Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:17])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[N:7]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].C(N1C2C(=CC(C3C=NN(C4CC4)C=3)=C(N)C=2)N(C(OC(C)C)=O)C[C@@H]1C)(=O)C>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:17])=[C:11]([NH2:14])[CH:12]=2)[N:7]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc([N+](=O)[O-])c(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Product: CC(=O)N1c2cc(N)c(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C

Procedure:
Isopropyl (S)-4-acetyl-6-amino-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was prepared from isopropyl (S)-4-acetyl-7-bromo-3-methyl-6-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate according to the procedure described above for isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 233). MS (ESI, pos. ion) m/z 392,394 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[CH3:7][N:8]([CH3:13])[CH2:9][CH2:10][CH2:11]N.N.[OH-].[Na+]>>[CH3:7][N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][NH:6][C:4](=[O:5])[CH:3]=[CH2:2]
Reactant: NC(=O)CCO
Reactant: CN(C)CCCN
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: C=CC(=O)NCCCN(C)C

Procedure:
59.3 g of β-hydroxypropionic acid amide and 68 g of 3-dimethylaminopropylamine were heated for 5 hours in a temperature range of 125°-168° C. until the evolution of ammonia was complete. After adding 1 g of pulverised sodium hydroxide the reaction mixture was distilled.
Reaction SMILES: [N:1]1([C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)[S:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)[S:12][CH:11]=2)=[O:9])[CH2:2][CH2:3]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1csc(-c2cn[nH]c2)c1)N1CCCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCN(C(=O)c2csc(-c3cn[nH]c3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
[1,4]Diazepan-1-yl-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone (0.075 g, 0.27 mmol) was dissolved in DCM (30 mL) and cooled in an ice-bath before addition of triethylamine (0.082 g, 0.82 mmol) and methanesulfonyl chloride (0.038 g, 0.33 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by evaporation and the residue taken up in methanol (2.5 mL) and treated with sodium hydroxide (1 M, 0.3 mL). After 1 hour the solvent was removed and the crude material was purified by HPLC, eluting with 5%-98% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were combined and freeze-dried to give the title compound (0.045 g). LCMS m/z 355.14 [M+H]+ R.T.=5.95 min (Analytical Method 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[S:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[S:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Cc1ccc(C(=S)CBr)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(C(=S)Cn2cc(Cl)cnc2=O)cc1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 63.3 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (312 mg) and 2-bromo-4'-methylthioacetophenone (525 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 2.25 hours. The resulting suspension was concentrated at reduced pressure then diluted with water (50 ml). The collected precipitate was crystallised from acetone to give the title pyrimidinone (404 mg,); m.p. 192°-197°, λmaxEtOH 229 nm (ε 14450), 312 nm (ε 21470), λinf 239.5 nm (ε 9930).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:5][CH:4]=1.[CH2:16]([O:18][C:19](=[O:42])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28](=[O:40])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:30]=2)[CH:25]=[CH:24][C:23]=1O)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:42])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28](=[O:40])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:30]=2)[CH:25]=[CH:24][C:23]=1[O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]#[C:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:17]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1O
Reactant: COc1ccc(C#CCCCCO)cc1
Product: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCC#Cc1ccc(OC)cc1
Yield: 55 %

Procedure:
Following the procedure of Example 92B, 0.38 g of 6-(4-methoxyphenyl)-5-hexynyl alcohol were converted to the mesyl ester and reacted with 0.69 g of 5-[3(ethoxycarbonyl)benzoyl]-2-hydroxybenzenepropanoic acid ethyl ester to provide the title product in 55% yield as an oil.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][CH:14]1[NH:18][C:17](=[O:19])[CH2:16][CH2:15]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCC.O1CCCC1>[C:20]([N:18]1[CH:14]([O:13][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][CH2:16][C:17]1=[O:19])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCCCCCOC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCOC1CCC(=O)N1C(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
16.5 cm3 of a 15% solution butyllithium in hexane is added at -60° C. to 4.98 g of 5-n-heptyloxy pyrrolidin-2-one in solution in 100 cm3 of tetrahydrofuran. After 20 minutes of agitation at -60° C., 3.5 g of benzoyl chloride in 25 cm3 of tetra-hydrofuran is added at this temperature. Agitation is carried out for 4 hours, allowing the mixture to return to ambient temperature. After concentration at 40° C., the residue is taken up in water, extracted with ether and concentrated to dryness. The residue is chromatographed on silica (eluent: toluene-ethyl acetate 8-2) and 1.2 g of the product sought is obtained.
Reaction SMILES: [NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([O:46]C)=O)[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].O.[NH2:59][NH2:60]>CO>[NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([NH:59][NH2:60])=[O:46])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: NN
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)NN
Reaction time: 20 h

Procedure:
3.97 g of Z-Asn-Lys(BOC)-Phe-His-OMe are dissolved in 20 ml of boiling methanol. 2.5 ml of hydrazine hydrate are added to the solution whilst it is still at about 30°C and the mixture is allowed to stand for 20 hours at room temperature. The peptide-hydrazine is precipitated by adding water, filtered off and washed with water until free of hydrazine. The product is reprecipitated from dimethylformamide-water.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([OH:12])=[C:7]([N+:13]([O-:15])=[O:14])[C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH4+:20].[OH-]>C1(C)C=CC=CC=1>[Cl:11][C:9]1[CH:10]=[C:2]([Cl:1])[C:3]([C:4]([NH2:20])=[O:5])=[C:7]([N+:13]([O-:15])=[O:14])[C:8]=1[OH:12]
Reactant: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Reactant: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2,4-dichloro-5-hydroxy-6-nitrobenzoic acid (Step A) (4.40 g, 17.6 mmol) and thionyl chloride (2 mL, 27 mmol) in toluene (60 mL) was heated under reflux for 1 h and allowed to cool to room temperature. The solution was added to conc NH4OH (40 mL) at 0° C. The cooling bath was removed and the mixture stirred at room temperature for 2 h and then concentrated to give crude 4,6-dichloro-3-hydroxy-2-nitrobenzamide as a brown solid.—1H NMR (CD3OD): δ 7.33 (s, 1H); mass spectrum: m/z 249, 251, 253 (M+−1, 100%, 66%, 11%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:13]([O:1][C@@H:2]1[O:10][C@H:9]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@@H:7]([O:8][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:5]([O:6][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:3]1[O:4][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 100 °C
Yield: 89.5 %

Procedure:
To a solution of D-glucose 42 (500 mg, 2.77 mmol) in 25 mL of pyridine is added pivaloyl chloride (3.42 mL, 3.34 g, 27.75 mmol) followed by DMAP (34 mg, 0.27 mmol). The reaction mixture is heated at 100° C. for 12 h, cooled to room temperature and quenched with 2 mL methanol. The reaction mixture is concentrated and the resulting residue is taken up in 25 mL CH2Cl2, washed with 1N HCl (3×25 mL), saturated NaCl (25 mL), dried over Na2SO4, filtered, concentrated and purified by flash chromatography (10% EtOAc/hexane) to afford 1.49 g (90%) of 1,2,3,4,6-penta-O-pivaloyl-β-D-glucopyranose 43: Rf 0.18 (5% EtOAc/hexane); 1H NMR (CDCl3, 270 MHz) δ 5.69 (d, J=8.2 Hz, 1H, H-1), 5.37 (app t, J=9.2 Hz, 1H, H-3), 5.21 (app t, J=8.7 Hz, 1H, H-4), 5.16 (app t, J=9.5 Hz, 1H, H-2), 4.06-4.17 (m, 2H, H-6), 3.86 (ddd, J=9.8, 4.8, 2.3 Hz, 1H, H-5), 1.21 (s, 9H), 1.17 (s, 9H), 1.15 (s, 9H), 1.12 (s, 18H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].CC(C)([O-])C.[K+].[NH:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](O)=[O:25].P(C#N)(=O)(OCC)OCC>CN(C)C=O.O>[O:25]=[C:24]([C:20]1[NH:19][CH:23]=[CH:22][CH:21]=1)[CH:3]([C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2]
Reactant: N#CCC(=O)Nc1ccccc1
Reactant: O=C(O)c1ccc[nH]1
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(C#N)OCC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1ccc[nH]1

Procedure:
to a solution of 1.6 g of α-cyanoacetanilide in 10 ml of dimethylformamide is added 3.4 g of potassium t-butoxide. The stirred cooled suspension is treated with a solution of 1.1 g of pyrrole-2-carboxylic acid and 1.4 ml of diethyl phosphorocyanidate in 6 ml of dimethylformamide. After standing for one half hour, solution is treated with 80 ml of cold water, filtered and acidified with 6N hydrochloric acid. The suspended product is collected, washed with water, dried, and dissolved in ethyl acetate. The ethyl acetate solution is filtered and evaporated to dryness. Recrystallization from ether-ethanol yields β-oxo-α-(phenylcarbamoyl)-β-(2-pyrrolyl)-propionitrile of Example 1.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:33])[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[C:26]([O:28]C(C)(C)C)=[O:27])=[O:20])=[O:7])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl.O>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[C:26]([C@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:19](=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:33])([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)CCNCCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(O)[C@H]1CCCN1C(=O)CCNCCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 16 h
Yield: 76 %

Procedure:
To a stirred solution of 33 mg (0.07 mmol) (R)-1-[3-[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propylamino]-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml dichloromethane at 0° C. was added dropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded, after resuspension in water and subsequent lyophilization, 19 mg (76%) of the title compound as a yellow glassy solid. MS m/e (%): 354 ([M−H]−, 100).
Reaction SMILES: [CH3:1][CH:2]([S:4]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH3:3].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH:24]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:23]([C:32](Cl)=[O:33])[C:22]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=3[O:45][CH2:46][CH3:47])=[N:21]2)=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH:24]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[N:23]([C:32]([N:10]3[CH2:9][CH2:8][N:7]([S:4]([CH:2]([CH3:1])[CH3:3])(=[O:5])=[O:6])[CH2:12][CH2:11]3)=[O:33])[C:22]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:37][C:36]=3[O:45][CH2:46][CH3:47])=[N:21]2)=[CH:16][CH:15]=1
Reactant: CC(C)S(=O)(=O)N1CCNCC1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(S(=O)(=O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(Propane-2-sulfonyl)-piperazine (0.0286 mmol) was dissolved in 0.25 mL of methylene chloride and added to a solution of 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (0.024 mmol, example 3) and diisopropylethylamine (0.072 mmol) in. 25 mL of methylene chloride in a 4 mL vial. The vial was capped and shaken overnight at room temperature. The reaction mixture was diluted with 1 mL of methylene chloride and 1 mL of water. The vial was agitated and centrifuged. The organic layer was transferred to a 4 mL vial and concentrated in vacuo to give [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(propane-2-sulfonyl)-piperazin-1-yl]-methanone. LR-MS (M+H)+=697.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:19])[C@@H:12]([CH2:17]O)[C:13]([O:15]C)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:19])[C:12](=[CH2:17])[C:13]([OH:15])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CO)N(C)S(=O)(=O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C(=O)O)N(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 50 °C
Yield: 56.3 %

Procedure:
A solution of 3A (2.3 g, 7.2 mmol) in dioxane (35 mL) was added with 20% NaOH aq. solution (20 mL) and the mixture was heated at 50° C. for 2 h. The organic solvent was removed under reduced pressure and the aqueous phase acidified with 10% HCl. The solid formed was collected by filtration, washed with water (2×20 mL) and dried to obtain 4A as white solid (1.05 g, 51% yield). 1HNMR (DMSO, 200 MHz) δ 2.92 (s, 3H), 5.57 (s, 1H), 6.09 (s, 1H), 7.50 (m, 2H), 7.85 (m, 2H), 13.01 (bs, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[CH3:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:17]3[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: CC1Cc2cccc(Cl)c2C1=O
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: OCCO
Solvent: O
Product: Cc1ccc(-c2cccc3c2C(=O)C(C)C3)cc1
Temperature: 125 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
Using a method similar to Example 16 d), 3.61 g (0.020 mol) of (1), 3.0 g (0.022 mol) of 4-methylphenylboronic acid, 4.66 g (0.044 mol) of sodium carbonate were placed in 60 ml of ethylene glycol/12 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 22.4 mg (0.1 mmol) of palladium acetate and 0.114 g (0.2 mmol) of TMSPP, the reaction mixture was stirred for 2 hours at 125° C. After addition of 60 ml of water, the aqueous phase was extracted 4 times with 50 ml each time of ether, the combined ether phases were washed with 50 ml of water and 50 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 4.5 g of (21) as solid.
Reaction SMILES: [Li+].[C:2]([O:6][C:7]([C:9]1[S:13][C:12]([CH2:14][N:15]([CH3:24])[C@H:16]([C:21]([O-:23])=O)[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].Cl.[CH3:26][O:27][C:28](=[O:36])[C@H:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[NH2:30].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:26][O:27][C:28](=[O:36])[C@H:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[NH:30][C:21](=[O:23])[C@H:16]([CH2:17][CH:18]([CH3:19])[CH3:20])[N:15]([CH2:14][C:12]1[S:13][C:9]([C:7]([O:6][C:2]([CH3:3])([CH3:4])[CH3:5])=[O:8])=[CH:10][CH:11]=1)[CH3:24]
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: CC(C)C[C@@H](C(=O)[O-])N(C)Cc1ccc(C(=O)OC(C)(C)C)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H](NC(=O)[C@H](CC(C)C)N(C)Cc1ccc(C(=O)OC(C)(C)C)s1)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
The compound (0.20 g, 0.58 mmol) obtained in step 2, aspartic acid dimethyl ester hydrochloride (0.12 g, 0.58 mmol), WSC hydrochloride (0.17 g, 0.87 mmol), 1-hydroxybenzotriazole monohydrate (0.090 g, 0.58 mmol), and N,N-diisopropylethylamine (0.39 mL, 2.8 mmol) were dissolved in dichloromethane (5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added. The mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.15 g, 0.31 mmol, 53%).
Reaction SMILES: Cl[CH:2]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[CH2:18][CH3:19].[NH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+].[OH-].[Na+].Cl>C(OCC)(=O)C.C(O)C.O1CCCC1.CN(C)C(=O)C>[CH:20]1([CH:2]([NH:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)[C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[S:5][C:4]=2[CH2:18][CH3:19])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Cl)C1CCCCC1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a mixture of 3-[chloro(cyclohexyl)methyl]-2-ethyl-5-[4-(trifluoromethyl)phenyl]thiophene (1.00 g) synthesized above, methyl 4-aminobenzoate (780 mg), sodium iodide (1.55 g) and N,N-dimethylacetamide (10 mL) was added sodium carbonate (547 mg), and the mixture was stirred under an argon atmosphere at 100° C. overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark-brown oil. To a mixture of the obtained oil, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at 60° C. for 1 hr, and stirred with heating under reflux for 30 min. 1N Hydrochloric acid (10 mL) was added to the reaction mixture, the organic solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7, volume ratio) to give a brown oil. The obtained oil was dissolved in ethyl acetate, washed with 1N hydrochloric acid and brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (369 mg, 29%) as a pale-brown solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[OH-].[K+].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Br)[CH:15]=1>CC(C)=O>[N:1]1([CH2:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[CH2:20][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: BrCc1cccc(CBr)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: c1cc(Cn2cnc3ccccc32)cc(Cn2cnc3ccccc32)c1
Yield: 18.8 %

Procedure:
To a 1 L round bottom flask equipped with a stirbar was added 26.8 g benzimidazole (227 mmol) and 12.7 g (227 mmol) finely pulverized potassium hydroxide. These were stirred in 500 mL acetone for 20 minutes at reflux. 20.0 g (78.5 mmol) α,α′-dibromo-m-xylene was then added, and the solution was stirred at reflux for 6 hours followed by room temperature stirring for 72 hours. The cloudy solution was filtered, and the white solids rinsed with acetone. The resulting filtrate was dried on silica and partitioned on a silica gel column using a gradient of 100% acetonitrile→90% acetronitrile/10% MeOH as eluent. The product fractions were evaporated of solvent to give 5 g 1-[3-(1H-benzimidazole-1yl-methyl)benzyl]-1H-benzimidazole as a white solid.
Reaction SMILES: F[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[N:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.[CH3:20][NH2:21]>O.C1COCC1>[CH3:9][O:8][C:7]1[C:2]([NH:21][CH3:20])=[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=[N:5][CH:6]=1
Reactant: COc1cnnc(-c2cccc(C(F)(F)F)c2)c1F
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNc1c(OC)cnnc1-c1cccc(C(F)(F)F)c1
Yield: 95 %

Procedure:
4-Fluoro-5-methoxy-3-[3-(trifluoromethyl)phenyl]pyridazine (0.6 g, 0.0022 mole, Compound No. 46) and methylamine (1.54 g of a 40% solution in water, 0.0194 mole) were stirred at RT in THF (20 mL) under N2 for 24 h. The mixture was poured into water and extracted 3×50 mL with ethyl acetate. The organic layer was dried (MgSO4), filtered, and evaporated in vacuo. The crude solid was recrystallized from cyclohexane/ethyl acetate to give 5-methoxy-N-methyl-3-[3-(trifluoromethyl)phenyl]-4-pyridazinamine (0.59 g, 95% yield, Compound No. 86) as an off white solid.