an ethanol solution of sodium ethoxide, which had been prepared from 0.57 g (24.8 mmol) of sodium and 30 ml of EtOH, was 6.61 g (24.7 mmol) of 1-amidino-4-benzylpiperazine sulfate, followed by a dropwise addition of an ethanol solution (10 ml) of 5.0 g (24.7 mmol) of ethyl 2-formylsuccinate [the compound described in Ann. 363, 340] over 15 minutes. The resultant mixture was then refluxed for 4.5 hours. After cooling the reaction mixture, crystals were collected by filtration and then washed with water to obtain 3.65 g of the above-identified compound (yield: 41%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)=[O:23])=[CH:4][CH:3]=1.Br[CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1>>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][CH2:37][CH2:36][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=3[C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]3)=[O:23])=[CH:4][CH:3]=2)=[CH:40][CH:41]=1
Reactant: COC(=O)c1ccc(OCCCc2ccc(O)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Reactant: Clc1ccc(CCCBr)cc1
Product: COC(=O)c1ccc(OCCCc2ccc(OCCCc3ccc(Cl)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Methyl 4-(3-{4-[3-(4-chlorophenyl)propoxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate is prepared in analogy to the process described in Example 34 from methyl 4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate and 1-(3-bromopropyl)-4-chlorobenzene.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=1.Cl([O-])(=O)(=O)=O.[CH2:26]1[C:33]2[CH2:32][CH2:31][CH2:30][N+:29]=2[CH2:28][CH2:27]1.Cl>C1COCC1.CCOC(C)=O>[Cl:13][C:14]1[C:19]([C:33]23[CH2:32][CH2:31][CH2:30][N:29]2[CH2:28][CH2:27][CH2:26]3)=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=1
Reactant: Clc1cccc(Cl)n1
Reactant: C1CC2=[N+](C1)CCC2
Agent: Cl
Agent: [Li]CCCC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1ccc(C23CCCN2CCC3)c(Cl)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 17.2 %

Procedure:
A solution of 2.5M nBuLi (675 μL, 1.7 mmol) in hexanes was added to diisopropylamine (220 μL, 1.7 mmol) in THF (4.5 mL) at ambient temperature. After 10 minutes of stirring, the reaction mixture was cooled to -78° C., 2,6-dichloropyridine (237 μL, 1.60 mmol) was added neat, and stirring was continued for 1 hour at -78° C. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (500 mg, 2.40 mmol) was added, and the reaction mixture was allowed to stir for 2 hours at -78° C. then warm to ambient temperature. A solution of 2N HCl was added, and the mixture was then poured over EtOAc. The phases were separated, and the aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a clear oil (70.6 mg, 17%). MS (CI/NH3) m/e: 257/259 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.47-1.61 (m, 2H), 1.77-1.90 (m, 2H), 2.10-2.25 (m, 4H), 2.67-2.75 (m, 2H), 3.03-3.11 (m, 2H), 7.19 (d, J=8.5 Hz, 1H), 8.37 (d, J=8.5 Hz, 1H).
Reaction SMILES: [C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:12][C:10](=[O:11])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19]>>[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:19][C:13](=[O:14])[C@H:8]([CH2:9][C:10](=[O:11])[OH:12])[NH:7][C:1](=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CC(C)=O

Procedure:
reacting N-acetoacetyl-L-aspartic anhydride with L-phenylalanine methyl ester to form N-acetoacetyl-α-L-aspartyl-L-phenylalanine methyl ester.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[OH:41][CH:42]([C@@H:53]1[CH2:57][C@H:56]([SH:58])[CH2:55][N:54]1[C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([N+:69]([O-:71])=[O:70])=[CH:65][CH:64]=1)=[O:60])[CH2:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]1)=[O:45]>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:58][C@@H:56]3[CH2:55][N:54]([C:59]([O:61][CH2:62][C:63]4[CH:64]=[CH:65][C:66]([N+:69]([O-:71])=[O:70])=[CH:67][CH:68]=4)=[O:60])[C@H:53]([CH:42]([OH:41])[CH2:43][C:44]([N:46]4[CH2:47][CH2:48][N:49]([CH3:52])[CH2:50][CH2:51]4)=[O:45])[CH2:57]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CN1CCN(C(=O)CC(O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(O)CC(=O)N4CCN(C)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 76.5 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (3.078 g) and (2S,4S)-2-[1-hydroxy-2-[4-methylpiperazin-1-ylcarbonyl]ethyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.232 g), reaction and purification were carried out in a similar manner to that described Example 40-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[1-hydroxy-2-[4-methylpiperazin-1-ylcarbonyl]ethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (3.007 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:22])=[C:16]([CH:21]=2)[C:17]([O:19]C)=[O:18])=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9].[OH-].[Na+].Cl>CO.O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:22])=[C:16]([CH:21]=2)[C:17]([OH:19])=[O:18])=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9]
Reactant: CNC(=O)c1nc(-c2ccc(Cl)c(C(=O)OC)c2)cnc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)c1nc(-c2ccc(Cl)c(C(=O)O)c2)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.5 %

Procedure:
To a solution of methyl 5-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}-2-chlorobenzoate (96 mg, 31 mmol) in methanol/tetrahydrofuran (1:1, 5.0 mL) was added 2.0 N aqueous sodium hydroxide (0.16 g, 4.00 mmol). The reaction was stirred overnight at room temperature. Reaction was neutralized with 2.0 N aqueous hydrochloric acid (4 mL) and diluted with ethyl acetate (100 mL). The organic layer was washed with water (20 mL), saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate, filtered, and concentrated to afford 5-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}-2-chlorobenzoic acid (45 mg, 48% yield). 1H NMR (400 MHz, d6-DMSO): 13.42 (br s, 1H), 8.90 (br s, 1H), 8.45 (d, 1H), 8.32 (dd, 1H), 7.85 (br s, 2H), 7.60 (d, 2H), 2.82 (s, 3H); MS (EI) for C13H11N4O3Cl: 307 (MH+).
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][O:7]1)=[O:5].[CH2:12]([Mg]Br)[CH3:13]>C1COCC1>[O:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[C:4](=[O:5])[CH2:12][CH3:13]
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)[C@H]1CCCO1
Solvent: C1CCOC1
Product: CCC(=O)[C@H]1CCCO1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of (R)-N-methoxy-N-methyltetrahydrofuran-2-carboxamide (20.15 g, 1 equiv) in THF (250 ml) was added ethyl magnesium bromide (44.3 ml of a 3M solution in THF, 1.05 equiv) The reaction was stirred at −78° C. for 1 h and then quenched with saturated NH4Cl solution. EtOAc was added and the organic portion was separated and washed further with saturated NH4Cl solution, dried (MgSO4) and concentrated in vacuo to afford the title compound; NMR (CDCl3) 1.05 (3H, t, CH3), 1.9 (3H, m), 2.2 (1H, m, CH), 2.6 (2H, m, CH2), 3.95 (2H, CH2O), 4.3 (1H, m, CHO).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(OCC)C.ClCCl>[Cl:15][CH2:16][C:17]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)=[O:18]
Reactant: CC1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC1CCN(C(=O)CCl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-Methyl-piperidine (5.00 g, 50.42 mmol) and triethylamine (7.65 g, 75.63 mmol) in ethyl ether (25 ml) was added dropwise a solution of chloroacetyl chloride (6.83 g, 60.50 mmol) in ethyl ether (30 mL). The mixture was warmed to room temperature and stirred overnight. Then the mixture was diluted with dichloromethane, washed with water, dried and concentrated in vacuo to afford the crude titled compound (crude yield 100%), which was used directly in the subsequent step reaction.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31]Cl)[N:18]=[C:17]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:39]1([O-:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[Na+].C1(O)C=CC=CC=1.[OH-].[Na+]>CC(C)=O.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31][O:45][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:18]=[C:17]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc(Cl)c(Oc2c(CCl)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COc1ccc(Cl)c(Oc2c(COc3ccccc3)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
0.145 g of 4-tert.-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-chloromethyl-2-(morpholin-4-yl)-pyrimidin-4-yl]benzenesulphonamide (Example 4) in 3 ml of acetone was added to a sodium phenolate solution from 0,024 g of phenol and 0.06 g of NaOH in 2 ml of acetone and 1 ml of water. The reaction mixture was stirred at 80° C. under argon for 48 hours. Thereafter, the acetone was distilled off and the residue was partitioned between chloroform and water. The chloroform phase was washed with water, dried over sodium sulphate and the solvent was distilled off. The residue was chromatographed over silica gel with chloroform. 0.07 g of 4-tert.-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-morpholin-4-yl-6-phenoxymethyl-pyrimidin-4-yl]benzenesulphonamide, MS: M=639, was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]2[C:6]([N:7]=[CH:8][C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:18])=O.CCCCCC>C(OCC)(=O)C>[Cl:18][C:9]1[CH:8]=[N:7][C:6]2[C:11](=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc2ncc(=O)[nH]c2c1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(Cl)nc2c1OC
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A solution of 7,8-dimethoxy-quinoxalin-2-one (5.0 g, 24.25 mmol, 1.0 eq) in phosphorus oxychloride (25 mL, 268.21 mmol, 11.06 eq) is heated under reflux for 1 hour. Then the reaction mixture is cooled down to room temperature and the solvent is evaporated. The residue is poured into ice water, the resulting mixture is neutralized with saturated sodium hydrogen carbonate and extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: hexane:ethyl acetate, 2:1 to 1:1, v/v) to afford 2-chloro-7,8-dimethoxy-quinoxaline as a light yellow solid (4.2 g, 77% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=1.[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1)[CH3:13].C1COCC1.C(N(CC)CC)C>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=2)=[CH:17][CH:16]=1)[CH3:13]
Reactant: COCOc1ccc(Br)nc1
Reactant: C#Cc1ccc(OCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccc(C#Cc2ccc(OCOC)cn2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
To a solution of 2-bromo-5-(methoxymethoxy)pyridine (2.50 g, 11.5 mmol), 1-ethoxy-4-ethynylbenzene (2.57 mL, 17.2 mmol) and copper(I) iodide (220 mg, 1.15 mmol) in a mixed solvent of THF-triethylamine (20 ml-10 mL) was added bis(triphenylphosphine)palladium(II) chloride (807 mg, 1.15 mmol), and the mixture was stirred under an argon stream at 60° C. for 15 min. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 3:7) to give the title compound (3.21 g, yield 98%) as a yellow solid.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][OH:13])=[C:8]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(OCC)(=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][O:13][S:38]([C:35]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:40])=[O:39])=[C:8]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2CO)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCc2c(SCc3ccc(C(C)(C)C)cc3)cnn(C(C)(C)C)c2=O)cc1
Reaction time: 4 h

Procedure:
To a 15 ml round bottom flask charged with 2-tert-butyl-4-hydoxymethyl-5-(4-tert-butylbenzyl)thio-3(2H)-pyridazinone (1.0 g, 2.77 mmol) is added pyridine. p-Toluenesulfonyl chloride (0.79 g, 4.15 mmol) is then added to it and the mixture stirred for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using (silica gel; ethyl acetate/hexanes) as the eluting mixture to give the product.