Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C@@H:10]([CH2:14][CH3:15])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C@H:17]([C:25]([O:27][CH3:28])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([CH2:8][CH2:9][C@@H:10]([CH2:14][CH3:15])[C:11]([NH:16][C@@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](CCC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Reaction time: 24 h
Yield: 83 %

Procedure:
Compound 4 (139 mg, 0.6 mmol) was dissolved in dry CH2Cl2 (6 mL) and treated with L-Phe-OMe.HCl (142 mg, 0.66 mmol), EDCI.HCl (138 mg, 0.72 mmol), DIEA (128 uL, 0.72 mmol). The reaction mixture was stirred for 24 h, diluted with EtOAc, acidified with 10% citric acid and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaHCO3 and brine, dried (MgSO4) and concentrated. The crude residue was purified via column chromatography eluting with EtOAc/hexane to afford pure product 5 (188 mg, 80%) as a white solid. An analytical sample was purified by recrystallization (hexanes/EtOAc): m.p. 119.5-121° C. TLC Rf=0.60 (EtOAc/hexanes, v/v, 1:1). 1H NMR (500 MHz, CDCl3) δ 7.32-7.23 (m, 3H), 7.17-7.15 (m, 2H), 6.36 (bd, J=6.6 Hz, 1H), 4.96-4.89 (m, 1H), 4.54 (bs, 1H), 3.72 (s, 3H), 3.18, 3.07 (AB of ABX, JAB=13.9 Hz, JAX=6.0 Hz, JBX=7.2 Hz, 2H), 3.00-2.84 (m, 2H), 2.08-1.98 (m, 1H), 1.73-1.49 (m, 3H), 1.44 (s, 9H), 1.47-1.36 (m, 1H), 0.85 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 175.23, 172.47, 156.43, 136.40, 129.38, 128.79, 127.28, 79.42, 53.16, 52.46, 46.46, 38.72, 38.18, 33.16, 28.61, 26.21, 12.04; HRMS m/z (ESI): calc. for C21H32N2O5Na [M+Na]+ 415.2204, found 415.2199. Optical rotation: [α]rtD +14.9 (c 1.06, CHCl3). In addition, N-Boc γ-lactam (7.6 mg, 6%) was isolated via column chromatography eluting with EtOAc/hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH:10]=[CH:11][N:12]([CH3:14])C)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.NC1[N:19]=[CH:20][NH:21][C:22]=1[C:23]([NH2:25])=[O:24]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:19]3[CH:20]=[N:21][C:22]([C:23]([NH2:25])=[O:24])=[C:14]3[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CN(C)C=CC(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c(-c3ccc(Cl)c(Cl)c3)ccnc12
Reaction time: 16 h
Yield: 49.6 %

Procedure:
A stirred mixture of 12.0 g of 3',4'-dichloro-3-dimethylaminoacrylophenone (prepared as described in Example 9) and 6.3 g of 4-amino-5-imidazolecarboxamide hydrochloride in 450 ml of glacial acetic acid was heated at reflux for 24 hours. The reaction mixture was allowed to stand at room temperature for 16 hours then the mixture was filtered and the crystals that were collected were washed with 300 ml of saturated sodium bicarbonate and then were washed with water. This material was dried, washed with hot methanol and filtered to give 5.9 g of the desired product as yellow crystals, mp 302°-304° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl>>[F:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][NH:11][CH2:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OC1(c2cccc(F)c2)CCCNC1
Agent: Cl
Product: Fc1cccc(C2=CCCNC2)c1
Yield: 96 %

Procedure:
A mixture of 3 parts of 3-(3-fluorophenyl)-3-piperidinol hydrochloride and 100 parts of a hydrochloric acid solution 6N was stirred and refluxed for 3 hours. The reaction mixture was evaporated. The residue was taken up in water and ammonium hydroxide. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated, yielding 2.2 parts (96%) of 5-(3-fluorophenyl)-1,2,3,6-tetrahydropyridine as a residue (intermediate 85).
Reaction SMILES: [NH2:1]C1C(N[C@H]2C[C@@H](CO)C=C2)=NC=NC=1Cl.Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[C@H:27]1[CH2:31][C@@H:30]([CH2:32][OH:33])[CH:29]=[CH:28]1.Cl>C(OC(OCC)OCC)C>[NH2:1][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[C@H:27]1[CH2:31][C@@H:30]([CH2:32][OH:33])[CH:29]=[CH:28]1
Reactant: OC[C@H]1C=C[C@@H](n2cnc3c(Cl)ncnc32)C1
Reactant: Nc1c(Cl)ncnc1N[C@@H]1C=C[C@H](CO)C1
Agent: Cl
Solvent: CCOC(OCC)OCC
Product: Nc1ncnc2c1ncn2[C@@H]1C=C[C@H](CO)C1

Procedure:
(1R,4S)-4-(6-Chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (1R,4S)-4-[(5-Amino-6-chloro-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol (from part d of this example, 9.63 g, 40.0 mmol), triethylorthoformate (150 mL), and concentrated hydrochloric acid (14 mL) were stirred for 3 hours. Volatiles were evaporated and the residual solid was partitioned between chloroform (300 mL) and saturated aqueous sodium carbonate (100 mL). The aqueous layer was extracted with chloroform (2×100 mL). The combined chloroform layers were dried (sodium sulfate). Volatiles were evaporated under reduced pressure and the residual yellow glass was chromatographed on silica gel. Elution with ethyl acetate gave title compound as white needles from ethyl acetate (7.45 g, 74%), m.p. 121-124° C.; 1H-NMR (DMSO-d6) δ: 8.81 (s, 1H), 8.64 (s, 1H), 6.24 and 6.21 (two m, 2H), 5.75 (m, 1H), 4.75 (t, J=5.4 Hz, 1H), 3.34 (m, 2H), 2.95 (m, 1H), 2.75 (m, 1H), 1.75 (m, 1H).
Reaction SMILES: [CH3:1][S:2](O[C@@H]1CCC[C@H]1OC1C=CC(Br)=CC=1)(=[O:4])=[O:3].[Br:19][C:20]1[N:25]=[CH:24][C:23]([O:26][C@@H:27]2[CH2:31][O:30][CH2:29][C@H:28]2[OH:32])=[CH:22][CH:21]=1>>[CH3:1][S:2]([O:32][C@H:28]1[C@H:27]([O:26][C:23]2[CH:24]=[N:25][C:20]([Br:19])=[CH:21][CH:22]=2)[CH2:31][O:30][CH2:29]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)O[C@@H]1CCC[C@H]1Oc1ccc(Br)cc1
Reactant: O[C@@H]1COC[C@H]1Oc1ccc(Br)nc1
Product: CS(=O)(=O)O[C@@H]1COC[C@H]1Oc1ccc(Br)nc1

Procedure:
The title compound of Step 2 was prepared according to the general procedure for the synthesis of trans-2-(4-bromophenoxy)cyclopentyl methanesulfonate in Example 5, except that trans-4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran-3-ol was used instead of trans-2-(4-bromophenoxy)cyclopentanol. The product was obtained as a solid. Yield: 5.95 g, 17.6 mmol, 87%. 1H NMR (400 MHz, CDCl3) δ 3.07 (s, 3H), 3.94 (br dd, J=10.5, 1.8 Hz, 1H), 4.00 (m, 1H), 4.11 (dd, J=11.1, 4.1 Hz, 1H), 4.18 (dd, J=10.6, 4.5 Hz, 1H), 4.97 (br d, J=4.4 Hz, 1H), 5.13 (br d, J=3.8 Hz, 1H), 7.19 (dd, J=8.7, 3.2 Hz, 1H), 7.35 (dd, J=8.7, 0.5 Hz, 1H), 8.04 (dd, J=3.2, 0.5 Hz, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Br:14])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][Br:14])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: BrCc1ccc(Cc2ccccc2)cc1
Yield: 52.5 %

Procedure:
4-Benzoylbenzyl bromide (2.75 grams, 10.0 mmole) and triethylsilane (2.33 grams, 20 mmole) in trifluoroacetic acid (4.56 grams, 40 mmole) were warmed to 60° C. for 18 hours. The cooled mixture was diluted with ethyl acetate (50 ml) and carefully washed with saturated sodium bicarbonate solution (2×50 ml). After drying with magnesium sulfate, the extract was filtered and concentrated. The residue was chromatographed (0.5:99.5 to 2:98--ethyl acetate:hexane) to give 1.37 grams (52%) of 4-benzylbenzyl bromide as a colorless oil.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][C:22]=1O.C(N(CC)CC)C>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][C:22]=1[O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9]
Reactant: COC(=O)Cc1ccc(O)c(F)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 65.5 %

Procedure:
Trifluoromethanesulphonic anhydride (2.67 mL, 16.29 mmol) was added dropwise to a stirred solution of methyl 2-(3-fluoro-4-hydroxyphenyl)acetate (2 g, 10.86 mmol) in DCM (47.1 mL) cooled to 0° C., over a period of 5 minutes under nitrogen. Triethylamine (4.54 mL, 32.58 mmol) was added dropwise over 5 minutes and the resulting solution stirred at rambient temperature for 4 hours under nitrogen. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with water (100 mL), saturated NaHCO3 (100 mL), and water (100 mL). The organic layer was dried by passing through a phase seperating cartridge and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(3-fluoro-4-(trifluoromethylsulfonyloxy)phenyl)acetate (2.250 g, 65.5%) as a straw yellow oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>C1COCC1.B.CSC>[F:15][C:12]([F:13])([F:14])[CH2:11][N:8]1[CH2:9][CH2:10][C:5]2([O:1][CH2:2][CH2:3][O:4]2)[CH2:6][CH2:7]1
Reactant: O=C(N1CCC2(CC1)OCCO2)C(F)(F)F
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: FC(F)(F)CN1CCC2(CC1)OCCO2
Yield: 100.8 %

Procedure:
In the solution of 1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2,2,2-trifluoroethanone (20 g, 83.7 mmol) in THF, borane-methyl sulfide complex (83.7 ml, 2M solution in THF) was added at 0° C. After refluxing the reaction mixture for 12 h, the reaction was cooled and quenched with MeOH. After removal of THF, the residue was extracted with ethyl acetate and washed with brine, dried with MgSO4 and concentrated to give 8-(2,2,2-trifluoroethyl)-1,4-dioxa-8-aza-spiro[4.5]decane (19 g) was obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([NH:13][C:14]([C:16]3[S:17][C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:19][CH:20]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([NH:13][C:14]([C:16]3[S:17][C:18]([C:21]4[CH:22]=[N+:23]([O-:36])[CH:24]=[CH:25][CH:26]=4)=[CH:19][CH:20]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(-c2cccnc2)s1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(-c2ccc[n+]([O-])c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a slurry of N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-5-(pyridin-3-yl)thiophene-2-carboxamide (Example 149, 30 mg, 0.079 mmol) in CH2Cl2 (0.5 mL) at rt was added m-CPBA (19 mg, 0.083 mmol) and the resulting slurry was stirred at rt for 30 min then at 35° C. for 4.5 h. The mixture was concentrated under vacuum and the resulting solid was slurried in MeOH (˜2 mL) and the solid was collected by vacuum filtration and rinsed with add'n MeOH (˜1 mL). The resulting solid was dried in the funnel then under vacuum overnight to afford 25 mg (80%) of an off-white solid as the title compound (Example 196). HPLC Ret. Time=2.34 min, LCMS [M+H]+ 394.10.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH2:23][CH3:24])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1)[CH3:2].[Br:25][CH2:26][C:27](Br)=[O:28].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:25][CH2:26][C:27]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:10]2[NH:15][C:14](=[O:16])[C:13]3=[C:17]([CH2:23][CH3:24])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]3[N:11]=2)[CH:6]=1)=[O:28]
Reactant: CCCc1nc(CC)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCc1nc(CC)c2c(=O)[nH]c(-c3cc(C(=O)CBr)ccc3OCC)nn12
Temperature: 25 °C

Procedure:
A solution, cooled to 0° C., of 1 g (3.1 mmol) of the compound from example 17A in 80 ml of CH2Cl2 was admixed dropwise with 1.2 g (6.1 mmol) of bromoacetyl bromide and a little at a time with 1.2 g (9.1 mmol) of AlCl3. The reaction mixture was warmed to room temperature (30 min.) and then heated at reflux for 2 h and carefully poured into ice-water. Following extraction with CH2Cl2, drying over MgSO4 and concentration under reduced pressure, the residue was triturated with ether. This gave 1.33 g (33% pure according to LC-MS) of the desired product which was reacted further without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.C(N(CC)CC)C.C(O[CH:20]=[C:21]([C:27](=O)[C:28]([F:31])([F:30])[F:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>C(#N)C>[CH2:25]([O:24][C:22]([C:21]1[CH:20]=[N:9][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=2)[C:27]=1[C:28]([F:29])([F:30])[F:31])=[O:23])[CH3:26]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Reactant: NNc1cccc(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(-c2cccc(Cl)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-chloro-6-hydrazinopyridine (5.00 g, 34.8 mmol) and triethylamine (4.85 mL, 34.8 mmol) in acetonitrile (174 mL) was added ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (6.77 mL, 34.8 mmol). After 20 min, the reaction mixture was placed in a 60° C. oil bath. After 30 min, the reaction mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexanes) gave the title compound: LCMS m/z 319.9 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.88 (t, J=7.5 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 4.38 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][CH2:10]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:24]1(B(O)O)[CH2:26][CH2:25]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[Cl:8][C:5]1[N:4]=[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][CH2:10]2)[C:2]([CH:24]2[CH2:26][CH2:25]2)=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(Cl)ncc2Br)CC1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CCN(c2nc(Cl)ncc2C2CC2)CC1
Temperature: 100 °C
Reaction time: 20 h
Yield: 128.4 %

Procedure:
A mixture of tert-butyl (1-(5-bromo-2-chloropyrimidin-4-yl)piperidin-4-yl)methylcarbamate (112 mg, 0.276 mmol), cyclopropylboronic acid (40 mg, 0.465 mmol), K3PO4 (200 mg, 0.943 mmol) and tricyclohexyl phosphine (20 mg, 0.071 mmol) in toluene (3 mL) and H2O (0.2 mL) was degassed with argon, then Pd(OAc)2 (10 mg, 0.044 mmol) was added. The mixture was stirred at 100° C. for 20 h. Water and EtOAc were added. The organic phase was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give tert-butyl (1-(2-chloro-5-cyclopropylpyrimidin-4-yl)piperidin-4-yl)methylcarbamate (130 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([NH:18][N:19]=[C:20]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)=[N:23][NH:22][C:21]2=[O:35])=[CH:8][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:42][CH2:43][CH2:44][NH:45][CH3:46]>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([C:24]2[C:20](=[N:19][NH:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:45]([CH2:44][CH2:43][OH:42])[CH3:46])=[CH:7][CH:8]=3)[C:21](=[O:35])[NH:22][N:23]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH3:32]
Reactant: COc1ccc(C2=NNC(=O)C2=NNc2ccc(OCCCBr)c(-c3ccccc3)c2)cc1OC
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(C2=NNC(=O)C2=NNc2ccc(OCCCN(C)CCO)c(-c3ccccc3)c2)cc1OC
Temperature: 50 °C

Procedure:
4-{[6-(3-Bromo-propoxy)-biphenyl-3-yl]-hydrazono}-5-(3,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one (s) and Cs2CO3 were dissolved in 1 mL (2-hydoxy)ethylmethyl amine and the resulting soultion was heated to 50° C. for one hour. The solvent was evaporated and the residue was purified by silica gel chromatography eluent: 10% methanol/DCM) to afford 15 mg 5-(3,4-dimethoxy-phenyl)-4-[(6-{3-[(2-hydroxy-ethyl)-methyl-amino]-propoxy}-biphenyl-3-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one (compound 120): HPLC (Rt): 5.525 minutes; m/e: 531.24, MS (ES+): 532.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:16])=[N:8][N:9]2[CH2:12][CH:13](O)[CH3:14])=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>ClCCl.O.CCOCC>[N:29]([CH:13]([CH3:14])[CH2:12][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[C:7]([CH3:16])=[N:8]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(C)nn(CC(C)O)c2c1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(C)nn(CC(C)N=[N+]=[N-])c2c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of the product from Step C (0.66 g, 3.0 mmol) in dichloromethane (10 ml) at 0° C. was added triethylamine (0.55 ml, 3.9 mmol) and methanesulfonyl chloride (0.31 ml, 3.9 mmol). After stirring for 30 min, ether (50 ml) and water (50 ml) were added. The organic layer was separated and the aqueous extracted with ether (2×50 ml). The combined ether extracts were washed with brine (30 ml), dried (MgSO4), and evaporated. The residue was taken up in DMF (6 ml) and sodium azide (0.26 g, 3.9 mmol) added. This mixture was heated at 70° C. for 12 h, poured into water, and extracted with ether (3×50 ml). The combined extracts were washed with brine, dried (MgSO4), and evaporated to a residue, which was purified by chromatography (silica, hexane to 10% ethyl acetate in hexane) to give an oil (0.51 g, 69%): MS (ES) m/z 246 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1)[C:13]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:28][CH:27]=1)=[C:12]2[CH3:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:41]([OH:44])[CH2:42][OH:43].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)CCC.[Cu](I)I>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:43][CH2:42][CH2:41][OH:44])=[CH:21][CH:20]=1)[C:13]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:28][CH:27]=1)=[C:12]2[CH3:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(I)cc2)c2ccc(OCc3ccccc3)cc12
Reactant: OCCO
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC#N
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCO)cc2)c2ccc(OCc3ccccc3)cc12
Temperature: 125 °C
Yield: 61.5 %

Procedure:
A mixture of 5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-1-(4-iodobenzyl)-3-methyl-1H-indole (1.01 g, 1.58 mmol), ethylene glycol (0.44 mL, 7.89 mmol), copper iodide (32 mg, 0.17 mmol), 1,10-phenanthroline (60 mg, 0.33 mmol), and potassium carbonate (436 mg, 3.15 mmol) in butyronitrile (3 mL) was degassed with three vacuum/N2 cycles. The reaction was heated at 125° C. for 26 hrs and upon completion, allowed to cool to room temperature. It was then diluted with water. The aqueous layer was extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with water (40 mL) and brine (40 mL), dried (MgSO4), filtered, concentrated and purified by silica gel chromatography (0%-40% ethyl acetate in hexanes) to give 554 mg of 2-(4-((5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethanol as a pale yellow foam. 1H NMR (400 MHz, DMSO-d6): δ 7.48 (d, 4H), 7.45-7.37 (m, 4H), 7.37-7.32 (m, 2H), 7.30 (d, 2H), 7.21 (d, 1H), 7.15-7.10 (m, 3H), 6.81 (dd, 1H), 6.74 (s, 4H), 5.20-5.10 (m, 6H), 4.81 (t, 1H), 3.87 (t, 2H), 3.64 (q, 2H), 2.16 (s, 3H). LCMS: 570.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:29][CH2:30][C:25]([OH:33])([C:16]4[CH:17]=[CH:18][C:19]5[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:15]=4)[CH2:26][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: OC1(c2ccc3ccccc3c2)CCN(CCCOc2cccc3[nH]ccc23)CC1

Procedure:
The title compound was prepared in similar fashion from 1-chloro-3-(1H-indole-4-oxy)propane and 4-(2-naphthyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 24% overall yield as a foam. FDMS m/e=400 (M+ of free base).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:2]=1[O:1][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])#[N:5]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1cc([N+](=O)[O-])ccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.9 %

Procedure:
To a stirred mixture of 2-hydroxy-4-nitrobenzonitrile (4 g, 24.37 mmol) and cesium carbonate (11.91 g, 36.6 mmol) in DMF (40 mL) was added tert-butyl 3-bromopropylcarbamate (8.71 g, 36.6 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was taken in ethyl acetate (250 mL), washed with brine (2×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo to give tert-butyl 3-(2-cyano-5-nitrophenoxy)propylcarbamate (5 g, 63.8%) as a yellow solid. LC-MS (M+H)+=321.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.89-7.87 (1H, m), 7.81 (1H, s), 7.75 (1H, d, J=8.4 Hz), 4.76 (1H, br s), 4.27-4.24 (2H, t, J=6.4 Hz), 3.40-3.36 (2H, q, J=6.4, 12.8 Hz), 2.15-2.09 (2H, m), 1.43 (9H, s).