Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[CH3:17][CH:18]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[NH:21]1)[CH3:19].[Li]CCCC>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH:18]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:6](=[O:8])[CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:10])[F:9])([CH3:19])[CH3:17]
Reactant: O=C(O)CCCC(F)(F)F
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)[C@H]1COC(=O)N1C(=O)CCCC(F)(F)F
Temperature: 0 °C

Procedure:
To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 min. The solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give a pale yellow oil. To a separate flask, charged with a solution of (4S)-4-(propan-2-yl)-1,3-oxazolidin-2-one (4.18 g, 32.4 mmol) in THF (100 mL) at −78° C. was added n-BuLi (13.0 mL, 32.5 mmol, 2.5M in hexane) dropwise via syringe over 5 min. After stirring for 10 min, the above acid chloride, dissolved in THF (20 mL), was added via cannula over 15 min. The reaction mixture was warmed to 0° C. and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was then added saturated NH4Cl, and it was then extracted with EtOAc (2×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (hexanes/EtOAc) to provide Intermediate S-1G (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.44 (1H, dt, J=8.31, 3.53 Hz), 4.30 (1H, t, J=8.69 Hz), 4.23 (1H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2H, m), 2.32-2.44 (1H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2H, m), 1.88-2.00 (2H, m), 0.93 (3H, d, J=7.05 Hz), 0.88 (3H, d, J=6.80 Hz).
Reaction SMILES: N[C:2]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([N:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:7])=O.N([O-])=[O:22].[Na+]>C(O)C.Cl.O1CCCC1.O>[N+:18]([C:16]1[CH:17]=[C:4]2[C:3]([C:2](=[O:22])[NH:7][N:6]2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:14][CH:15]=1)([O-:20])=[O:19]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)N(N)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]n(-c2ccccc2)c2cc([N+](=O)[O-])ccc12
Temperature: 72 °C
Reaction time: 0.67 h

Procedure:
Into a 1000-mL 4-necked round-bottom flask, was placed a solution of 2-amino-4-nitro-N-phenylbenzohydrazide (23 g, 84.56 mmol, 1.00 equiv) in ethanol (250 mL), 1N hydrogen chloride (250 mL), tetrahydrofuran (100 mL). To the resulting mixture was then added a solution of NaNO2 (17.5 g, 253.62 mmol, 3.00 equiv) in water (45 mL) dropwise with stirring at 72° C. in 40 min. The resulting solution was heated to reflux for 1 hr. The resulting mixture was then cooled to 25° C. The solids were collected by filtration to yield 6-nitro-1-phenyl-1,2-dihydroindazol-3-one as a brown solid. MS: 256 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C:18]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:19]([NH:21][OH:22])=[O:20])[C:12](=[O:28])[CH:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[CH3:30][O:31][NH2:32].C([O-])(=O)C.[Na+]>C(O)C>[OH:22][NH:21][C:19](=[O:20])[C:18]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:17][CH2:16][N:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4](/[C:1](=[N:32]/[O:31][CH3:30])/[CH3:2])=[CH:5][CH:6]=2)=[CH:11][C:12]1=[O:28]
Reactant: CC(=O)c1ccc(-c2ccn(CCC(C)(C(=O)NO)S(C)(=O)=O)c(=O)c2)cc1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CO/N=C(\C)c1ccc(-c2ccn(CCC(C)(C(=O)NO)S(C)(=O)=O)c(=O)c2)cc1
Temperature: 70 °C
Reaction time: 0.13 h
Yield: 80.7 %

Procedure:
A suspension of 4-[4-(4-acetylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (105 mg, 0.258 mmol), O-methylhydroxylamine hydrochloride (86.2 mg, 1.03 mmol) and sodium acetate (107 mg, 1.03 mmol) in ethanol (10 mL, 0.025M) was heated in an oil bath at 70° C. for 3 hours. The volatiles were removed by rotary evaporation. The remaining material was redissolved in 1.5 mL DMSO and run on Shimadzu HPLC 30×100 mm reverse phase column. The material was eluted with 20-35% acetonitrile in water with 0.1% ammonium hydroxide modifier. The gradient was run for 8 min then held at 35% for an additional two minutes. The desired material eluted at about 30% acetonitrile. This solution was concentrated down by rotary evaporation yielding 90.7 mg (80.7%) of the title compound a white solid. LC/MS m/z 436 (M+1). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.57 (s, 3H) 2.13-2.21 (m, 1H) 2.21 (s, 3H) 2.39-2.48 (m, 1H) 3.11 (s, 3H) 3.70-3.81 (m, 1H) 3.94 (s, 3H) 4.12 (td, J=11.90, 5.00 Hz, 1H) 6.68 (dd, J=7.20, 1.83 Hz, 1H) 6.75 (d, J=1.95 Hz, 1H) 7.71-7.82 (m, 5H) 9.27 (br. s., 1H) 11.14 (br. s., 1H)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10](Br)=[C:9]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[C:34]2[C:29](=[CH:30][C:31](B(O)O)=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([C:31]2[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=2)[NH:26][CH:27]=[CH:28]3)=[C:9]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)c1c(Br)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccc3[nH]ccc3c2)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1

Procedure:
Ethyl 1-benzyl-5-nitro-1H,1′H-3,5′-biindole-2-carboxylate was prepared from ethyl 1-benzyl-3-bromo-5-nitro-1H-indole-2-carboxylate and indole-5-boronic acid followed the procedure of Example 17 Step 2 as a yellowish solid: 1H NMR (DMSO-d6) δ 0.90 (t, J=7.1 Hz, 3H, 4.10 (q, J=7.1 Hz, 2H, 5.89 (s, 2H, 6.52 (t, J=1.1 Hz, 1H, 7.11 (d, J=8.4 Hz, 2H, 7.20 (dd, J=8.3, 1.7 Hz, 1H, 7.22-7.35 (m, 3H, 7.42 (t, J=2.7 Hz, 1H, 7.52 (d, J=8.4 Hz, 1H, 7.66 (s, 1H, 7.90 (d, J=9.3 Hz, 1H, 8.21 (dd, J=9.2, 2.2 Hz, 1H, 8.40 (d, J=2.2 Hz, 1H, 11.23 (s, 1H; MS (ESI) m/z 440 (MH+); MS (ESI) m/z 438 [M-H]−; HRMS calcd for C26H22N3O4: 440.1608; found (ESI+): 440.1596; Anal. calcd for C26H21N3O4.0.25H2O: C, 70.34; H, 4.88; N, 9.47. Found: C, 70.23; H, 4.89; N, 9.58.
Reaction SMILES: Br[CH:2]1[C:7](=O)[CH2:6][CH2:5][CH2:4][CH:3]1[C:9]([O:11][CH3:12])=[O:10].[NH2:13][C:14]([NH2:16])=[S:15]>CCO>[NH2:16][C:14]1[S:15][C:2]2[CH:3]([C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:5][CH2:6][C:7]=2[N:13]=1
Reactant: COC(=O)C1CCCC(=O)C1Br
Reactant: NC(N)=S
Solvent: CCO
Product: COC(=O)C1CCCc2nc(N)sc21

Procedure:
A soln. of methyl 2-bromo-3-oxocyclohexanecarboxylate (1.00 g, 4.25 mmol) and thiourea (0.36 g, 4.68 mmol) in EtOH (16 mL) was stirred at 70° C. overnight. Subsequently, the mixture was quenched with aq. sat. NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. Purification by means of CC (0-1% MeOH/DCM) provided a yellow solid.
Reaction SMILES: C(Br)Br.C1(C2C=CC=CC=2O)C=CC=CC=1.C([Si](CC)(CC)C1C2OC3C=CC=CC=3C=2C=CC=1)C.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:40]=1[OH:51].COC1C=C(C2C=CC=CC=2O)C=CC=1>>[CH3:37][O:38][C:39]1[C:40]2[O:51][C:50]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[C:41]=2[CH:42]=[CH:43][CH:44]=1
Reactant: COc1cccc(-c2ccccc2)c1O
Agent: CC[Si](CC)(CC)c1cccc2c1oc1ccccc12
Agent: COc1cccc(-c2ccccc2O)c1
Agent: Oc1ccccc1-c1ccccc1
Solvent: BrCBr
Product: COc1cccc2c1oc1ccccc12

Procedure:
The reaction was conducted according to the General Procedure by heating 4-MeO-dibenzofuran (8, 89 mg, 0.5 mmol, 1 equiv.), KOt-Bu (112 mg, 1 mmol, 2 equiv.) and Et3SiH (401 microliters, 2.5 mmol, 5 equiv.) in 2 ml of toluene for 20 hours at 100° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica using hexanes and hexanes-ether to recover unconsumed starting material 8 (3 mg, 0.015 mmol, 3%) and isolate dibenzofuran (1, 8.4 mg, 0.05 mmol, 10%; since fractions of 1 contained small amounts of starting 8, quantification was done by 1H-NMR with CH2Br2 as an internal standard), 1,1′-biphenyl-2-ol (2, 4.3 mg, 0.025 mmol, 5%), 4-Et3Si-dibenzofuran (3, 11 mg, 0.039 mmol, 8%), 2-methoxy-6-phenyl-phenol (9, mg, 0.025 mmol, 5%), 2-(3′-methoxyphenyl)phenol (10, 47 mg, 0.235 mmol, 47%). Note: only compounds with the yield exceeding 2% were characterized. 1H and 13C NMR spectral assignments of 9 and 10 were consistent with literature reports.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:31]([NH:33][NH2:34])=[O:32])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:35](N1C=CN=C1)(N1C=CN=C1)=[O:36].C(=O)(O)[O-].[Na+].O>O1CCCC1>[C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:31]4[O:32][C:35](=[O:36])[NH:34][N:33]=4)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)(C(=O)NN)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)(c2n[nH]c(=O)o2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 378 mg of tert-butyl 4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)-4-(hydrazinocarbonyl)piperidine-1-carboxylate in 10 ml of tetrahydrofuran was added 130 mg of 1,1′-carbonyldiimidazole at room temperature. After stirring at room temperature for 3 hours, 100 mg of 1,1′-carbonyldiimidazole was added at room temperature, followed by stirring at room temperature for 5 days. To the reaction mixture was added 10 ml of saturated aqueous sodium bicarbonate solution, followed by stirring the reaction mixture at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1−1/2) to give the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)#[N:2].Br[C:19]1[CH:20]=[C:21]([C:26]2([C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)[C:34]3[C:29](=[C:30]([F:35])[CH:31]=[CH:32][CH:33]=3)[C:28]([NH2:36])=[N:27]2)[CH:22]=[CH:23][C:24]=1[F:25].C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[NH2:36][C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:26]([C:21]2[CH:20]=[CH:19][C:24]([F:25])=[C:23]([C:7]3[CH:6]=[N:5][CH:4]=[C:3]([CH:8]=3)[C:1]#[N:2])[CH:22]=2)([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[N:27]=1
Reactant: NC1=NC(c2ccncc2)(c2ccc(F)c(Br)c2)c2cccc(F)c21
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1cncc(-c2cc(C3(c4ccncc4)N=C(N)c4c(F)cccc43)ccc2F)c1
Yield: 8.1 %

Procedure:
3-Cyanopyridine-5-boronic acid pinacol ester (58.1 mg, 0.25 mmol), 1-(3-bromo-4-fluorophenyl)-4-fluoro-1-(pyridin-4-yl)-1H-isoindol-3-amine (67.4 mg, 0.17 mmol), [1,1′-bis (diphenylphosphino)ferrocene]palladium(II) chloride (6.88 mg, 8.42 μmol), 2 M aqueous potassium carbonate (0.253 mL, 0.51 mmol) and DMF (2.00 mL) were put in a microwave vial and irradiated in a microwave oven at 110° C. for 20 min. Additional 3-cyanopyridine-5-boronic acid pinacol ester (25.2 mg, 0.11 mmol) and [1,1′-bis (diphenylphosphino)ferrocene]palladium(II) chloride (6.88 mg, 8.42 μmol) were added and the resulting mixture was irradiated at 110° C. for 30 min. Additional 3-cyanopyridine-5-boronic acid pinacol ester (25.2 mg, 0.11 mmol) and [1,1′-bis (diphenylphosphino)ferrocene]palladium(II) chloride (6.88 mg, 8.42 μmol) were added and the resulting mixture was irradiated at 110° C. for 30 min. The product was purified by preparative HPLC. The desired fractions were pooled and concentrated in vacuo. The residue was partitioned between water and ethyl acetate (×3). The organic layer was collected, dried (Na2SO4), filtered and concentrated in vacuo. The residue was redissolved in methanol and concentrated in vacuo three times to give the title compound 5.80 mg, (7.4% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C@@H:15]([NH2:17])[CH3:16])[C:6]=2[N:18]=1.C1CCC([N:28]=[C:29]=[N:30]C2CCCCC2)CC1.C(OC(NC(NC(OC(C)(C)C)=O)=S)=O)(C)(C)C.C(O)C(N)(CO)CO>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C@@H:15]([NH:17][C:29]([NH2:30])=[NH:28])[CH3:16])[C:6]=2[N:18]=1
Reactant: C[C@H](N)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Product: C[C@@H](Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21)NC(=N)N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
To a solution of 2-amino-9-[(2S)-2-aminopropyl]-9H-pyrido[2,3-b]indole-3-carboxamide (30, 100 mg, 0.350 mmol) in methylene chloride (3 mL) was added PL-DCC resin (394 mg, 0.575 mmol) and the mixture was stirred at room temperature for 15 min. N,N′-bis-tert-butoxycarbonylthiourea (112 mg, 0.406 mmol) was added and the reaction mixture was stirred at room temperature overnight. PS-trisamine resin (4.12 g, 3.6 mmol/g, 14.8 mmol) was subsequently added and the resulting mixture was stirred at room temperature overnight. The resins were removed by suction filtration and the filtrate was concentrated under reduced pressure. Purification of the crude material by reverse phase C-18 silica gel chromatography [0-70% acetonitrile in water (containing 0.1% TFA)] afforded 2-amino-9-((2S)-2-{[amino(imino)methyl]amino}propyl)-9H-pyrido[2,3-b]indole-3-carboxamide (71, 48 mg 26%). NH4OAc standard conditions. DAD Retention time =4.98 min. M+H=326.
Reaction SMILES: C[Li].[CH3:3][C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1.CN(C)P(N(C)C)(N(C)C)=O.[C:22]([C:27]#N)(=[O:26])[O:23][CH2:24][CH3:25]>CCOCC.[Cu]I.O>[OH:10][C:6]1[CH2:7][CH2:8][CH2:9][C:4]([CH3:5])([CH3:3])[C:27]=1[C:22]([O:23][CH2:24][CH3:25])=[O:26]
Reactant: CC1=CC(=O)CCC1
Reactant: CCOC(=O)C#N
Agent: [Cu]I
Agent: [Li]C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1=C(O)CCCC1(C)C
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Into a 500 mL flame dried round-bottomed flask was added copper(I) iodide (18 g) in ether (200 mL) to give a suspension. After cooling to −5° C., methyllithium (120 mL, 1.6M in ether) was added dropwise. After stirring at −5° C. for 1 hour, 3-methylcyclohex-2-enone (5.15 mL) in 15 ml ether was added dropwise, and the mixture was stirred at −5° C. for 1 hour. After cooling to −78° C., hexamethylphosphoramide (60 mL) was added dropwise. Ethyl carbonocyanidate (23.74 mL) was added. After stirring at −78° C. for 20 minutes, the mixture was warmed up to room temperature, and stirred for 1 hour. The mixture was poured into cold water, and the layers were separated. The aqueous layer was extracted with ether (3×20 mL). The combined organic layers were washed with saturated aqueous NH4Cl (3×20 mL), dried over Na2SO4, filtered, and dried under vacuum. The crude product was added to a silica gel column and purified by eluting with 0-10% ethyl acetate in hexane.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[N:6][N:7]=1.[I-].[K+].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[I:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:4][C:3]([CH2:2][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: ClCc1nnc(-c2ccc(I)cc2)o1
Reactant: C1CCNC1
Agent: [I-]
Agent: [K+]
Product: Ic1ccc(-c2nnc(CN3CCCC3)o2)cc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
2-Chloromethyl-5-(4-iodophenyl)-[1,3,4]oxadiazole (Intermediate 7) (48 mg, 0.15 mmol) and potassium iodide (25 mg, 0.15 mmol) were dissolved in pyrrolidine (2 ml) and stirred for 18 hours at 20° C. The amine was then removed in vacuo and the product was purified on a 10 g silica SPE cartridge (stepped solvent gradient 80:20 ethyl acetate:cyclohexane, 100% ethyl acetate, 95:5 ethyl acetate:methanol).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1([CH2:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:25]1([C:8]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH:15]3[C:38](=[O:39])[CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])([OH:17])[CH2:10][CH2:9]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: Cl
Product: Cc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2C(C(=O)Cc3ccccc3)NC[C@H]21

Procedure:
By working in accordance with the operating method of Use Example 22 below, starting from 0.68 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methylphenyl)-perhydroisoindol-4-ol hydrochloride and 0.28 cm3 of phenylacetyl chloride, 0.4 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methylphenyl)-2-phenylacetyl-perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 208° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]2[Br:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=1)[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]2[Br:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCOc1cccc2ccccc12
Reactant: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Br)c2cc(OCc3ccccc3)ccc2n1CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 135A (500 mg) and 1-(3-bromopropoxy)naphthalene (354 mg) in N,N-dimethylformamide (10 ml) was added Cs2CO3 (871 mg). The reaction was stirred at room temperature overnight, diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 0%-50% dichloromethane in hexane, to provide the desired product.
Reaction SMILES: Cl.Br[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.[OH-].[Na+].[CH3:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+].O.O.[C:63]([OH:68])(=[O:67])[C:64]([OH:66])=[O:65]>CC([O-])=O.CC([O-])=O.[Pd+2].C(Cl)Cl>[C:63]([OH:68])(=[O:67])[C:64]([OH:66])=[O:65].[CH3:21][O:20][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][C:15]=1[O:18][CH3:19])[CH:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([C:30]3[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=3)=[CH:4][CH:5]=1)[NH:9][CH2:10][CH2:11]2
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(Br)cc1)NCC2
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(Cc1ccc(-c3ccc(C)cc3)cc1)NCC2
Temperature: 25 °C

Procedure:
6,7-dimethoxy-1-(4′-methyl-biphenyl-4-ylmethyl)-1,2,3,4-tetrahydro-isoquinoline oxalate (36) was prepared as follows: 1-(4-bromo-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline hydrochloride (0.452 g, 1 mmol) was added to a mixture of 20 mL CH2Cl2 and 20 ml of 1N NaOH. The reaction mixture was stirred at room temperature. After dissolving of precipitate organic phase was separated, dried over Na2SO4, filtered and evaporated. A residue was dissolved in 6 mL i-PrOH. 4-Methyl-phenyl-boronic acid (0.148 g, 1.09 mmol) was added. The resulting solution was stirred for 30 min at room temperature. Pd(OAc)2 (1 mg, 0.0045 mmol), PPh3 (7 mg, 0.0267 mmol) and 2N Na2CO3 (1 mL, 2 mmol) were added, the reaction mixture was refluxed for 6 h under Ar and evaporated. A residue was dissolved in chloroform and washed with 1N NaOII. Organic phase was dried under Na2SO4, filtered and evaporated. A residue was dissolved in MeOH, a solution of oxalic acid dihydrate (0.265 g, 2.1 mmol) was added under reflux. Oxalic acid salt was crystallized from MeOH-Et2O mixture. Yield is 0.219 g (47.3%).
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[Na+]>C(O)C(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: [OH-]
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Na+]
Solvent: CC(C)CO
Product: N#Cc1ccc(C(N)=O)cc1
Yield: 65.7 %

Procedure:
Terephthalonitrile (12.8 g, 0.1 mol) and isobutanol (243.2 g) were mixed, and the resultant mixture was heated to 80° C. with stirring. To the mixture, a 20% aqueous solution of sodium hydroxide (4 g) was added over three hours. Liquid chromatographic analysis revealed the reaction mixture contained 9.6 g of p-cyanobenzamide (yield 66%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:34])([F:33])[C:13]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][C:17]1=[O:24].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[F:34][C:12]([F:11])([F:33])[C:13]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH:22]=[O:23])[CH2:18][C:17]1=[O:24]
Reactant: O=C1CC(CO)CCN1Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(=O)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.2 %

Procedure:
To a solution of oxalyl chloride (4.5 mL) in dichloromethane (80 mL) was added a solution of dimethyl sulfoxide (7.3 mL) in dichloromethane (50 mL) under cooling to −78° C. The reaction mixture was stirred for 30 min under cooling to −78° C., and to the reaction mixture was added dropwise a solution of 1-[2,4-bis(trifluoromethyl)benzyl]-4-(hydroxymethyl)piperidin-2-one (10 g) in dichloromethane (50 mL). The reaction mixture was stirred for 40 min under cooling to −78° C., triethylamine (19.7 mL) was added, and the mixture was further stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.7 g).