Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N([CH2:30][CH3:31])CC)C.[CH2:32]([S:39](Cl)(=[O:41])=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([N:17]([S:39]([CH2:32][C:31]3[CH:30]=[CH:35][CH:34]=[CH:33][CH:38]=3)(=[O:41])=[O:40])[S:39]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:41])=[O:40])=[N:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-c2cnc(N(S(=O)(=O)Cc3ccccc3)S(=O)(=O)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 4.5 h

Procedure:
Under an argon atmosphere, 5-(4-acetoxyphenyl)-2-amino-3-benzylpyrazine (c-19) (367 mg, 1.15 mmol) was dissolved in anhydrous dichloromethane (9 mL) and to this was added triethylamine (480 μL, 3.44 mmol), and cooled to 0° C. To this was added benzylsulfonyl chloride (658 mg, 3.45 mmol) and stirred for 4.5 h after warming to room temperature. To this was further added benzylsulfonyl chloride (658 mg, 3.45 mmol) and the mixture was stirred for 1.5 h. To this was added 2 M hydrochloric acid to stop the reaction and after separating the aqueous layer and organic layer, the organic layer was washed once with water and once with saturated brine, and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was purified by silica gel column chromatography (23 g, n-hexane/ethyl acetate=4/1→7/3) to give 5-(4-acetoxyphenyl)-3-benzyl-2-bis(benzylsulfonyl)aminopyrazine (c-20) as a yellow amorphous (487 mg, 67.4%). Rf=0.53 (n-hexane/ethyl acetate=3/2). Mp. 84-86.5° C. UV (MeOH) λmax (log ε) 307 (4.26), 293.5 (4.21), 259.5 (4.19). UV (pH 7.4 PB) λmax (log ε) 320 (4.30), 298.5 (4.25), 265 (4.29). 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.90 (s, 2H), 5.00 (s, 1H), 5.03 (s, 1H), 5.18 (s, 1H), 5.22 (s, 1H), 7.13-7.17 (m, 2H), 7.18-7.23 (m, 1H), 7.25-7.33 (m, 4H), 7.39-7.45 (m, 10H), 8.09-8.14 (AA′BB′, 2H), 9.21 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6) δ 20.9, 37.4, 61.0 (1C×2), 122.7 (2C), 126.4, 126.8 (1C×2), 128.2 (2C), 128.5 (2C), 128.8 (2C×2), 129.3, 129.6 (2C), 131.6 (2C×2), 132.1, 137.5, 139.2, 141.0, 151.3, 152.5, 155.6, 169.0. IR (KBr, cm−1) 509, 534, 611, 696, 777, 876, 912, 1144, 1163, 1198, 1354, 1375, 1416, 1433, 1757. HRMS (FAB+) m/z 628.1582 (M+H, C33H30N3O6S2 requires 628.1576).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=3)=[N:7][O:8][C:4]=2[C:3]=1[C:20](O)=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:47]1[CH:52]=[C:51]([NH2:53])[CH:50]=[N:49][CH:48]=1>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH2:16][CH3:17])=[CH:14][CH:15]=3)=[N:7][O:8][C:4]=2[C:3]=1[C:20]([NH:53][C:51]1[CH:52]=[N:47][CH:48]=[N:49][CH:50]=1)=[O:21]
Reactant: Nc1cncnc1
Reactant: CCc1ccc(Nc2noc3c(C(=O)O)c(Cl)ccc23)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCc1ccc(Nc2noc3c(C(=O)Nc4cncnc4)c(Cl)ccc23)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
6-Chloro-3-(4-ethylphenylamino)benzo[d]isoxazole-7-carboxylic acid (0.195 g, 0.615 mmol) was dissolved in DMF, followed by TEA (0.223 ml, 1.61 mmol) and HATU (0.285 g, 0.749 mmol). The mixture was allowed to stir for 5 min before adding pyrimidin-5-amine (0.0509 g, 0.535 mmol) and the mixture was heated to 50° C. overnight. The mixture was then cooled to RT, partitioned between EtOAc/brine, the layers were separated, and the aqueous was extracted with EtOAc (3×). The combined organics were washed with H2O and brine, filtered and concentrated. The crude material was purified by silica gel chromatography using 20:1 DCM/MeOH to give 6-Chloro-3-(4-ethylphenylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide as a light brown solid. MS calculated 393.8, found M+H+=394.1.
Reaction SMILES: C(N(CC)CC)C.[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH:17]=O)=[N+:9]=[N-:10].[NH2:19][C:20]1[C:27]([Cl:28])=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[Cl:29]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1/[CH:17]=[N:19]/[C:20]1[C:21]([Cl:29])=[CH:22][C:23]([C:24]#[N:25])=[CH:26][C:27]=1[Cl:28])=[N+:9]=[N-:10]
Reactant: N#Cc1cc(Cl)c(N)c(Cl)c1
Reactant: [N-]=[N+]=Nc1ccncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(Cl)c(/N=C/c2cnccc2N=[N+]=[N-])c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (8.9 mL, 64.2 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (3.2 g, 21.4 mmol) and 4-amino-3,5-dichlorobenzonitrile (4.0 g, 21.4 mmol) in DCM (80 mL) under nitrogen. Titanium tetrachloride (1M, 12.8 mL, 12.8 mmol) was added and then the reaction mixture was stirred for 1 hour at 0° C. After warming to room temperature, the reaction was stirred for an additional 2 h and then concentrated under reduced pressure. The residue was suspended in toluene and filtered though a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as an orange solid. This crude material was employed in the next step without further purification or analysis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Cl:20][C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH2:23]Cl.CCN(CC)CC>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:13][C:14]1[N:18]=[CH:17][N:16]([CH2:23][C:22]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:21]=2[Cl:20])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cn(Cc2ccc(Cl)cc2Cl)cn1)NC(=O)OC(C)(C)C

Procedure:
N-(tert-butoxycarbonyl)-L-histidine methyl ester (1.0 g) was added to a solution of 2,4-dichlorobenzyl chloride (0.73 g) and Et3N (0.27 g) in benzene (10 ml) and the mixture was heated under reflux for 1 hr. The mixture was cooled and the precipitate was removed by filtration. The filtrate was washed with H2O, dried over Na2SO4, and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluent; 95:5, CHCl3/MeOH) to give N-(tert-butoxycarbonyl)-1-[(2,4-dichlorophenyl)methyl]-L-histidine methyl ester. The obtained compound was treated in a similar manner as described in R. Example 4 to give 1-[(2,4-Dichlorophenyl)methyl]-L-histidine methyl ester, dihydrochloride salt.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:8][NH:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[S:25][C:24]3[C:19](=[N:20][CH:21]=[CH:22][C:23]=3[Cl:26])[CH:18]=2)=[O:16])[CH2:11]1>>[CH3:8][N:9]([CH:10]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[S:25][C:24]3[C:19](=[N:20][CH:21]=[CH:22][C:23]=3[Cl:26])[CH:18]=2)=[O:16])[CH2:11]1)[S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CNC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Product: CN(C)S(=O)(=O)N(C)C1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from dimethylsulfamoyl chloride and (3-methylamino-pyrrolidin-1-yl)-(7-chloro-thieno[3,2-b]pyridin-2yl)-methanone by a procedure analogous to Example 64C. MS: 403/405 (MH+); HPLC Rf: 4.76 min.; HPLC purity 98%.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=O.[CH3:27][NH:28][CH3:29]>>[CH3:27][N:28]([CH2:1][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH3:29]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C=O)cc(C(F)(F)F)c2)CC1
Product: CN(C)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the method of Example 41, Step 2 using tert-butyl 4-[3-formyl-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate and dimethylamine as starting materials. LCMS (M+H)+: 403.2.
Reaction SMILES: [C:1](=[O:24])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:2][C:3]1[C:8]2[NH:9][C:10](=[O:12])[S:11][C:7]=2[C:6]([C:13](=[O:15])[CH3:14])=[CH:5][CH:4]=1.[Br-:25].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1.O>[C:1](=[O:24])([O:2][C:3]1[C:8]2[NH:9][C:10](=[O:12])[S:11][C:7]=2[C:6]([C:13](=[O:15])[CH2:14][Br:25])=[CH:5][CH:4]=1)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OC(=O)OCc2ccccc2)c2[nH]c(=O)sc12
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)Oc1ccc(C(=O)CBr)c2sc(=O)[nH]c12
Temperature: 80 °C
Yield: 86.5 %

Procedure:
To a solution of 7-acetyl-2-oxo-2,3-dihydro-1,3-benzothiazol-4-yl benzyl carbonate (280 mg) in dry THF (20 ml) stirring under nitrogen, was added phenyltrimethylammonium tribromide (330 mg). The mixture was heated at 80° C. for 2 h and then diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified on a 40 g silica biotage cartridge and eluted with 20% ethyl acetate-cyclohexane to give the title compound (186 mg). LCMS RT=3.43 min.
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[N:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:8]=[CH:7][C:6]=1[C:14]([O:16]CC)=[O:15])#[N:4]>C(O)C>[C:3]([C:5]1[N:9]([C:10]([CH3:12])([CH3:13])[CH3:11])[N:8]=[CH:7][C:6]=1[C:14]([OH:16])=[O:15])#[N:4]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C#N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1ncc(C(=O)O)c1C#N
Temperature: 0 °C
Yield: 72 %

Procedure:
Potassium hydroxide (1.7 grams, 0.027 mole) was dissolved in 20 ml. of ethanol. This solution was poured into a refluxing solution of 5-cyano-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester, in 50 ml. of ethanol. The reaction mixture was heated on a steam bath for five minutes, then poured into ice-water, filtered, and acidified with concentrated hydrochloric acid. The precipitated product was collected and dried, yielding 3.2 grams of 5-cyano-1-tert-butyl-1H-pyrazole-4-carboxylic acid (72% yield).
Reaction SMILES: ClC1C=C(N[C@H](C2CC2)C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)=O)C=C(F)C=1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49](OC(C)(C)C)=O)[CH2:44]2)=[O:41])[CH:34]=[C:35]([Cl:37])[CH:36]=1.NC1C(C#N)=C(Cl)N=CN=1.ClC1[N:72]=[CH:71][N:70]=[C:69]([NH:73][C:74](=[O:76])[CH3:75])[CH:68]=1>>[C:74]([NH:73][C:69]1[N:70]=[CH:71][N:72]=[C:49]([N:45]2[CH2:46][CH2:47][CH2:48][C@@H:43]([NH:42][C:40](=[O:41])[CH2:39][NH:38][C:33]3[CH:34]=[C:35]([Cl:37])[CH:36]=[C:31]([Cl:30])[CH:32]=3)[CH2:44]2)[CH:68]=1)(=[O:76])[CH3:75]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)CNc2cc(Cl)cc(Cl)c2)C1
Reactant: CC(=O)Nc1cc(Cl)ncn1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)[C@H](Nc2cc(F)cc(Cl)c2)C2CC2)C1
Agent: N#Cc1c(N)ncnc1Cl
Product: CC(=O)Nc1cc(N2CCC[C@@H](NC(=O)CNc3cc(Cl)cc(Cl)c3)C2)ncn1

Procedure:
The title compound of Example 141 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-tert-butyl 3-(2-(3,5-dichlorophenylamino)acetamido)piperidine-1-carboxylate and the 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for N-(6-chloropyrimidin-4-yl)acetamide. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.17 (s, 1H), 7.96 (d, J=7.78 Hz, 1H), 6.56 (t, J=1.88 Hz, 1H), 6.47 (d, J=1.76 Hz, 2H), 4.02 (br. s., 1H), 3.79 (br. s., 1H), 3.61 (d, J=9.29 Hz, 3H), 2.84-3.17 (m, 2H), 2.00 (s, 3H), 1.75 (br. s., 2H), 1.33-1.57 (m, 2H). EIMS (m/z): calcd. for C19H22Cl2N6O2 (M+1H) 437. found 437.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[F:12].CN(C=O)C.C(N(CC)CC)C.[CH3:25][O:26][CH2:27][C:28]#[CH:29]>CCOC(C)=O.[Cu]I>[F:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[C:29]#[C:28][CH2:27][O:26][CH3:25])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C#CCOC
Reactant: COC(=O)c1ccc(Br)c(F)c1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC#Cc1ccc(C(=O)OC)cc1F
Temperature: 0 °C
Reaction time: 1.17 h
Yield: 61 %

Procedure:
To a mixture of methyl 4-bromo-3-fluoro-benzoate (2.5 g, 10.7 mmol) and copper (I) iodide (204 mg, 1.07 mmol) and palladium dichlorobis(triphenylphosphine) complex (753 mg, 1.07 mmol) under an atmosphere of argon was added DMF (21 mL) and the reaction mixture was cooled to 0° C. Triethylamine (1.95 mL, 13.9 mmol) was added followed by 3-methoxyprop-1-yne (997 μL, 11.8 mmol) and the reaction mixture was stirred at 60° C. for 70 minutes. The reaction mixture was cooled, diluted with EtOAc and filtered over Celite®. The filtrate was washed sequentially with 1 M HCl, 10% NH4OH and brine. The organic layer was separated, dried and concentrated in vacuo and the resulting residue was purified by silica gel column chromatography using EtOAc-hexanes (10-100%) as eluent to give methyl 3-fluoro-4-(3-methoxyprop-1-ynyl)benzoate (1.45 g, 61%). ESI-MS m/z calc. 222.2. Found 223.2 (M+1)+; Retention time: 1.53 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 7.75 (ddd, J=11.2, 8.8, 1.5 Hz, 2H), 7.50 (dd, J=7.9, 7.0 Hz, 1H), 4.37 (s, 2H), 3.92 (s, 3H), 3.47 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=O.[NH:12]([C:14](=[S:16])[NH2:15])[NH2:13].O=P(Cl)(Cl)Cl>C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]1[S:16][C:14]([NH2:15])=[N:12][N:13]=1
Reactant: NNC(N)=S
Reactant: O=C(O)c1ccc(I)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(-c2ccc(I)cc2Cl)s1
Temperature: 78 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
A stirred mixture of 2-chloro-4-iodobenzoic acid (2 g, 7.08 mmol) and hydrazinecarbothioamide (0.968 g, 10.62 mmol) was cooled under nitrogen in an ice bath. POCl3 (1.98 mL, 21.24 mmol) was added drop-wise and the reaction mixture was heated at 78° C. for 3 hours. The reaction mixture was cooled in an ice bath before quenching by addition of ice water (50 mL). The resulting solid/cake was sonicated for 1 hour to give a free stirring suspension. This material was left to slurry at room temperature for ˜18 hours then filtered under vacuum and rinsed with water to afford the crude product as a pale yellow/orange solid. The solid was re-suspended in saturated NaHCO3(aq) (50 mL), slurried at room temperature for 2 hours, then collected by vacuum filtration to afford the title compound as a pale yellow solid (2.05 g, 86% yield). LC-MS: Rt 1.20 min; MS m/z 337.8 [M]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (d, J=1.52 Hz, 1H), 7.76-7.82 (m, 2H), 7.50 (s, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].ClC(Cl)(O[C:26](=[O:32])OC(Cl)(Cl)Cl)Cl.Cl.Cl.[NH:36]1[CH2:40][CH2:39][CH:38]([C:41]2[CH:42]=[N:43][NH:44][CH:45]=2)[CH2:37]1.C(=O)([O-])O.[Na+]>ClCCl.CN1CCOCC1.O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:26]([N:36]3[CH2:40][CH2:39][CH:38]([C:41]4[CH:42]=[N:43][NH:44][CH:45]=4)[CH2:37]3)=[O:32])[CH2:12][CH2:11]2)=[CH:20][CH:21]=1)(=[O:3])=[O:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1n[nH]cc1C1CCNC1
Reactant: CS(=O)(=O)c1ccc(CN2CCNc3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CN2CCN(C(=O)N3CCC(c4cn[nH]c4)C3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.6 %

Procedure:
0.3 g of 4-(4-(methanesulfonyl)benzyl)-3,4-dihydro-2H-quinoxaline is dissolved in 10 ml of dichloromethane and 0.1 ml of N-methylmorpholine. 0.118 g of triphosgene is added at 0° C. and then the reaction mixture is left stirring at ambient temperature for four hours. 0.208 g of 4-(pyrrolidin-3-yl)-1H-pyrazole dihydrochloride is subsequently added and the reaction mixture is stirred for eighteen hours. A saturated solution of sodium hydrogencarbonate in water and dichloromethane are added. The aqueous phase is extracted twice with dichloromethane. The organic phases are combined, washed with water and with a saturated aqueous sodium chloride solution and dried over magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel, a first time with a gradient of dichloromethane/methanol 1/0 to 85/5 mixture and then a second time with a gradient of dichloromethane/ethyl acetate/methanol 1/0/0 to 70/25/5 mixture. 0.064 g of [4-(4-(methanesulfonyl)benzyl)-3,4-dihydro-2H-quinoxalin-1-yl][3-(1H-pyrazol-4-yl)pyrrolidin-1-yl]methanone is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17](O)=[O:18].[CH:20]([NH:23][NH:24][C:25]([C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)=[O:26])([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25]([C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)=[O:26])=[O:18]
Reactant: CC(C)NNC(=O)c1ccco1
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccco2)C(C)C)c1C
Yield: 53.6 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (227 mg, 0.89 mmoles) and furan-2-carboxylic acid N′-isopropyl-hydrazide (150 mg, 0.89 mmoles) in DMF (8 mL) was treated with triethylamine (0.37 mL, 2.67 mmoles), HOBT (144 mg, 1.07 mmoles) and EDCI (205 mg, 1.07 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and dichloromethane. The organic layer was washed successively with 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product (193 mg, 54%). LC-MS m/e 405.46 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@@H:17]([C:18]([O:20]CC)=[O:19])[CH:16]3[CH2:23][CH2:24][CH:13]2[CH2:14][CH2:15]3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@@H:17]([C:18]([OH:20])=[O:19])[CH:16]3[CH2:23][CH2:24][CH:13]2[CH2:14][CH2:15]3)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)[C@H]1C2CCC(CC2)N1S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2C3CCC(CC3)[C@@H]2C(=O)O)cc1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl (3R)-2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.2]octane-3-carboxylate (399 mg, 1.13 mmol) in tetrahydrofuran (7 ml)-methanol (4 ml) was added 1N sodium hydroxide (7 ml), and the mixture was stirred at 65° C. for 12 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, to give (3R)-2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.2]octane-3-carboxylic acid.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[N:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:20])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:1]([C:3]1[S:4][C:5]2[N+:11]([O-:20])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2cccnc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nc2ccc[n+]([O-])c2s1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 83.1 %

Procedure:
2-Ethyl-7-azabenzothiazole (2.95 g) was dissolved in dichloromethane (30 ml), and meta-chloroperbenzoic acid (4.7 g) was added to the solution at room temperature. After 3.5 hours, meta-chloroperbenzoic acid (2.3 g) was further added. After completion of a reaction, the reaction mixture was treated with an aqueous solution of sodium sulfite while chilling with ice water. The thus-treated reaction mixture was diluted with dichloromethane, and the resultant organic layer was washed with aqueous sodium hydrogencarbonate, water and saline in that order, and dried. The solvent was distilled out to obtain 2-ethyl-7-azabenzothiazole-7-oxide (2.69 g). This compound was added to dichloromethane (27 ml), and dimethylaminocarbamoyl chloride (4.16 g), trimethylsilyl cyanide (5.69 ml) and triethylamine (6.3 ml) were successively added to conduct a reaction for 8 hours at room temperature. Trimethylsilyl cyanide (2.5 ml) and dimethylaminocarbamoyl chloride (2.5 ml) were further added. After the reaction was conducted for 2 days at room temperature, aqueous sodium hydrogencarbonate was added to the reaction mixture, followed by stirring for 1 hour. The reaction mixture was subjected to extraction with ethyl acetate, and the resultant organic layer was washed with water, dried and evaporated. After purifying the residue through a silica gel column (eluthion with dichloromethane:methanol=200:1), recrystallization from dichloromethane-isopropyl ether was conducted to form 2-ethyl-6-cyano-7-azabenzothiazole (1.37 g). The intended compound was obtained in accordance with the same procedure as that of Example 106 except that the above compound was used in place of 2-ethyl-6-chlorobenzothiazole. Physical properties of this compound are described below.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[CH2:17](I)[CH3:18].[ClH:20]>CN(C=O)C.CCOCC>[ClH:20].[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:17][CH3:18]
Reactant: COC(=O)c1cc(N)c2cc[nH]c2c1
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCn1ccc2c(N)cc(C(=O)OC)cc21
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of methyl 4-amino-1H-indole-6-carboxylate (D201) (900 mg, 4,74 mmol, 1 equiv) in DMF (25 ml) at room temperature was added NaH (60% dispersion in mineral oil, 200 mg, 5 mmol, 1.05 equiv) and after 15 min ethyl iodide (400 μl, 5 mmol, 1.05 equiv). The resulting mixture was stirred for 30 min then most of the solvent was removed in vacuo. The residue was diluted with AcOEt and the organic phase was washed with a 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 1/1) gave an oil which was diluted with Et2O and treated with a 4N HCl solution in Et2O. The precipitate obtained was filtrated off to give methyl 4-amino-1-ethyl-1H-indole-6-carboxylate hydrochloride salt (D202) (800 mg, 66%) as a white solid. [M+H]+=219.0, RT=2.50 min.