Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Sodium hydride, 80% dispersion in oil (0.14 g, 4.8 mmoI) was added to a solution of 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (1.0 g, 4.8 mmol) [prepared from 4-hydroxypiperidine and di-tert-butyl dicarbonate] in dimethylformamide (30 ml) and the mixture stirred for 30 minutes. Benzyl bromide (0.68 ml, 5.7 mmol) was added and the reaction mixture stirred overnight. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with water and brine, dried (MgSO4) and the residue after evaporation purified by flash chromatography eluting with 0-20% ethyl acetate in hexane to give 1-(tert-butoxycarbonyl)-4-benzyloxypiperidine (1.1 g, 94% ); δH (CDCl3) 1.39 (9H, s, C(CH3)3), 1.82 (2H, m, piperidinyl. H), 3.04 (2H, m, piperidinyl H), 3.59 (3H, m, piperidinyl H), 4.51 (2H, s, OCH2Ph), 7.24-7.39 (5H, m, PhH).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11](N)=[O:12])=[N:4][C:5]([Br:10])=[C:6](Br)[C:7]=1Br.[NH3:14].C[OH:16]>>[NH2:14][C:7]1[CH:6]=[C:5]([Br:10])[N:4]=[C:3]([C:11]([OH:12])=[O:16])[C:2]=1[Br:1]
Reactant: NC(=O)c1nc(Br)c(Br)c(Br)c1Br
Reactant: CO
Reactant: N
Product: Nc1cc(Br)nc(C(=O)O)c1Br

Procedure:
3,4,5,6-Tetrabromopyridine-2-carboxamide (5.0 g) was selectively aminated with ammonia gas at RT in 100 mL methanol. The resultant solution was concentrated to an off-white solid and hydrolyzed with conc. sulfuric acid (25 mL) at 140° C. for 3 hr. the mixture was made basic with NaOH, extracted with EtOAc (2×100 mL), acidified and filtered to give 1.4 g of pure 4-amino-3,6-dibromopyridine-2-carboxylic acid; mp 205° C. dec.
Reaction SMILES: C(OC([N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:22]3[O:23][C:24]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:25][C:26](=[O:28])[CH:27]=3)[C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:29]1([C:24]2[O:23][C:22]([C:17]3[C:16]4[S:15][C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:21]=4[CH:20]=[CH:19][CH:18]=3)=[CH:27][C:26](=[O:28])[CH:25]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2Sc2c(-c3cc(=O)cc(N4CCOCC4)o3)cccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1cc(-c2cccc3c2Sc2ccccc2N3)oc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.1 %

Procedure:
To a stirred solution of 4-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-phenothiazine-10-carboxylic acid tert-butyl ester (3.65 g, 7.63 mmol), in CH2Cl2 (30 ml) was added trifluoroacetic acid in a single portion. The mixture was stirred at room temperature for 20 hours whereupon the reaction was concentrated in vacuo to give a thick syrup that was basified in a dropwise fashion with saturated NaHCO3 (40 ml). The dark green mixture was then stirred at room temperature for 18 hours. The mixture was filtered and the filtrant retained, washed with water and dried to give the title compound as a dark green solid (2.89 g, 83.74% over 3 steps) m/z (LC-MS, ESP): 479 [M+H]+, R/T=4.05 mins
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].[CH3:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1>O>[Na+:5].[CH3:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][S:1]([O-:4])(=[O:3])=[O:2])=[CH:10][CH:9]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(CS(=O)(=O)[O-])cc1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a solution of sodium sulfite (14.3 g, 113 mmol) in water (60 mL) was added 4-methylbenzyl chloride (15.0 ml,, i13 mmol). The mixture was stirred under reflux for 12 hours, and cooled to rt. The precipitate was collected by filtration, and washed with water and ether to give 4-methylphenylmethanesulfonic acid sodium salt (12.5 g, 60 mmol, 53%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][OH:19])[CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH:26]([C:27]([O:19][CH2:18][CH2:17][C:13]1[CH:12]=[C:11]([CH2:10][CH:4]([O:3][CH2:1][CH3:2])[C:5]([OH:7])=[O:6])[CH:16]=[CH:15][CH:14]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OCC
Reactant: O=C=Nc1ccccc1
Product: CCOC(Cc1cccc(CCOC(=O)Nc2ccccc2)c1)C(=O)O

Procedure:
Using ethyl 2-ethoxy-3-[3-(2-hydroxyethyl)phenyl]propanoate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 160b).
Reaction SMILES: [CH2:1]([O:3][CH:4]=[C:5]([CH3:8])[CH:6]=O)[CH3:2].[CH3:9][N:10]([CH3:12])[NH2:11].C(O)(=O)C>C(OCC)C>[CH3:9][N:10]([CH3:12])[N:11]=[CH:6][C:5]([CH3:8])=[CH:4][O:3][CH2:1][CH3:2]
Reactant: CCOC=C(C)C=O
Reactant: CN(C)N
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC=C(C)C=NN(C)C

Procedure:
A mixture of 3-ethoxy-2-methyl-2-propenal, (E)- and (Z)- (4.0 g, 35 mmol), 1,1-dimethylhydrazine (2.73 g, 46 mmol) and acetic acid (0.04 g, 0.7 mmol) in diethyl ether is refluxed for one hour, cooled, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13]([C@H:15]2[CH2:20][CH2:19][C@H:18]3[C@H:21]4[C@H:31]([CH2:32][CH2:33][C@:16]23[CH3:17])[C@:29]2([CH3:30])[C:24]([CH:25]=C(C#N)[CH2:27][CH2:28]2)=[CH:23][CH2:22]4)=[O:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[OH-:36].[K+].Cl.[CH2:39]([OH:42])[CH2:40]O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13]([C@H:15]2[CH2:20][CH2:19][C@H:18]3[C@H:21]4[C@H:31]([CH2:32][CH2:33][C@:16]23[CH3:17])[C@:29]2([CH3:30])[C:24]([CH:25]=[C:40]([C:39]([OH:42])=[O:36])[CH2:27][CH2:28]2)=[CH:23][CH2:22]4)=[O:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Reactant: OCCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C(=O)O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 25 °C

Procedure:
280 mg of N-[1-(4-methoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide [prepared as described in step (c) above] were suspended in 15 ml of ethylene glycol, and a solution of 2.2 g of potassium hydroxide in 5 ml of water was added to the resulting suspension. The mixture was then heated under reflux for 24 hours in a nitrogen stream. At the end of this time, the reaction mixture was cooled to room temperature and made acidic by the addition of 10% w/v aqueous hydrochloric acid, and then the mixture was extracted with methylene chloride. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed from the mixture by evaporation under reduced pressure. The residue was recrystallized from a mixture of acetone and diethyl ether, and the resulting crystals were collected by filtration. The mother liquor was purified by silica gel column chromatography using a gradient elution method, with mixtures of methylene chloride and acetone in ratios ranging from 9:1 to 7:3 by volume as the eluent, to give 268 mg of the title compound as white powdery crystals.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]([CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]=2[N:10]=1)#[N:7].[OH-:22].[Na+]>S(=O)(=O)(O)O>[NH2:7][C:6](=[O:22])[CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]=2[N:10]=1
Reactant: COC(=O)c1cccc2[nH]c(CC#N)nc12
Reactant: O=[N+]([O-])[O-]
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: COC(=O)c1cc([N+](=O)[O-])cc2[nH]c(CC(N)=O)nc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under ice-cooling, potassium nitrate (117 mg) was added slowly portion-wise to a stirring solution of methyl 2-(cyanomethyl)-1H-benzimidazole-4-carboxylate (prepared as described in EP1479681) (226 mg) in conc. sulfuric acid (5 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice, and alkalified with 3N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was washed with MeOH, filtered and dried to obtain the titled compound (243 mg).
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[C:6](=[C:8]1[S:12]C(=S)N[C:9]1=[O:14])[CH3:7])([OH:3])=O.[OH-:19].[Na+].Cl>>[CH3:7][C:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[C:1](=[O:3])[S:12][C:8]=1[C:9]([OH:19])=[O:14]
Reactant: [OH-]
Reactant: CC(=C1SC(=S)NC1=O)c1ccccc1C(=O)O
Agent: Cl
Agent: [Na+]
Product: Cc1c(C(=O)O)sc(=O)c2ccccc12

Procedure:
A stirred solution of 2.00 g. (7.17 mM) of the carboxylic acid of Example 13 in 15 ml. of 15% sodium hydroxide is refluxed for 0.75 hour, cooled, and poured into dilute hydrochloric acid, whereupon a precipitate forms. The solid is collected and recrystallized from ethyl acetate-hexane to give a tan solid. This solid is heated briefly to 245°, cooled, and the residue recrystallized from ethyl acetatehexane to give 4-methyl-1-oxo-1H-2-benzothiopyran-3-carboxylic acid as tan crystals, m.p. 247°-248°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:37]=[CH:36][C:31]2[N:32]=[C:33]([NH2:35])[S:34][C:30]=2[CH:29]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:35][C:33]3[S:34][C:30]4[CH:29]=[C:28]([F:27])[CH:37]=[CH:36][C:31]=4[N:32]=3)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1nc2ccc(F)cc2s1
Yield: 37.4 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 6-fluorobenzo[d]thiazol-2-amine (0.067 g, 0.397 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.050 g of desired product. 1HNMR (DMSO-d6): δ 3.99 (s, 3H), 7.32 (t, J=7.2 Hz, 1H), 7.51 (t, J=9.3 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.68-7.80 (m, 4H), 7.94 (t, J=6.3 Hz, 2H), 11.98 (s, 1H), 12.83 (br s, 1H); MS (m/z): 512.97 [M−H]−.
Reaction SMILES: C([O:8][C:9]1[N:14]2[N:15]=[C:16]([CH3:23])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[CH:12]=[C:11]([CH3:24])[CH:10]=1)C1C=CC=CC=1.C1CCCCC=1>C(O)C.[Pd]>[OH:8][C:9]1[N:14]2[N:15]=[C:16]([CH3:23])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[CH:12]=[C:11]([CH3:24])[CH:10]=1
Reactant: CCOC(=O)c1c(C)nn2c(OCc3ccccc3)cc(C)cc12
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn2c(O)cc(C)cc12
Yield: 85.7 %

Procedure:
2 g (5.98 mmol) of ethyl 7-(benzyloxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate from Example 7A were initially charged in 80 ml of ethanol under argon, and 636 mg (0.59 mmol, 10%) of palladium on activated carbon and 18 ml (179.42 mmol) of cyclohexene were added. The reaction mixture was stirred under reflux for 2.5 hours. Then the reaction mixture was filtered through kieselguhr and washed with ethanol, and the filtrate was concentrated. The residue was taken up in DMSO and acetonitrile and purified by means of preparative HPLC (RP 18 column, eluent:acetonitrile/water gradient with addition of 0.1% TFA). The product fractions were combined, concentrated and lyophilized. 1.2 g of the target compound were obtained (86% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[CH:22][S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1>CO.[OH-].[Pd+2].[OH-]>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][S:23]([NH2:26])(=[O:24])=[O:25])[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc(C=CS(N)(=O)=O)c2)cnn1-c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Nc1c(C(=O)c2cccc(CCS(N)(=O)=O)c2)cnn1-c1ccc(F)cc1
Reaction time: 96 h
Yield: 45 %

Procedure:
A mixture of 5-amino-4-[3-(2-aminosulfonylethenyl)benzoyl]-1-(4-fluorophenyl)-pyrazole (2.1 g, 5.43 mmol) and palladium hydroxide (0.6 g) in methanol (150 ml) was shaken in a Parr apparatus under hydrogen atmosphere at 50 psi. After 4 days, the reaction mixture was filtered through CELITE® and the filtrate was concentrated. The residue was purified by flash chromatography (elution gradient: 40-100% ethyl acetate/hexane) to give a crude product which was recrystallized from methanol/ethyl acetate/hexane to give 5-amino-4-[3-(2-aminosulfonylethyl)benzoyl]-1-(4-fluorophenyl)pyrazole (0.95 g, mpt. 170-170.4° C.) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.Cl[C:17]1[CH:26]=[CH:25][N:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([C:27]([F:30])([F:29])[F:28])=[N:22]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH:8][C:17]2[C:18]3[C:23](=[N:22][C:21]([C:27]([F:30])([F:29])[F:28])=[CH:20][CH:19]=3)[N:24]=[CH:25][CH:26]=2)[CH:7]=1
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: FC(F)(F)c1ccc2c(Nc3cc(Cl)ccc3Oc3ccccc3)ccnc2n1

Procedure:
The product from Example 42b (60 mg, 0.27 mmol) was reacted with the product from Example 7d (63 mg, 0.27 mmol) for 24 h following the procedure from Example 1g giving the crude title compound as a solid which was triturated with 4:1 ether/THF giving the product as a hydrochloride salt (112 mg, 91%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 6.82 (d, J=6.99 Hz, 1H) 6.98 (d, J=7.72 Hz, 2H) 7.13 (m, 2H) 7.32 (dd, J=7.73 Hz, J=8.82 Hz, 2H) 7.57 (dd, J=2.57 Hz, J=8.82 Hz, 1H) 7.71 (d, J=2.57 Hz, 1H) 8.36 (d, J=8.82 Hz, 1H) 8.69 (d, J=6.99 Hz, 1H) 9.42 (d, J=8.82 Hz, 1H) 11.47 (br s, 1H) 14.40 (br s, 1H); MS (ESI+) m/z 416 (M−Cl)+; (ESI−) m/z 414 (M−HCl)−.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][C:12]=1[O:19][CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:4]([CH3:9])([CH3:5])[CH:3]=[O:1])=[CH:13][C:12]=1[O:19][CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: COc1cc(CCl)ccc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(CC(C)(C)C=O)ccc1OCc1ccccc1
Temperature: 70 °C

Procedure:
Under argon, a mixture of sodium hydroxide (1.43 g, 35.85 mmol) and tetrabutylammonium iodide (0.30 g, 0.82 mmol) in 8 ml benzene and 2.8 ml H2O was heated at 70° C. to form a homogeneous mixture. A mixture of the product of Step 1 (8.05 g, 30.64 mmol) and isobutraaldehyde (2.95 g, 40.85 mmol) in 20 ml benzene was added to the above solution dropwise. The resulting reaction mixture was heated at 70-75° C. for 6 h. The product was extracted with ethyl acetate and washed with H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with MgSO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/9) to yield a colorless oil in 8.32 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:19]#[N:20])[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:9]=2[NH:8][C:7]1=[O:21])[CH3:2].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>CN(C)C=O>[F:16][C:15]([F:18])([F:17])[C:36]([OH:37])=[O:39].[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:19]([NH2:20])=[O:37])[CH:13]=[C:14]([C:15]([F:16])([F:17])[F:18])[C:9]=2[N:8]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([C:25]([F:35])([F:34])[F:24])=[CH:27][CH:28]=2)[C:7]1=[O:21])[CH3:23]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)CCn1c(=O)[nH]c2c(C(F)(F)F)cc(C#N)cc21
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCn1c(=O)n(Cc2ccc(C(F)(F)F)cc2)c2c(C(F)(F)F)cc(C(N)=O)cc21
Product: O=C(O)C(F)(F)F
Temperature: 80 °C
Yield: 166 %

Procedure:
A solution of 3-[2-(diethylamino)ethyl]-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-5-carbonitrile (12.5 mg), 4-trifluoromethylbenzyl bromide (24.9 mg) and potassium carbonate (12.9 mg) in N,N-dimethylformamide (1.5 ml) was stirred with heating at 80° C. for 1.5 hours. The reaction mixture was concentrated in vacuo. To the resultant residue was added t-butanol (3 ml), and the mixture was stirred with heating at 60° C. To the solution was added powdered potassium hydroxide crashed in mortar (47.9 mg), and the mixture was stirred with heating at 60° C. for 45 minutes. To the reaction mixture was added 1N hydrochloric acid, and the mixture was concentrated in vacuo. The resultant residue was purified by HPLC using condition 2 to give the title compound (19.6 mg, 83%).
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(O)[CH3:7].C(O)=O.O.[NH2:19][NH2:20]>C(O)C>[C:9]1([CH:6]([C:2]2[N:19]=[N:20][CH:5]=[CH:4][CH:3]=2)[CH3:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NN
Reactant: CC(O)(c1ccccc1)c1ccco1
Solvent: O=CO
Solvent: CCO
Solvent: O
Product: CC(c1ccccc1)c1cccnn1
Reaction time: 1 h

Procedure:
(±) 1-(2-Furyl)-1-phenylethanol (43 g.) was dissolved in a solution of hydrazine hydrate (25 ml.) in ethanol (100 ml.). Formic acid (23 ml.) was added to the solution cautiously in portions and the heterogeneous mixture was heated at reflux on a steam bath for 4 hours. After 1 hour the mixture became homogeneous. The solution was evaporated to low volume and the residue was digested with a mixture of diethyl ether (100 ml.) and water (200 ml.). Dilute sodium hydroxide solution was added to adjust the pH to 9 and the ether layer was separated. The aqueous layer was extracted with diethyl ether (2 × 150 ml.) and the combined ethereal extracts were washed with water (3 × 150 ml.) and filtered. The filtrate was extracted with 2N hydrochloric acid (5 × 100 ml.). The combined acidic extracts were washed with diethyl ether (2 × 200 ml.) and basified by the addition of 50% aqueous sodium hydroxide solution. The oil which was deposited was extracted with diethyl ether (2 × 200 ml.) and the combined extracts were washed with water (2 × 200 ml.), dried over sodium sulphate, filtered and evaporated to give a brown oil, which was distilled to give 3-(1-phenylethyl)pyridazine (5.4 g.), m.p. 43°-48° C. (b.p. 120° C./0.05 mm.Hg), as an off-white solid.
Reaction SMILES: B.C1CCCCC=1.[NH:8]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:9]([C:21]([OH:23])=[O:22])[CH2:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:31]([C@@:34]([C:43]([NH2:45])=[O:44])([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH2:35])[CH:32]=[CH2:33].OO>C1COCC1.C(O)C>[NH:8]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:9]([C:21]([OH:23])=[O:22])[CH2:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH:12][CH2:33][CH2:32][CH2:31][C@@:34]([C:43]([NH2:45])=[O:44])([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH2:35]
Reactant: C=CC[C@](N)(Cc1ccccc1)C(N)=O
Agent: B
Agent: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: OO
Solvent: C1CCOC1
Solvent: CCO
Solvent: C1=CCCCC1
Product: NC(=O)[C@](N)(CCCO)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of borane in THF (1.44 mL of a 1M solution, 1.44 mmol) at 0° C. under nitrogen, was added cyclohexene (0.29 mL, 2.88 mmol) by syringe, and the mixture was stirred for 0.5 hour, during which time a white precipitate formed. A prechilled (0° C.) solution of t-BOC-Asp(OBn)-α-allylphenylalaninamide (480 mg, 0.92 mmol), from Step e, in anhydrous THF (4 mL) was added and stirring was continued for 2 hours at 0° C., then at ambient temperature overnight. The solution was diluted with pH 7 buffer and ethanol and treated with excess 30% aqueous H2O2 and stirred overnight. The reaction mixture was then partitioned between ethyl acetate and brine and the aqueous phase was extracted with two portions of ethyl acetate. The ethyl acetate solutions were combined, dried over anhydrous sodium sufate, filtered and concentrated. The residue (514 mg) was chromatographed on silica gel eluting with hexane/acetone (1:1) to give 266 mg (54% yield) of the title compound (1:1 diastereomeric mixture) as a colorless solid, m.p. 75°-79° C.; 1H NMR (CDCl3) δ1.37 (s) and 1.40 (s) (total of 9H), 1.50-1.71 (m,2H), 1.92-2.12 (m) and 2.13-2.27 (m) (total 2H), 2.21-2.38 (overlapping dd's,J=6 and 18 Hz and J=5 and 16 Hz,total 2H), 3.10 (dd,J=4.5 and 17 Hz,2H), 3.25-3.48 (m,2H), 3.61 (m,2H), 4.60 (m,1H), 5.10 (s) and 5.12 (s) (total 2H), 5.32 (br m,1H), 5.45 (br t,J=9 Hz,1H), 6.42 (br m,1H), 7.12 (m,2H), 7.16-7.40 (m,8H). MS (DCl/NH3) m/e 528 (M+H)+, 545 (M+NH4)+ . Analysis calculated for C28H37N3O7.0.1H2O: C, 63.52; H, 7.08; N, 7.94. Found: C, 63.21; H, 7.03; N, 7.68.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]([F:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1>C1COCC1>[F:31][C:11]([F:10])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]3=[N:24][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:20]3[CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(C(F)(F)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(C(F)(F)c4ccccc4)cc3)C2=N1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 196 mg) in THF (dry) (20 mL) was added 2-chloroethanesulfonyl chloride (0.310 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(difluoro(phenyl)methyl)phenyl)pyridin-2-amine (291 mg) in THF (dry) (10 ml) was added at 0° C. and the mixture was stirred at room temperature under a dry atmosphere with anhydrous calcium chloride tube for 2 hr. The mixture was quenched with water/THF then water at 0° C. and extracted with EtOAc/THF. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo. The residue was washed with IPE to give the title compound (49 mg) as a white solid.