Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:41])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:42]([NH:52][CH2:53][C:54](O)=[O:55])([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>>[C:42]([NH:52][CH2:53][C:54]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:41])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:55])([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]
Reactant: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Product: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-dodecyl-dodecanamide and N-carbobenzoxy-glycine.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][N:6]1[S:30]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)(=[O:32])=[O:31])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.CCOC(C)=O>[CH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[CH:42][C:33]=1[S:30]([N:6]1[CH2:7][C@H:8]([S:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][C@H:5]1[CH2:4][NH2:1])(=[O:32])=[O:31]
Reactant: [N-]=[N+]=NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Yield: 97.7 %

Procedure:
1.7 g (2.9 mmol) (2S,4R)-2-Azidomethyl-1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine were treated with 2.3 g (8.8 mmol, 3 eq) of triphenyl phosphine in 12 ml THF and 0.5 ml H2O for 2 days at RT. The solution was diluted with EtOAc, extracted with H2O and aqueous saturated NaHCO3 solution, washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica gel with CH2Cl2/MeOH 95:5 yielded 1.6 g (99%) (2S,4R)-C-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-yl]-methylamine as white foam, MS: 565 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]2C(=O)O[C:16](C)(C)[O:15][C:14]2=[O:22])=[CH:11][C:10]([CH3:23])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>>[CH3:16][O:15][C:14](=[O:22])[CH2:13][C:12]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[C:10]([CH3:23])[CH:11]=1
Reactant: Cc1cc(C2C(=O)OC(C)(C)OC2=O)n(Cc2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)Cc1cc(C)nn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To the solution of 5-(2-benzyl-5-methyl-2H-pyrazol-3-yl)-2,2-dimethyl-[1,3]dioxane-4,6-dione obtained in step 1, pTsOH (3.74 g, 19.4 mmol) was added and stirring was continued for 2 h at 60° C. The reaction mixture was cooled to 0° C. and TEA (1.96 g, 19.4 mmol) was added drop by drop. Stirring was continued for 15 minutes. The mixture was concentrated under reduced pressure, the residue taken up into DCM (30 ml), washed with water (2×15 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 1.03 g (96%) of (2-benzyl-5-methyl-2H-pyrazol-3-yl)-acetic acid methyl ester which was used in the next step without further purification. LC-MS: tR=0.83 min; [M+H]+=245.16.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C1CN2C(=NCCC2)C1.C([O:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]Br)C1C=CC=CC=1.COC(C)(C)C>[Cl-].C[N+](C)(C)C.C1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[O:7][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][C:42]([OH:54])=[O:41])(=[O:3])[CH3:2]
Reactant: O=C(CCCCCCCCCCBr)OCc1ccccc1
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C1CN=C2CCCN2C1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: c1ccccc1
Product: CC(=O)OC[C@H]1OC(OCCCCCCCCCCC(=O)O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture that consists of 34.83 g (100 mmol) of 2,3,4,6-tetra-O-acetylglucopyranose, 0.55 g (5 mmol) of tetramethylammonium chloride and 12.42 g (100 mmol) of DBN in 350 ml of benzene is cooled to 0° C. At 0° C., 53.30 g (150 mmol) of 11-bromoundecanoic acid benzyl ester, dissolved in 50 ml of benzene, is added in drops over 30 minutes while being stirred vigorously. It is stirred for two hours at 20° C. 250 ml of methyl-tert-butyl ether is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol. 5 g of palladium (10%) on activated carbon is added thereto and hydrogenated until hydrogen absorption is completed. Catalyst is filtered out, it is rewashed with a little ethanol, and the combined solutions are evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/n-hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [OH-].[Na+].[O:3]1[C:9]2[CH:8]3[O:10][CH:5]([CH2:6][CH:7]3[S:11]([O:14]C)(=[O:13])=[O:12])[C:4]1=2.Cl>>[OH:3][CH:4]1[CH:9]2[O:14][S:11](=[O:12])(=[O:13])[CH:7]3[CH:8]2[O:10][CH:5]1[CH2:6]3
Reactant: COS(=O)(=O)C1CC2OC1C1=C2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=S1(=O)OC2C(O)C3CC1C2O3
Temperature: 0 °C
Yield: 16.6 %

Procedure:
To a four-necked flask having a capacity of 300 mL and equipped with a stirrer, a dropping funnel, and a thermometer, 5.0 (mol/L) aqueous sodium hydroxide solution was added, and 29.5 g of methyl 2,3-epoxy-7-oxabicyclo[2.2.1]hept-2-ene-5-sulfonate was added dropwise to the flask from the dropping funnel at an internal temperature of 20 to 23° C. After completion of the addition, the resultant mixture was stirred for 4 hours, and then concentrated hydrochloric acid was added dropwise to the mixture under cooling with ice water, to thereby adjust the pH of the mixture to 7.3. Subsequently, the mixture was subjected to extraction four times with 300 mL of ethyl acetate, and then the resultant organic layers were combined and concentrated. Thereafter, the resultant concentrate was subjected to separation/purification through silica gel column chromatography, to thereby obtain 4.75 g (purity: 98.8%, 0.024 mol) of 5-hydroxy-7-oxanorbornane-2,6-sultone.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13](=[O:26])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]#[N:25])[CH:17]=1.[H-].[Na+].S(OC)(O[CH3:33])(=O)=O>>[CH3:33][O:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13](=[O:26])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]#[N:25])[CH:17]=1
Reactant: N#CCOc1cccc(C=CC(=O)c2c(O)c3ccccc3oc2=O)c1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COc1c(C(=O)C=Cc2cccc(OCC#N)c2)c(=O)oc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a mixture of 5 ml of hexamethylphosphoramine and 0.40 g of 4-hydroxy-3-[3-[3-(cyanomethoxy)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one was added 52 mg of sodium hydride (60% oily), and the mixture was stirred at room temperature for 1 hour. Then, 0.17 g of dimethyl sulfate was added, and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was added to ice water, and the mixture was extracted with ethyl acetate. The organic layer washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 81 mg of 4-methoxy-3-[3-[3-(cyanomethoxy)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (15d)] as a pale yellow crystal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[C:2]1([N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A typical procedure is given for the reaction of Entry 1 in Table 2. A 4 ml vial was charged with bromobenzene (171 mg, 1.10 mmol), diphenylamine (169 mg, 1.00 mmol), Pd(dba)2 (5.9 mg, 1 mol %), Ph5FcP(t-Bu)2(7.1 mg, 2 mol %), and sodium tert-butoxide (144 mg, 1.50 mmol). Anhydrous toluene (1 ml) was added into the mixture, and the vial was then sealed with a cap containing PTFE septum. The reaction mixture was stirred at room temperature for 1 h. After the starting aryl halide was consumed detected, as determined by GC, the reaction solution was directly absorbed onto silica gel, and the product was isolated by eluting with hexane/ethyl acetate to give 244 mg (99%) of triphenylamine as a white solid. Reaction of chlorobenzene (62 mg, 0.55 mmol) with diphenylamine (85 mg, 0.50 mmol) proceeded at 80° C. over 21 h to give triphenylamine (121 mg, 98%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:41][CH:42]([CH3:48])[CH2:43][NH:44][CH2:45][CH2:46][NH2:47]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:47][CH2:46][CH2:45][NH:44][CH2:43][CH:42]([OH:41])[CH3:48])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: CC(O)CNCCN
Product: CC(O)CNCCNC(=O)[C@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and N-(2-hydroxypropyl)ethylenediamine (34 mg) according to Method B to give the title compound (26 mg). 1H-NMR (400 MHz, CD3OD) d 7.56 (d, J=2.4 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.28-7.17 (m, 5H), 7.05 (d, J=8.5 Hz, 1H), 4.37 (m, 1H), 4.27 (dd, J=5.2 Hz, J=8.9 Hz, 1H), 1.35 (s, 9H), 1.22 (dd, J=1.8 Hz, J=6.3 Hz, 3H); HRMS m/z 630.2883 (calc. of monoisotopic mass for C31H42N4O10 gives 630.2901).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].NO.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](OC)=[O:20])[CH:17]=2)[N:12]=[CH:11][N:10]1[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24].C(O)(=O)C>CO.CN(C=O)C>[OH:3][NH:2][C:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]([C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24])[C:9]2=[O:8])=[O:20]
Reactant: COC(=O)c1ccc2ncn(C(C)(C)c3ccccc3)c(=O)c2c1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(c1ccccc1)n1cnc2ccc(C(=O)NO)cc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
A mixture of hydroxylamine hydrochloride (2.0 g, 29 mmol) in methanol (10.0 mL) was heated at 90° C. under a dry nitrogen atmosphere until homogeneous. To this heated solution was added a solution of potassium hydroxide (2.85 g, 50.8 mmol) in methanol (6.0 mL). A precipitate formed on mixing. After heating at 90° C. for 30 minutes, the mixture was cooled to rt and the solids were allowed to settle. The resulting solution was assumed to contain 1.7 M hydroxylamine.potassium salt and was carefully removed by syringe to exclude solids. An aliquot of the above solution (2.0 mL, 3.5 mmol) was added to a solution of methyl 4-oxo-3-(2-phenylpropan-2-yl)-3,4-dihydroquinazoline-6-carboxylate (0.11 g, 0.35 mmol) in methanol (0.75 mL) and DMF (0.50 mL). After stirring for 4 h at rt, excess reagent was quenched by the addition of acetic acid (0.2 mL, 3.5 mmol). The mixture was concentrated to dryness and the residue was twice co-evaporated with toluene. The crude product was purified by preparative HPLC to afford N-hydroxy-4-oxo-3-(2-phenylpropan-2-yl)-3,4-dihydroquinazoline-6-carboxamide (84 mg, 75%). LC-MS: (FA) ES+ 324; 1H NMR (400 MHz, DMSO) δ 11.25 (s, 1H), 9.11 (s, 1H), 8.72 (s, 1H), 8.36 (d, J=1.9 Hz, 1H), 8.14 (dd, J=8.5, 2.1 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.34-7.14 (m, 5H), 1.96 (s, 6H).
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:35](Br)[C:36]#[CH:37]>C(#N)C>[OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:37][C:36]#[CH:35])[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: C#CCBr
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C#CCN1CC[C@@H](CCC(O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Temperature: 20 °C
Reaction time: 40 h

Procedure:
A suspension of 2.45 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate, 2.1 g of potassium carbonate, 0.95 g of potassium iodide, and 0.6 cm3 of propargyl bromide in 50 cm3 of acetonitrile was stirred for 40 hours at a temperature in the region of 20° C. in an inert atmosphere. After filtering the reaction mass, the filtrate was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography on a column of silica gel (particle size 20-45 μm; diameter 2.5 cm; mass 50 g), elution was carried out with ethyl acetate, and 60-cm3 fractions were collected. Fractions 6 to 12 were combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 1.35 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate were obtained in the form of a gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([O:23]C)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[NH:26]1[CH2:30][CH2:29][N:28]=[C:27]1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH:39][CH3:40])=[CH:33][CH:32]=1.C[Al](C)C>C(Cl)Cl>[NH:28]1[CH2:29][CH2:30][N:26]=[C:27]1[C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][N:39]([CH3:40])[C:21]([C:19]2[O:20][C:16]([CH2:15][N:13]([S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:25])(=[O:11])=[O:12])[CH3:14])=[N:17][N:18]=2)=[O:23])=[CH:35][CH:36]=1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)CCc3ccc(C4=NCCN4)cc3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (50 mg, 0.135 mmol), 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine (110 mg, 0.54 mmol) and trimethylaluminium (2 M in toluene, 0.27 mL) in DCM (10 mL). A portion of the crude product was purified using prep method A, then prep method B.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][C:12]([OH:14])=O)[N:5]=[N:4][N:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:47][C:48]1[CH:49]=[CH:50][C:51]([Cl:58])=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:53]=1>C(OCC)(=O)C.CN(C=O)C>[Cl:58][C:51]1[CH:50]=[CH:49][C:48]([NH:47][C:12](=[O:14])[CH2:11][O:10][C:9]2[CH:15]=[CH:16][CH:17]=[C:7]([N:6]3[C:2]([CH3:1])=[N:3][N:4]=[N:5]3)[CH:8]=2)=[CH:53][C:52]=1[C:54]([F:55])([F:56])[F:57]
Reactant: Cc1nnnn1-c1cccc(OCC(=O)O)c1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: Cc1nnnn1-c1cccc(OCC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.4 %

Procedure:
To a 25 mL recovery flask was added [3-(5-methyl-tetrazol-1-yl)-phenoxy]-acetic acid 16 (424 mg, 1.81 mmol, 1.0 eq.) and a stirbar. 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (521 mg, 2.72 mmol, 1.5 eq.) and 1-hydroxybenzotriazole (367 mg, 2.72 mmol, 1.5 eq.) were added to the flask. DMF (12 mL) and N-methylmorpholine (611 μL, 5.44 mmol, 3.0 eq.) were added to the reaction flask. The mixture was allowed to stir for 30 min at room temperature. 5-Amino-2-chlorobenzotrifluoride (709 mg, 3.62 mmol, 2.0 eq.) was added to the flask and the resulting mixture was allowed to stir overnight at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with a succession of H2O (1×50 mL), 10% aq. LiCl (3×50 mL), and sat'd aq. NaCl (1×50 mL). The aqueous phases were combined and extracted with ethyl acetate (2×30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, concentrated and purified by flash chromatography to yield an off-white solid (40 mg, 5%). LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 412.0 (M+H)+1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 10.55 (s, 1H), 8.21 (d, 1H), 7.92-7.89 (m, 1H), 7.70-7.68 (m, 1H), 7.57 (t, 1H), 7.36-7.35 (m, 1H), 7.29-7.27 (m, 2H), 4.85 (s, 2H), 2.53 (s, 3H) ppm.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([CH2:25][C:26]#[N:27])[N:24]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([CH2:25][C:26]5[NH:30][N:29]=[N:28][N:27]=5)[N:24]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cc4nc(CC#N)cs4)ccc3o2)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(-c2cc3cc(Cc4nc(Cc5nnn[nH]5)cs4)ccc3o2)n1
Temperature: 120 °C
Reaction time: 72 h
Yield: 56.9 %

Procedure:
A mixture of 4-tert-butyl-2-{5-{[4-(cyanomethyl)thiazol-2-yl]methyl}benzofuran-2-yl}thiazole (0.19 g), sodium azide (0.43 g) and ammonium chloride (0.36 g) in N,N-dimethylformamide (3 ml) was stirred at 120° C. for 3 days. After being cooled, the mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (50:1), successively with a mixture of chloroform and methanol (10:1). The fractions containing object compound were combined and concentrated under reduced pressure to give 5-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}thiazol-4-ylmethyl}-1H-tetrazole (0.12 g).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](O)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:4]=1)#[N:2].P(Cl)(Cl)([Cl:21])=O.C(N(CC)CC)C>>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([Cl:21])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:4]=1)#[N:2]
Reactant: N#Cc1nc(O)c(-c2cccc(Cl)c2)nc1C#N
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1nc(Cl)c(-c2cccc(Cl)c2)nc1C#N
Yield: 84 %

Procedure:
2,3-Dicyano-5-hydroxy-6-(m-chlorophenyl)pyrazine (25.67 g; 0.10 mole) was put into 46.2 g (0.30 mole) of phosphorus oxychloride. The mixture was cooled to 0° to 5° C., and with stirring 10.1 g (0.1 mole) of triethylamine was added dropwise over the period of 30 minutes. After the addition, the mixture was refluxed for 3 hours. The reaction mixture was worked up in the same way as in Example 3. Petroleum ether (50 ml) was added to the resulting oily product, and the precipitate was collected by filtration. Recrystallization from carbon tetrachloride afforded 23.1 g (yield 83%) of 2,3-dicyano-5-chloro-6-(m-chlorophenyl)pyrazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([Cl:33])[CH:24]=1>>[Cl:33][C:25]1[CH:24]=[C:23]([NH:22][C:15](=[O:17])[CH:14]([N:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:20]#[N:21])=[CH:9][C:10]2=[O:19])[CH3:18])[CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: COC(=O)c1ccc(N)cc1Cl
Product: COC(=O)c1ccc(NC(=O)C(C)n2ccc(-c3cc(Cl)ccc3C#N)cc2=O)cc1Cl

Procedure:
120 mg (0.39 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of methyl 4-amino-2-chlorobenzoate were reacted according to General Method 5A. Following aqueous work-up, the desired product was precipitated using a mixture of a little water, acetonitrile and DMF. Yield: 69 mg (38% of theory)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:24]=[CH:23][C:7]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=1.I[CH3:26]>CN(C)P(=O)(N(C)C)N(C)C>[Cl:3][C:4]1[CH:24]=[CH:23][C:7]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:9](=[O:11])[N:10]([CH3:26])[C:6]=2[CH:5]=1
Reactant: CI
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)N1CCC(n2c(=O)n(C)c3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 1.9 parts of sodium hydride dispersion 78% and 100 parts of hexamethylphosphoric triamide are added portionwise 16.2 parts of ethyl 4-(5-chloro-2-oxo-1-benzimidazolinyl)-1-piperidinecarboxylate (exothermic reaction: temperature rises to 40° C.). After stirring for one hour at room temperature, there are added dropwise 10.6 parts of iodomethane (temperature rises to 40° C). Upon completion, stirring is continued overnight at 60° C. The reaction mixture is cooled, poured onto ice-water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The oily residue is triturated in 2,2'-oxybispropane. The product is filtered off and dried, yielding ethyl 4-(5-chloro-1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl)-1-piperidinecarboxylate; mp. 121.9° C.