Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:5]2.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:5]3)[CH2:27][CH2:26]1
Reactant: O=C1c2ccc(Br)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: CN1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN1CCN(c2ccc3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)CC1
Yield: 15.5 %

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.104 g, 0.27 mmol), 1-methyl piperazine (0.047 mL, 0.4 mmol), Pd2.dba3 (0.009 g, 0.01 mmol), BINAP (0.012 g, 0.02 mmol), and sodium tertiary-butoxide (0.040 g, 0.4 mmol) in toluene (3 mL) was heated to reflux for 3 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-(4-methyl-piperazin-1-yl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.017 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.36 (s, 3H), 2:58 (m, 4H), 3.32 (m, 4H), 4.20 (s, 2H), 4.76 (s, 2H), 6.83-7.32 (m, 6H), 7.73 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:9]([N:12]2[C:16]([CH3:17])=[N:15][N:14]=[N:13]2)C=O)=[CH:4][CH:3]=1.C1(P(=[CH:44][CH:45]=[O:46])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:47]1C=CC=CC=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]([N:12]2[C:16]([CH3:17])=[N:15][N:14]=[N:13]2)[CH:47]=[CH:44][CH:45]=[O:46])=[CH:19][CH:20]=1
Reactant: Cc1nnnn1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccccc1
Product: Cc1nnnn1C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 85 %

Procedure:
Following the general procedure of Example 7, 3.8 g (11.6 mmoles) of 3,3-bis(4-fluorophenyl)-2-(5-methyl-1H-tetrazol-1-yl)-2-propenal in 200 mL of dry benzene was treated with 3.8 g (12.5 mmoles) of triphenylphosphoranylidene acetaldehyde to produce 3.5 g (85%) of the title compound; m.p.=72°-78° C. (foam).
Reaction SMILES: Cl.C(C1C=CC2[NH:14][CH:13]([CH2:15]C(OC)=O)[C:12](=[O:20])N(C)CC=2C=1)(O)=O.O[N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:14][CH:13]([C:15]1[NH:24][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH2:12][OH:20]
Reactant: On1nnc2ccccc21
Reactant: COC(=O)CC1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(CO)c1nc2ccccc2[nH]1

Procedure:
HCl (Maekawa; Ohtani, Agric. Biol. Chem., 40, 1976, 791) and 0.88 g of methyl 7-carboxy-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate are dissolved in 30 ml of DMF and treated with 0.49 g of 1-hydroxybenzotriazole and 0.58 g of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide.hydrochloride and 1.55 g of diiso-propylethylamine.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:17])([F:16])[F:15])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27](Br)[CH3:28].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:15])([F:16])[F:17])[C:7]([C:18]([O:20][CH2:27][CH3:28])=[O:19])=[CH:6]2)[CH3:2]
Reactant: CCc1cc2c(cc1O)OC(C(F)(F)F)C(C(=O)O)=C2
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(CC)c(O)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a solution of 0.3 g (1.04 mmol) of 6-ethyl-7-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 5 mL of anhydrous dimethylformamide was added 255 mg (0.78 mmol) of cesium carbonate in one portion, followed by addition of 103 uL (1.7 mmol) of ethyl bromide. The reaction was stirred at room temperature overnight. The reaction was added to 100 mL of ethyl acetate. The organic phase was washed with brine three times, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified by silica chromatography with EtOAc/hexane (3:7) to afford 0.21 g (67%) of a light yellow solid: 1H NMR (CDCl3/400 MHz) 7.68(s, 1H), 7.00(s, 1H), 6.42(s, 1H), 5.63 (q, J=7.2 Hz, 1H), 5.38(s, 1H), 4.28(m, 2H), 2.54(q, J=7.2 Hz, 2H), 1.31(t, J=7.2 Hz, 3H), 1.20(t, J=7.6 Hz, 3H), MS (ESI+) 317 (M+1, 100).
Reaction SMILES: Br.[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:10]=2[CH2:9][O:8]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:25][N:3]([CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:16]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[NH:17])=[CH:15][C:10]=2[CH2:9][O:8]1
Reactant: C1COCCN1
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: Br
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C(=N)N3CCOCC3)ccc21
Temperature: 80 °C
Yield: 15 %

Procedure:
Using 400 mg of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile hydrobromide (citalopram HBr) and morpholine (1.5 equiv) gave, after heating at 80° C. for 28 h, title product (75 mg, 15% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:49]1([CH3:59])[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1>CCOCC>[C:49]1([CH3:59])[CH:54]=[CH:53][C:52]([S:55]([O:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:57])=[O:56])=[CH:51][CH:50]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC(CCCCCCCCCCCCOCc1ccccc1)CCCCCCCCCCCCOCc1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(CCCCCCCCCCCCOCc2ccccc2)CCCCCCCCCCCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.1 %

Procedure:
First, 3 g of bis(12-benzyloxydodecyl)methanol and 20 ml of pyridine were placed in a 100 ml flask. Then, 1.15 g of p-toluenesulfonylchloride was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ether. The diluted mixture was washed with diluted hydrochloric acid, aqueous sodium bicarbonate, and water in this order, and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was recrystallized from acetone to obtain 1.6 g of bis(12-benzyloxydodecyl)methyl p-toluenesulfonate (Y: 42%). The compound thus obtained had a purity of 98.5% by HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Reaction time: 0.75 h
Yield: 80.6 %

Procedure:
To a solution of tert-butyl 1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamate (3.27 g, 8.09 mmol) in CH2Cl2 (75 mL) was added TFA (50 mL). The reaction was complete after 45 minutes After evaporating the solvents in vacuo, the crude material was diluted with CH2Cl2 and neutralized by adding a 1 N aqueous NaOH solution. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford 2-(4-(4-aminopiperidin-1-yl)quinazolin-2-yl)phenol as a solid (2.09 g, 84%). LC/MS: m/z 321.3 (M+H)+ at 1.28 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.ClC1C(C2C=CC=CC=2)=NN=C2N(CC(NC)=O)N=C(C3C=CC=CC=3)C=12.[N+:54]([C:57]1[C:62]2=[N:63][O:64][N:65]=[C:61]2[C:60]([NH:66][CH2:67][CH2:68][CH2:69][NH2:70])=[CH:59][CH:58]=1)([O-:56])=[O:55]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([NH:70][CH2:69][CH2:68][CH2:67][NH:66][C:60]3[C:61]4[C:62](=[N:63][O:64][N:65]=4)[C:57]([N+:54]([O-:56])=[O:55])=[CH:58][CH:59]=3)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: NCCCNc1ccc([N+](=O)[O-])c2nonc12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CNC(=O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)NCCCNc1ccc([N+](=O)[O-])c2nonc12

Procedure:
Compound 6 was synthesised from 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid following a similar procedure outlined in Example 16 (Compound 5), using N1-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)propane-1,3-diamine instead of methylamine hydrochloride in the final step.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][CH:17]([O:20][CH3:21])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:28])[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][CH:17]([O:20][CH3:21])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COC1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: COC1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)C1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(3-methoxypyrrolidin-1-yl)quinolin-7-yl]ethanone (0.0445 g, 0.146 mmol) and ammonium acetate (0.112 g, 1.46 mmol) in methanol (0.8 mL) and acetonitrile (0.8 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.36 mL, 0.36 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The organic layers were combined, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C16H21ClN3O (M+H)+: m/z=306.1; Found: 306.1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.C([O-])(=O)C.[NH4+:18].[N+:19]([CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=O)([O-:21])=[O:20]>C(O)C>[N+:19]([CH:22]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([O:3][C:2]([F:13])([F:12])[F:1])[CH:5]=2)[NH:18][C:25](=[O:27])[CH2:24][CH2:23]1)([O-:21])=[O:20]
Reactant: [NH4+]
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: COC(=O)CCC[N+](=O)[O-]
Agent: CC(=O)[O-]
Solvent: CCO
Product: O=C1CCC([N+](=O)[O-])C(c2cccc(OC(F)(F)F)c2)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Under a nitrogen atmosphere, in a round-bottom flask were placed 15 g (79 mmol) of 3-trifluoromethoxybenzaldehyde, 80 mL of ethanol, 11 g (0.26 mol)of ammonium acetate and 12.6 mL (79 mmol) of methyl 4-nitrobutyrate, and the mixture was heated at reflux for 6 hours. After cooling to room temperature, the mixture was concentrated. The remaining material was stirred with ca. 200 mL of CHCl3 for 30 minutes, filtered and concentrated. The residue purified by flash column chromatography, elutingwith 1:49 methanol/chloroform followed by 1:19 methanol/chloroform to obtain 24 g of 5-nitro-6-(3-trifluoromethoxyphenyl)piperidin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11]1([CH:17]=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH:11]1([CH2:17][NH:5][CH2:4][C:3]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=2[F:1])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NCc1ccc(F)cc1F
Reactant: O=CC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Fc1ccc(CNCC2CCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.1 %

Procedure:
To a solution of 2,4-difluorobenzylamine (2.84 g, 20.0 mmol) and cyclohexanecarbaldehyde (2.60 mL, 20.0 mmol) in methanol (100 mL) were added acetic acid (4.6 mL, 80 mmol) and sodium cyanoborohydride (1.51 g, 24.0 mmol) and the solution was stirred at room temperature for three days. Water (10 mL) was added and the mixture was concentrated in vacuo. The residue was diluted with aqueous 1 M KOH (125 mL) and ethyl acetate (100 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×100 mL) and the combined organic phase was dried over Na2SO4 and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g Si/150 mL) with ethyl acetate (33-100% gradient) in heptane as the eluent yielded 2.40 g (50%) of white solids.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[SH:7].[H-].[Na+].Br[C:11]1[CH:12]=[C:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.O>CC(N(C)C)=O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:13]2[C:14]([C:17]#[N:18])=[N:15][CH:16]=[C:11]([S:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:12]=2)=[CH:25][CH:24]=1
Reactant: Sc1ccccn1
Reactant: N#Cc1ncc(Br)cc1Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1ncc(Sc2ccccn2)cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.6 %

Procedure:
To a solution of pyridine-2-thiol (2.5 g, 23 mmol) in DMA (25 mL) cooled to 0° C. was added NaH (0.90 g, 23 mmol) and the reaction stirred at ambient temperature for 20 min, followed by addition of the 5-bromo-3-(4-fluorophenoxy)picolinonitrile (6.6 g, 23 mmol) and stirring over night at ambient temperature. The reaction was poured into water (250 mL) and a solid formed. The solid was collected, washed with water, and dried in vacuo to yield 3-(4-fluorophenoxy)-5-(pyridin-2-ylthio)picolinonitrile (5 g, 16 mmol, 70%).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29](COCC[Si](C)(C)C)[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([F:17])[CH:9]=2)[CH2:5]1)#[N:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:73][C:74]([F:79])([F:78])[C@@H:75]([NH2:77])[CH3:76].FC(F)(F)C(O)=O>ClCCCl>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:77][C@@H:75]([CH3:76])[C:74]([F:79])([F:78])[F:73])=[O:13])=[C:10]([F:17])[CH:9]=2)[CH2:5]1)#[N:2]
Reactant: C[C@H](N)C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)c(F)c5)C4)c3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-fluorobenzoic acid (25 mg, 0.046 mmol) (Example 15, Step 2) and N,N-diisopropylethylamine (24 μL, 0.14 mmol) in 1,2-dichloroethane (0.5 mL) was added sequentially N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (26 mg, 0.068 mmol) and (2S)-1,1,1-trifluoropropan-2-amine (12 mg, 0.11 mmol). After stirring at ambient temperature for 1.5 h, trifluoroacetic acid (0.5 mL) was added to the reaction mixture and stirring was continued for 1 h. The volatiles were removed in-vacuo and the residue was azeotropically washed with acetonitrile (3×3 mL). The resulting residue was dissolved in methanol (1 mL) and to this was added ammonium hydroxide (0.1 mL) and ethylenediamine (0.020 mL) and the reaction mixture was stirred at ambient temperature for 1 hour. The crude reaction mixture was subjected to RP-HPLC to afford the desired product. LCMS (M+H)+: m/z=513.1. 1H NMR (500 MHz, DMSO-d6): δ 12.64 (s, 1H), 9.06 (s, 1H), 8.85 (s, 1H), 8.56 (s, 1H), 8.33 (dd, J=8.9, 1.8 Hz, 1H), 7.79 (s, 1H), 7.52 (t, J=8.5 Hz, 1H), 7.23 (s, 1H), 6.47 (s, 1H), 6.45-6.42 (m, 1H), 4.83-4.75 (m, 1H), 4.59 (dd, J=8.9, 1.7 Hz, 2H), 4.34 (d, J=8.9 Hz, 2H), 3.77 (s, 2H), 1.31 (d, J=7.1 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([S:10][C:11]1[CH:33]=[CH:32][CH:31]=[CH:30][C:12]=1[C:13]([NH:15][NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=1)=O)[CH3:9].[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl>[CH2:8]([S:10][C:11]1[CH:33]=[CH:32][CH:31]=[CH:30][C:12]=1[C:13]1[O:29][C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=2)=[N:16][N:15]=1)[CH3:9]
Reactant: CCCCCc1ccc(C(=O)NNC(=O)c2ccccc2SCC)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCc1ccc(-c2nnc(-c3ccccc3SCC)o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (735 μL, 5.28 mmol) was added to a stirring solution of 2-(ethylthio)-N′-(4-pentylbenzoyl)benzohydrazide (1-D) (326 mg, 0.88 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (448 mg, 2.64 mmol) in methylene chloride (10 mL). After stirring at room temperature for 18 h, the mixture was diluted with methylene chloride and washed with water, 1N HCl, 10% NaHCO3, brine, dried (MgSO4) and evaporated in vacuo. The oily residue was purified by preparative TLC (silica gel, hexane:ethyl acetate, 4:1) to provide 2-[2-(ethylthio)phenyl]-5-(4-pentylphenyl)-1,3,4-oxadiazole (1-E).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2Cl)=[O:4].[CH3:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH2:24]>ClCCCl.C(O)(C)(C)C.C(OCC)(=O)C>[Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:24][C:23]1[CH:25]=[CH:26][C:27]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:21]([CH3:20])[CH:22]=1)=[O:4]
Reactant: Cc1cc(N)ccc1Oc1ccccc1
Reactant: O=C(CCl)NCC#Cc1ccc2ncnc(Cl)c2c1
Solvent: ClCCCl
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ncnc3ccc(C#CCNC(=O)CCl)cc23)ccc1Oc1ccccc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of 2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide (50 mg; 0.17mmol) and 3-methyl-4-phenoxyaniline (36 mg; 0.9 equiv.) in 1,2-dichloroethane (1 ml) and t-butanol (1 ml) was heated at 87° C. for 30 minutes. The mixture was then cooled to room temperature and diluted with ethyl acetate to further facilitate precipitation. The solution was then filtered to give the coupled product as a yellow powder (73 mg; 90%). 2.28 (3H, s), 4.10 (2H, s), 4.30 (2H, s), 6.93 (3H, d), 7.09 (1H, t), 7.34 (2H, t), 7.50-7.53 (1H, dd, J=2.6, 6 Hz), 7.63 (1H, d, J=2.4 Hz), 7.78 (I H, d, J=8 Hz), 8.06-8.08 (1H, dd, J=1.4, 7.2 Hz), 8.68 (1H, d, J=1.2 Hz), 8.75 (1H, s). Irms(M+): 457.0, 4.59.1; (M−): 455.7, 419.6
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH2:21][CH2:22][C:23](O)=[O:24])[C:13]3=[O:26])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:39]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N12CCCN=C1CCCCC2.Cl>C1COCC1.O>[CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH2:21][CH2:22][C:23]([NH:48][S:45]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)(=[O:47])=[O:46])=[O:24])[C:13]3=[O:26])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1cccc2scc(Cn3c(=O)n(CCC(=O)O)c4ccccc43)c12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccc2scc(Cn3c(=O)n(CCC(=O)NS(=O)(=O)c4ccccc4)c4ccccc43)c12
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid (150 mg, 0.41 mmol) is dissolved in dry THF (3.0 mL) and 1,1′-carbonyl diimidazole (150 mg, 0.92 mmol) is added into it at room temperature. The mixture is stirred for 30 min and then it is heated at 55° C. for 1 hr. After the mixture is cooled down to room temperature, benzenesulfonamide (130 mg, 0.82 mmol) is added and after 10 min, 1,8-diazabicyclo[5,4,0]undec-7-ene (0.12 mL, 0.82 mmol) is added. The mixture is stirred for 5 hr at room temperature and then 1.0 M HCl (3 mL) is added followed by water (30 mL). The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC using 75% EtOAc in Hexanes affords 123 mg (60%) of N-{3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionyl}-benzenesulfonamide. LCMS (ESMS): m/z 506.18 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N+:10]([O-])=[CH:9][C:8]([O:12][C:13]2[C:18]3[CH:19]=[C:20]([CH3:22])[O:21][C:17]=3[CH:16]=[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:14]=2)=[CH:7][CH:6]=1)=[O:4]>C(O)(=O)C.[Fe]>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:10]=[CH:9][C:8]([O:12][C:13]2[C:18]3[CH:19]=[C:20]([CH3:22])[O:21][C:17]=3[CH:16]=[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:14]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CCOC(=O)c1cc(Oc2ccc(C(=O)N(C)C)[n+]([O-])c2)c2cc(C)oc2c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2cc(C)oc2c1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
To a stirred solution of ethyl 4-({6-[(dimethylamino)carbonyl]-1-oxidopyridin-3-yl}oxy)-2-methyl-1-benzofuran-6-carboxylate (176 mg, 0.457 mmol) in 15 mL of acetic acid, was added powdered Fe while keeping the temperature at 70° C. for 2 hrs. LC-MS showed that the reaction was complete. The reaction was cooled to room temperature, and the insoluble material was filtered. The mother liquor was diluted with EtOAc, washed with NaHCO3, brine, and dried over Na2SO4, and concentrated. The crude product was introduced into a silica gel column and eluted with MeOH/CHCl3 (2/98 to 5/95) to provide the product (135 mg, 85% yield) as colorless oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.40 (t, J=7.16 Hz, 3H) 2.47 (s, 3 H) 3.15 (d, 6 H) 4.39 (q, J=7.03 Hz, 2 H) 6.25 (s, 1 H) 7.30 (d, J=2.45 Hz, 1 H) 7.55-7.64 (m, 1 H) 7.64-7.76 (m, 1 H) 8.00 (s, 1 H) 8.38 (s, 1 H); LC-MS (ESI)+m/z=369.00 (M+H)+.