Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CC(O)CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, rac-1-octyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 88 mg, 60%).
Reaction SMILES: [C:1]([C:9](=[CH:15]OCC)[C:10]([O:12]CC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([N:25]2[C:29]([NH2:30])=[CH:28][CH:27]=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C>[OH:12][C:10]1[C:9]([C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:8])=[CH:15][N:30]=[C:29]2[N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:26]=[CH:27][C:28]=12
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccccc1
Reactant: Nc1ccnn1-c1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1cnc2c(cnn2-c2ccccc2)c1O
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 42.5 %

Procedure:
A mixture of ethyl 2-benzoyl-3-ethoxyacrylate (0.99 g, 4.0 mmol) and 1-phenyl-1H-pyrazol-5-amine (0.64 g, 4.0 mmol) was stirred at 120° C. for 1.5 hr under argon and then cooled. After diphenyl ether (5 g) was added, the mixture was stirred at 240° C. for 2 hr under argon. Flash chromatography and crystallization in heptane and ethyl acetate mixture gave (4-hydroxy-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone (0.53 g, 1.7 mmol, 42% yield) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=4)=[N:15][N:14]4[CH2:24][CH2:25][CH2:26][C:13]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:27](C([Sn])=C(CCCC)CCCC)[CH2:28]CC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][C:19]1[N:18]=[C:17]([C:16]2[C:12]([C:6]3[C:5]4[C:10](=[CH:11][C:2]([CH:27]=[CH2:28])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[C:13]3[CH2:26][CH2:25][CH2:24][N:14]3[N:15]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cccc(-c2nn3c(c2-c2ccnc4cc(Br)ccc24)CCC3)n1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(-c3c(-c4cccc(C)n4)nn4c3CCC4)ccnc2c1
Temperature: 90 °C

Procedure:
Nitrogen is bubbled through a solution of 7-bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline (0.050 g, 0.14 mmol) and tributylvinyltin (0.079 mL, 0.22 mmol) in toluene (2.0 mL) for 20 min. Pd(PPh3)2Cl2 is added and nitrogen bubbled through the reaction mixture for another 10 min. The mixture is heated to 90° C. for 24 h, concentrated in vacuo, and the residue chromatographed on SiO2 (elute with 2% methanol in methylene choloride) to yield the title compound, 0.030 g (61%), as a yellowish solid.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[K+].[Br:15][C:16]1[C:17]2[C:18]3[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20](S)[C:19]=3[CH:26]=[CH:27][CH:28]=2>C(O)C>[Br:15][C:16]1[C:17]2[C:18]3[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[C:19]=3[CH:26]=[CH:27][CH:28]=2
Reactant: NCCCCn1ccnc1
Reactant: SC1=Nc2ccc(Br)c3cccc1c23
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Brc1ccc2c3c(cccc13)C(NCCCCn1ccnc1)=N2
Reaction time: 18 h

Procedure:
A mixture 4.2 g of 4-(1H-imidazol-1-yl)butanamine dihydrochloride in 75 ml of ethanol was treated with 2.2 g of potassium hydroxide and stirred for 18 hours. A 5.2 g portion of 6-bromo-benz[cd]indole-2-thiol and 6.4 g of mercuric acetate were added and the reaction proceeded as described in Example 1, giving 3.7 g of the desired product, mp 145°-147° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[I-].[Na+].CN(C=O)C.Cl[CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[N:26]([CH3:39])[N:27]=[C:28]2[C:37]=1[C:36]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:30]=[C:29]2[NH2:38]>O>[NH2:38][C:29]1[C:28]2=[N:27][N:26]([CH3:39])[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])=[C:37]2[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N:30]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc2c(N)nc3ccccc3c2c1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 70.2 %

Procedure:
Potassium phthalimide (4.90 mg, 26.4 mmol), sodium iodide (495 mg, 3.30 mmol), and DMF (22 mL) were added to 1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine (4.00 g, 13.2 mmol, prepared as described in Parts A-F of Examples 454-489), and the reaction was heated at 90° C. for two hours under a nitrogen atmosphere and allowed to cool to ambient temperature. Water (100 mL) was added and a precipitate formed and was isolated by filtration to yield 3.7 g of 2-[4-(4-amino-2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3(2H)-dione that was used in the next step.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[C:10]([C:14]1[CH:15]=[C:16]([NH2:35])[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:20]=2)[N:18]=1)([CH3:13])([CH3:12])[CH3:11]>>[Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](=[O:6])[NH:35][C:16]1[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:20]=2)[N:18]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:15]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1

Procedure:
The title compound was prepared starting from 2,2,2-trichloroethylchloroformate and Intermediate 4a by using an analogous procedure to that described for Example 3 step c. LCMS (Method 4): Rt 3.85, m/z 536 [MH+].
Reaction SMILES: [OH:1][CH:2]1[CH:8]([NH:9][C:10]([C@@H:12]([NH:17][C:18]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[CH:24]=2)=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:7][C:6]([CH3:30])([CH3:29])[CH2:5][N:4]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)(=[O:33])=[O:32])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[CH:8]([NH:9][C:10]([C@@H:12]([NH:17][C:18]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[CH:24]=2)=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:11])[CH2:7][C:6]([CH3:29])([CH3:30])[CH2:5][N:4]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)(=[O:32])=[O:33])[CH2:3]1
Reactant: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CC(C)(C)CN(S(=O)(=O)c2ccccn2)CC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CC(C)(C)CN(S(=O)(=O)c2ccccn2)CC1=O
Yield: 70.1 %

Procedure:
To a solution of benzofuran-2-carboxylic acid {(S)-1-[3-hydroxy-6,6-dimethyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide from Example 92i (100 mg, 0.18 mmol) in 2 ml CH2Cl2, was added Dess-Martin reagent (76 mg, 0.18 mmol) at r.t. The solution was stirred for 2 h when 20 ml CH2Cl2 was added and then washed with NaHCO3 and brine. Purification by column chromatograghy (50% ethyl acetate in hexane) gave 70 mg of the title compound in 70% yield. MS (M+H+): 555.4; 1H-NMR (400 MHz, CDCl3): •8.68-8.67(d, 1H), 7.97-7.93(m, 2H), 7.69-7.28(m, 6H), 7.32-6.92(m, 2H), 5.24(m, 1H), 4.79-4.69(m, 2H), 3.80-3.71(m, 2H), 2.54-2.50(d, 1H), 1.92-1.76(m, 4H), 1.45-1.40(m, 4H), 1.01-0.91(m, 9H).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]1[CH:24]([NH:26][C:27]1[N:32]=[C:31]([N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=[CH:34]2)[CH:30]=[CH:29][N:28]=1)[CH3:25])=O)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:9][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]1[CH:24]([NH:26][C:27]1[N:32]=[C:31]([N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=[CH:34]2)[CH:30]=[CH:29][N:28]=1)[CH3:25]
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CNCCN1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.8 %

Procedure:
A solution of 2-[1-(1-(benzyloxycarbonyl)-4-(tert-butyloxycarbonyl)-piperazin-2-yl)-ethylamino]-4-(benzimidazol-1-yl)-pyrimidine (EXAMPLE 14, Step E; 30 mg) in 3 mL of MeOH was stirred over Pd(OH)2/C (30 mg) under an H2 atmosphere (balloon) for 4 h, then filtered through Celite®, washing liberally with MeOH, and concentrated. The residue was dissolved in 1 mL of MeOH and NaBH3CN (6.8 mg) and 37% aqueous formaldehyde (26 μL) were added and the mixture was stirred for 5 h at room temperature, then diluted with 5 mL of EtOAc and poured into 10 mL of water. The phases were separated and the aqueous phase was extracted with 2×5 mL of EtOAc. The aqueous phase was basified (pH>10) by addition of 5N NaOH, then extracted with 5×5 mL of EtOAc. The combined organic extracts were washed with 5 mL of brine, dried over Na2SO4, and concentrated. The residue (16 mg) was dissolved in 1 mL of CH2Cl2 and 0.5 mL of trifluoroacetic acid was added. The mixture was stirred for 1 h at room temperature, then poured into 10 mL of water and extracted with 2×5 mL of CH2Cl2. The aqueous phase was basified (pH>10) by addition of 5N NaOH, then extracted with 4×5 mL of EtOAc. The combined organic extracts were washed with 5 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 9:1 CH2Cl2—2M NH3 in MeOH to provide 9.4 mg of the title compound. Mass spectrum (ESI) 338.3 (M+1).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:17])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8]1.[C:18](=[O:20])=[O:19].C(OCC)C>CCCCCC.C(OCC)C>[CH3:6][C:7]1([CH3:17])[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([C:18]([OH:20])=[O:19])[CH:11]=[CH:12][CH:13]=2)[O:8]1
Reactant: O=C=O
Reactant: CC1(C)CCc2ccccc2O1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)CCc2cccc(C(=O)O)c2O1
Temperature: 0 °C

Procedure:
To a solution of 1.6M n-butyllithium in hexane and 150 ml of diethyl ether were added a solution of 27 g of 2,2-dimethylchroman in diethyl ether over a one hour period at room temperature. The solution was then heated at reflux 160 minutes, cooled, and poured into dry ice/diethyl ether. The mixture was allowed to come to room temperature, poured into ice water, and layers separated. The organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo to provide 21 g of solid. The aqueous layer was acidified and the resulting precipitate extracted into diethyl ether/ethyl acetate. The organic extract was washed with water, dried over sodium sulfate, and concentrated in vacuo to provide 9 g of solid. The two isolated solids were combined and chromatographed over silica gel eluting with 10% ethyl acetate in toluene. The appropriate fractions were combined and concentrated in vacuo to provide 9.8 g of the desired title intermediate, m.p. 90°-92° C.
Reaction SMILES: [F:1][C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:15]C([O-])(C)C.[K+].CI>CN(C)C(=O)C>[F:1][C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]2[N:6]([CH3:15])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1cc2c(cc1F)OCC(=O)N2
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: CN1C(=O)COc2cc(F)c(C#N)cc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonitrile (CAS Reg. No. [151982-49-9], 4.71 g) in N,N-dimethylacetamide (108 ml) were added KOtBu (3.08 g) and methyl iodide (3.83 g). The mixture was stirred at room temperature for 3.5 h. Ice water was added. The suspension was filtered and the solid was washed with water and dried to give the title compound (4.07 g) as an off-white solid.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([CH2:15][N+:16]([O-:18])=[O:17])(=[O:14])=[O:13])=[C:7]([CH3:19])[CH:6]=1)(=O)C.Cl.O>C(O)C>[NH2:4][C:5]1[CH:6]=[C:7]([CH3:19])[C:8]([S:12]([CH2:15][N+:16]([O-:18])=[O:17])(=[O:14])=[O:13])=[C:9]([CH3:11])[CH:10]=1
Reactant: CC(=O)Nc1cc(C)c(S(=O)(=O)C[N+](=O)[O-])c(C)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 73 %

Procedure:
(4-Acetamido-2,6-dimethylphenylsulfonyl)nitromethane (11.5 g, 40 mM) is added in one portion to a boiling mixture of concentrated hydrochloric acid (22 mL), water (110 mL) and ethanol (45 mL). The mixture is stirred at reflux until a clear solution is formed (about 20 minutes) and then for a further 10 mins. The hot reaction mixture is then poured into an excess of ice-cold saturated sodium bicarbonate solution. The aqueous mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (MgSO4) and the solvent removed by evaporation to give (4-amino-2,6-dimethylphenylsulfonyl)nitromethane, as a solid, m.p. 132°-133° C. [after recrystallisation from ethanol] in 73% yield; NMR(d6 -DMSO, 200 MHz): 2.39(6H, s), 6.19(4H, s), 6.35(2H, s); microanalysis, found: C,44.5; H,4.9; N,11.6%; C9H12N2O4S requires: C,44.3; H,4.9; N,11.5%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18]>ClC1C=CC=CC=1>[F:13][C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=1[NH:1][C:17](=[O:18])[CH2:16][O:15][CH3:14]
Reactant: COCC(=O)Cl
Reactant: CCOC(=O)c1ccc(F)c(N)c1
Solvent: Clc1ccccc1
Product: CCOC(=O)c1ccc(F)c(NC(=O)COC)c1

Procedure:
A solution of 2.8 g (15.3 mmol) of ethyl 3-amino-4-fluorobenzoate (cf L. S. Fosdick and A. F. Dodds in J. Amer. Chem. Soc. 65, 2305 (1943)) and 1.56 mL (1.85 g=17.0 mmol) of methoxyacetylchloride in 50 mL chlorobenzene was stirred for 1 hour at 50° C. and then refluxed for 15 minutes. Then the solvent was distilled off in vacuo and the crude product obtained was purified by flash chromatography (silica gel; dichloromethane/ethanol=100:1). The desired compound, initially oily, solidified within a few days. Yield: 3.8 g (98% of theory); Rf value: 0.38 (silica gel; dichloromethane/ethanol=19:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][CH2:13][NH:14][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:18]2[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=2)=[CH:28][CH:27]=1
Reactant: NCCc1c[nH]c2cc(Cl)c(Cl)cc12
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2cc(Cl)c(Cl)cc12)c1ccc(Cc2cccc(F)c2)cc1
Yield: 14.6 %

Procedure:
N-(2-(5,6-Dichloro-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide was prepared according to Method A starting from 2-(5,6-dichloro-1H-indol-3-yl)ethanamine (0.149 g; 0.651 mmol), 4-(3-fluorobenzyl)benzoic acid intermediate (0.150 g, 0.651 mmol), HATU (0.248 g; 0.651 mmol) and N,N-diisopropylethylamine (0.281 mL; 1.63 mmol) in DMF (5 mL). Flash chromatography (twice) on silica gel (eluent 2 to 60% ethyl acetate in heptane and 1 to 10% ethyl acetate in dichloromethane) furnished 0.042 g (14%) of the title compound as a white solid.
Reaction SMILES: C(S)C.[H-].[Na+].[OH:6][C:7]1[C:12]2[C:13]([CH3:25])=[C:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)[O:15][C:11]=2[CH:10]=[CH:9][C:8]=1[CH2:26][CH2:27][CH3:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[OH:6][C:7]1[C:12]2[C:13]([CH3:25])=[C:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[O:15][C:11]=2[CH:10]=[CH:9][C:8]=1[CH2:26][CH2:27][CH3:28]
Reactant: CCCc1ccc2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CCCc1ccc2oc(Cc3ccc(O)cc3)c(C)c2c1O
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
Under nitrogen atmosphere, ethanethiol (4.9 g; 80 mmoles) was added dropwise over 5 minutes to a mixture of 99% sodium hydride (1.9 g; 80 mmoles) in dimethylformamide (100 ml). After stirring for 15 minutes, a solution of 4-hydroxy-2-(4-methoxybenzyl)-3-methyl-5-propylbenzofuran (2.4 g; 8 mmoles) in dimethylformamide (5 ml) was added in one portion. The mixture was refluxed for 2 hours, cooled, acidified with 20% citric acid solution and extracted with ether. The ether solution was washed with water, dried (Na2SO4), filtered, concentrated, and chromatographed to obtain 2.2 g of the title compound as an oil which crystallized from an ether-hexane mixture.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28](O)=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]1([CH2:40][S:41]([NH2:44])(=[O:43])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH2:40]([S:41]([NH:44][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([CH2:24][C@@H:19]2[CH2:20][CH2:21][CH2:22][CH:23]=[C:18]2[C:9]2[O:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:26]=1)(=[O:42])=[O:43])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: NS(=O)(=O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NS(=O)(=O)Cc1ccccc1)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
To a mixture of 3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (250 mg, 0.575 mmol) and α-toluenesulfonamide (98 mg, 0.575 mmol) in DMF (6 ml) was added 4-dimethylaminopyridine (105 mg, 0.863 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (220 mg, 1.15 mmol). After stirring the resulting mixture at room temperature for 16 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with 1N-hydrochloric acid, water and brine successively, dried over dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 1:1 elution) to give N-benzylsulfonyl-3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzamide (216.4 mg, 64%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[C:11]2[N:12]([CH3:17])[O:13][C:14](=[O:16])[N:15]=2)[N:6]=1.N1C=CC=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1>ClCCl>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](\[C:11]3[N:12]([CH3:17])[O:13][C:14](=[O:16])[N:15]=3)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:6]=2)=[O:39])=[CH:33][CH:32]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Cn1oc(=O)nc1/C(=N\OCc1csc(N)n1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1oc(=O)nc1/C(=N\OCc1csc(NC(=O)Cc2ccc(Cl)cc2)n1)c1ccccc1
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (300 mg, 0.905 mmol, 1 eq.) and pyridine (0.110 ml, 1.36 mmol, 1.5 eq) in dry dichloromethane (4.0 ml) at room temperature was added 4-chlorophenyl acetyl chloride (0.20 mL, 1.36 mmol, 1.5 eq) and stirring was allowed for 2 h. The reaction was quenched by addition of 2 ml of 1N NaOH. The layers were separated and the organic layer was dried over MgSO4. After concentration, the residue was purified by chromatography on silica gel to give 2-(4-chlorophenyl)-N-{4-[({[(Z)-(2-methyl-5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-yl}acetamide (365 mg, 79% yield).
Reaction SMILES: [F:1][CH2:2][C@H:3]([N:11]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.NN.C(O)C>[F:1][CH2:2][C@H:3]([NH2:11])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H](CF)Cc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: N[C@@H](CF)Cc1ccccc1
Temperature: 25 °C
Yield: 21.3 %

Procedure:
A mixture of (R)-2-(1-fluoromethyl-2-phenylethyl)isoindol-1,3-dione (52 mg) and hydrazine hydrate (two drops) and ethanol (1 mL) was heated to reflux for 2 hours. The reaction solution was allowed to be cooled to room temperature, and the deposited crystal was separated by filtration and concentrated under reduced pressure. The residue was purified by LC-MS and 6.0 mg of the title compound was obtained.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:26])[C:24]#[N:25])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:27]=[N+:28]=[N-:29].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([C:24]3[NH:29][N:28]=[N:27][N:25]=3)[CH3:26])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C#N)CCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1nnn[nH]1
Yield: 68.2 %

Procedure:
3 g of (RS)-7(4,5-diphenyl-2-oxazolyl)-2-methylheptanenitrile in 30 cm3 of dimethylformamide are treated with twice 1.7 g of sodium azide and twice 3.6 g of triethylamine hydrochloride under the (time and temperature) conditions defined in Example 1. After treatment, the product of the reaction is chromatographed on a column 2 cm in diameter containing 78 g of silica gel (50 to 200μ). The column is eluted, collecting 200 cm3 fractions, with 1 liter of diisopropyl ether and then with 1.6 liters of a diisopropyl ether/ethyl acetate (95:5 by volume) mixture. The fractions from the last eluent mixture are concentrated to dryness under reduced pressure (0.2 kPa). 2.3 g (68%) of (RS)-5-[7-(4,5-diphenyl-2-oxazolyl)-2-heptyl]-1H-tetrazole are obtained in the form of a yellowish oil.