Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21]([O:24][CH2:25][CH3:26])(=[O:23])C>>[CH2:25]([O:24][C:21](=[O:23])[NH:1][CH2:2][CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11])[C:26]1[CH:15]=[CH:16][CH:17]=[CH:12][CH:13]=1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCOC(C)=O
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)CCCCCNC(=O)OCc4ccccc4)c3C2=O)C(=O)N1
Yield: 48 %

Procedure:
A solution of 6-benzyloxycarbonylamino-hexanoic acid(2.65 g, 10 mmol) in thionyl chloride (15 ml) was heated to reflux 1 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo to give (5-chlorocarbonyl-pentyl)-carbamic acid benzyl ester as tan oil. The oil was used without further purification. (5-Chlorocarbonyl-pentyl)-carbamic acid benzyl ester was dissolved in THF (50 ml). To this solution was added 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.37 g, 5 mmol). The resulting suspension was to reflux for 4 hours. The solvent was evaporated in vacuo and the resulting solid was partially purified by flash chromatography (60/40 ethyl acetate/hexane) to give a light yellow solid. The solid was recystallized from minimal ethyl acetate to give 1.24 g (48%) of product as an off-white solid: mp 122–125 ° C.; 1H NMR (DMSO-d6) 11.18 (s, 1H), 9.70 (s, 1H), 8.49 (d, J=8.4 Hz, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.34–7.24 (m, 6H), 5.16 (dd, J=5.1 and 12.6 Hz, 1H), 5.00 (s, 2H), 3.02–2.84 (m, 3H), 2.65–2.43 (m, 4H), 2.12–2.05 (m, 1H), 1.65–1.15 (m, 6H; 13C NMR (DMSO-d6) 172.75, 171.95, 169.77, 167.72, 166.67, 156.08, 137.29, 136.57, 136.09, 131.43, 128.32, 127.70, 126.21, 118.25, 116.90, 65.08, 48.92, 36.47, 30.94, 30.67, 29.14, 25.77, 24.47, 21.99; Anal. Calcd. For C27H28N4O7: C, 62.30; H, 5.42; N, 10.76. Found: C, 62.40; H, 5.31; N, 10.48.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.[CH3:28][N:29]([CH2:31][C:32](O)=[O:33])[CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:32](=[O:33])[CH2:31][N:29]([CH3:30])[CH3:28])[CH2:2][CH2:3]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCN(C(=O)CN(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a solution of [(S)-1-(1-piperidin-4-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine 113 (97 mg, 0.268 mmol), dimethylaminoacetic acid (30 mg, 0.294 mmol) and DIPEA (230 μL, 1.34 mmol) in DMF (5 mL) was added HATU (153 mg, 0.401 mmol) and the mixture was stirred at RT for 1 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined, then concentrated in vacuo, purified by column chromatography (Si—PCC, gradient 0-20% 2M NH3/MeOH in DCM) and triturated with diethyl ether. The product thus obtained was further purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 5-60% 0.1% NH4OH in acetonitrile/water) and loaded into an Isolute® SCX-2. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The basic fractions were then combined and concentrated in vacuo affording 125 as a white solid (40 mg, 33%). LCMS: RT 1.67 min [M+H]+ 448.1. 1H NMR (CDCl3 plus MeOD, 400 MHz): δ 8.45 (1H, s), 7.94 (1H, s), 7.77 (1H, d, J=7.62 Hz), 7.41 (1H, d, J=7.73 Hz), 7.26-7.17 (3H, m), 6.10 (1H, s), 4.99-4.81 (1.5H, m), 4.64-4.53 (0.5H, m), 4.38-4.27 (0.5H, m), 4.21-4.08 (0.5H, m), 3.32-3.01 (2H, m), 2.87-2.16 (10H, m), 2.05-1.27 (6H, m). Signals split due to presence of rotamers
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.C(N(CC)CC)C.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CN(C)C=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3[nH]ccc23)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2ccn3C(=O)CCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To 4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole (37 mg, 0.10 mmol, 1 eq.) was added dimethylformamide (1 mL), triethylamine (0.154 ml, 1.1 mmol, 10 eq.) and succinic anhydride (30 mg, 0.3 mmol, 3 eq.) the reaction was stir at 80° C. for 8 hr and allowed to cool to room temperature. Lithium bis(trimethylsilyl)amide (1 M in THF, 1.2 mL, 1.2 mmol, 12 eq) was added and the reaction was allowed to proceed at room temperature for 24 hr. The reaction was purified by HPLC with a 30-100% acetonitrile in water gradient and dried from dichloromethane/hexanes mixture to yield 4-[4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-4-oxo-butyric acid as a white solid (16 mg, 34%). LC-MS (ES) calculated for C26H21F2NO5, 465.1; found m/z 466 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH3:15])[C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH2:14].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20](Cl)=[O:21]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20]([NH:14][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]1[N:7]([CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH3:15])=[O:21]
Reactant: CN(Cc1ccco1)[C@@H]1CCCC[C@H]1N
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccco1)[C@@H]1CCCC[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Yield: 50 %

Procedure:
This titled benzamide was prepared according to the general acid chloride method described above on a 0.01 mol scale by reacting the trans-2-[N-(2-furylmethyl)methylamino]cyclohexylamine, prepared as described in part (a) above with 3,4-dichlorobenzoyl chloride. The reaction product mixture was extracted with methylene dichloride to extract the benzamide product therefrom. The crude product was chromatographed on 380 g. of silica gel using a 1 percent methanol-in-chloroform eluant. Fraction 1 (1000 m.) and fractions 2 to 17 (25 ml. each) gave no material. Fractions 18 to 54 (25 ml. each) gave a solid which was crystallized from ether giving colorless needles, 1.91 g., (50% yield) of the named benzamide product, melting point 149°-150° C. The Ultraviolet, Infrared, and Nuclear Magnetic Resonance spectral analyses were consistent for the named benzamide.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12](OCC)=[O:13])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[BH4-].[Na+]>CC(O)=O>[C:1]1([C:7]2[S:11][C:10]([CH2:12][OH:13])=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OCc1nnc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 5-phenyl-1,3,4-thiadiazole-2-carboxylate (350 mgs, 1.494 mmol) in anhydrous methanol (5 mL, 124 mmol) was added NaBH4 (226 mgs, 5.98 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h. AcOH (2 mL) was added and the reaction was concentrated to dryness. The residue was dissolved in EtOAc, brine and water and extracted with EtOAc (3×). The combined organic extracts were washed with sat. aqueous NaHCO3 and brine, and dried over anhydrous magnesium sulfate. After filtration and evaporation, the residue was triturated with ethyl ether to give the title material as a first crop (150 mgs, 52%). LC (Method B): 2.022 min, LCMS (APCI) calcd for C9H9N2OS [M+H]+ m/z 193.04, found 193.2. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.92-8.03 (m, 2H), 7.44-7.59 (m, 3H), 5.14 (br. d, J=3.90 Hz, 2H), 2.63 (br. s., 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH:9]2[CH2:11][O:10]2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:18]=1[OH:30].C1(C)C=CC=CC=1>C(N(C(C)C)C(C)C)C>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:18]=1[O:30][CH2:11][CH:9]([OH:10])[CH2:8][O:7][C:6]1[CH:12]=[CH:13][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(OCC2CO2)cc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: OC(COc1ccc(C(F)(F)F)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl

Procedure:
8 g of 2-(4-trifluoromethyl-phenoxymethyl)-oxirane and 3.8 g of 2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenol are stirred in 80 ml of N-ethyl-diisopropylamine and 50 ml of toluene for 14 days at 100° C. The reaction mixture is concentrated, and the residue is taken up in ethyl acetate and washed with hydrochloric acid and water. After concentration of the organic phase and purification over silica gel, 1-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-3-(4-trifluoromethyl-phenoxy)-propan-2-ol is obtained. 1H-NMR (CDCl3) 300 MHz: 2.81 (d, 1H), 4.15-4.48 (m, 5H), 4.59 (d, 2H), 6.11 (t, 1H), 6.86 (s, 2H), 7.01 (d, 2H), 7.58 (d, 2H)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[NH2:19][C:20]1[N:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[N:21]=1>C(OCC)(=O)C>[Cl:27][C:22]1[CH:23]=[C:24]([Cl:26])[N:25]=[C:20]([N:19]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:21]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cc(Cl)nc(N2CCOCC2)n1
Yield: 28.1 %

Procedure:
2-bromoethylether (3.65 g), potassium carbonate (8.29 g), and N,N-dimethylformamide (75 mL) were added to 2-amino-4,6-dichloropyrimidine (2.46 g), and the mixture was refluxed for 3 hours while heated. Subsequently, the reaction mixture was diluted with ethyl acetate, was washed with water, and was dried over anhydrous sodium sulfate. The solvent was removed and the resulting residue was purified on a silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 4,6-dichloro-2-(morpholine-4-yl)pyrimidine (985 mg, 28%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[OH:16].Cl[CH2:18][C:19](Cl)=[O:20].[H-].[Na+]>C1COCC1>[Br:15][C:13]1[CH:12]=[CH:11][C:10]2[O:16][CH2:18][C:19](=[O:20])[NH:8][C:9]=2[CH:14]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1COc2ccc(Br)cc2N1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
Triethylamine (2.4 mL, 17 mmol) was added to 2-amino-4-bromophenol (2.5 g, 13 mmol) in THF (80 mL). The reaction was cooled in ice and chloroacetyl chloride (1.12 mL, 14 mmol) added portionwise. It was stirred with cooling for 10 min then allowed to warm to r.t. and stirred for a further 2 h. The reaction mixture was cooled in ice and sodium hydride (1.05 g of a 60% suspension in oil, 26 mmol) was added portionwise. The mixture was stirred with ice-bath cooling for 20 min then at r.t. for 2 h before being quenched with water (20 mL). The THF was removed in vacuo and the resulting mixture diluted with water (100 mL). The precipitate was filtered off, washed with water (3×50 mL) and dried in vacuo to yield the title compound as a beige solid (2.14 g, 70%). δH (DMSO-d6) 4.60 (2H, s), 6.92 (1H, d, J 8.5 Hz), 7.02 (1H, d, J 2.3 Hz), 7.08 (1H, dd, J 8.5, 2.3 Hz), 10.81 (1H, br s).
Reaction SMILES: [H-].[Na+].[Na+].[I-].[Br:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)=[O:14])=[CH:8][C:7]=1[CH3:20].Cl[CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26]>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:5][C:6]1[C:7]([CH3:20])=[CH:8][C:9]([C:13]([N:15]2[CH2:16][CH:17]([O:19][CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:18]2)=[O:14])=[CH:10][C:11]=1[CH3:12]
Reactant: CN(C)CCCCl
Reactant: Cc1cc(C(=O)N2CC(O)C2)cc(C)c1Br
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2CC(OCCCN(C)C)C2)cc(C)c1Br
Temperature: 110 °C
Reaction time: 15 h
Yield: 27.2 %

Procedure:
NaH (110 mg, 2.75 mmol, 60% oily suspension) and NaI (274 mg, 1.83 mmol) were added to a solution of (4-bromo-3,5-dimethyl-phenyl)-(3-hydroxy-azetidin-1-yl)-methanone (130 mg, 0.458 mmol) and (3-chloro-propyl)-dimethyl-amine (289 mg, 1.83 mmol) in toluene (1.8 ml). The mixture was stirred at 110° C. for 15 hours. The reaction mixture was diluted with AcOEt, and the organic layer was then sequentially washed with a saturated aqueous NaHCO3 solution, water and a saturated aqueous NaCl solution. Further, the organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/AcOEt) to give (4-bromo-3,5-dimethyl-phenyl)-[3-(3-dimethylamino-propoxy)-azetidin-1-yl]-methanone (46 mg, 27%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:33][CH2:34][NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:38]([O:37][C:36](=[O:45])[NH:35][CH2:34][CH2:33][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(NCCO)OCc1ccccc1
Reactant: Oc1ccc(-n2cccn2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(NCCOc1ccc(-n2cccn2)cc1)OCc1ccccc1
Temperature: 0 °C

Procedure:
A round-bottomed flask was charged with 4-pyrazole-1-yl-phenol (175 mg, 1.09 mmol), and 3.6 ml of toluene, triphenylphosphine (430 mg, 1.64 mmol), and benzyl N-(2-hydroxyethyl)carbamate (320 mg, 1.64 mmol) were then added. The solution was cooled to 0° C. and 1,1′-(azodicarbonyl)-dipiperidine (414 mg, 1.64 mmol) was added. The mixture was allowed to stir for about ten minutes at about 0° C. and was then allowed to warm to room temperature. An additional 3.6 ml of toluene and 3.6 ml of tetrahydrofuran were added to the viscous solution. The reaction mixture was stirred for about forty-eight hours, and the precipitated solids were filtered off and washed with a minimum volume of 1:1 toluene/tetrahydrofuran. The filtrate was concentrated in vacuo to afford the intermediate [2-(4-pyrazole-1-yl-phenoxy)-ethyl]-carbamic acid benzyl ester as an oil which was used directly in the next step.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[C@@H:13]1[CH2:17][C:16](=[O:18])[C:15]([CH2:19][CH:20]=[CH2:21])=[C:14]1[CH3:22]>C(Cl)(Cl)Cl>[CH3:22][C:14]1[C@H:13]([O:2][N+:1]([O-:4])=[O:3])[CH2:17][C:16](=[O:18])[C:15]=1[CH2:19][CH:20]=[CH2:21]
Reactant: C=CCC1=C(C)[C@H](O)CC1=O
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: C=CCC1=C(C)[C@H](O[N+](=O)[O-])CC1=O
Yield: 96.5 %

Procedure:
Into a mixed solution of 8 g of fuming nitric acid and 24 g of acetic anhydride, kept at a temperature of -5° to 10° C. was added dropwise 6 g of (R)-4-hydroxy-3-methyl-2-(2-propenyl)-2-cyclopenten-1-one ([α]D24 : -7.81° (C=1.07, in chloroform), (R)-isomer/(S)-isomer=77.4/22.6). Thereafter, with the same operations as in Example 1, 7.50 g of crude (R)-3-methyl-4-nitroxy-2-(2-propenyl)-2-cyclopenten-1-one was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:12][C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=1[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:28][CH2:29][CH:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:42])[CH3:43])[CH:36]=[CH:37][CH:38]=2)[CH2:31][CH2:32]1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(O)c3ccccc3F)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[7-(2-fluorophenyl)-7-hydroxyheptyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 617.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[OH-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[N:10]([S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)N1CCc2[nH]c3ccccc3c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCc2c(c3ccccc3n2S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3 g of 1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester in methylene chloride (50 mL) is treated with 0.982 g of sodium hydroxide and stirred and room temperature overnight. Benzenesulfonylchloride (6.30 mL) is added to the reaction and stirred at room temperature overnight. The reaction mixture is diluted with water (250 mL) and extracted with methylene chloride. The organics are combined, washed with water then a saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo The residue is loaded on Celite and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to give 5-benzenesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester as a yellow powder. MS (m/z): 385 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[CH:15][CH:14]=3)=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.CC([O-])(C)C.[K+].[Cl:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:38]=1[C:39](Cl)=[O:40]>C1COCC1>[Cl:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:38]=1[C:39]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:12]3[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=4)[N:9]=[N:10][N:11]=3)=[CH:18][CH:17]=2)=[N:20]1)=[O:40]
Reactant: COc1ccc(Cn2nnnc2-c2ccc(-c3n[nH]c4ccccc34)cc2)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnnc2-c2ccc(-c3nn(C(=O)c4c(Cl)cccc4Cl)c4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of a mixture of regio-isomers of 3-(4-(1-(4-Methoxybenzyl)-1H-tetrazol-5-yl)phenyl)-1H-indazole (Example 20, step i) (50 mg, 0.13 mmol) was dissolved in anhydrous THF (1 ml). After addition of t-BuOK (16 mg, 0.14 mmol,) the reaction mixture was stirred at room temperature for 15 min. Subsequently, 2,6-dichlorobenzoyl chloride (21 μl, 0.14 mmol) was added and the reaction mixture was stirred for another 2 h at room temperature. The solvent was evaporated under reduced pressure, the residue was dissolved in dichloromethane and washed with water, an aqueous solution of 5% K2CO3 and water. The organic solvent was evaporated under reduced pressure and the residue was dried in vacuo. The product was purified by preparative HPLC to afford (2,6-dichlorophenyl)(3-(4-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)-1H-indazol-1-yl)methanone as a mixture of 2 regioisomers in a 98 to 2 ratio (59 mg, 74%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:13])[CH:5]=[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:7]=1[OH:8].[OH-].[K+].Cl[CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>>[CH3:1][C:2]1[CH:3]=[C:4]([S:13][CH2:17][N:18]2[C:19](=[O:28])[C:20]3=[CH:27][CH:26]=[CH:25][CH:24]=[C:21]3[C:22]2=[O:23])[CH:5]=[C:6]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:7]=1[OH:8]
Reactant: O=C1c2ccccc2C(=O)N1CCl
Reactant: Cc1cc(S)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(SCN2C(=O)c3ccccc3C2=O)cc(C(C)(C)C)c1O
Yield: 46.3 %

Procedure:
The procedure of Example 1 was repeated using 8.46 grams of 3-methyl-4-hydroxy-5-tert-butylbenzenethiol, 1.72 grams of potassium hydroxide, and 8.43 grams of N-(chloromethyl) phthalimide . Recrystallization from ethyl acetate-heptane afforded 7.1 grams of product with m.p. 114°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]#[N:8])[NH:5][CH:6]=1.[H-].[Na+].[NH2:11]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:11][N:5]1[CH:6]=[C:2]([Cl:1])[CH:3]=[C:4]1[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)c[nH]1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cn1N
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a rapidly stirred solution of 4-chloro-1H-pyrrole-2-carbonitrile (3.6 g, 28.4 mmol) in DMF (75 mL) was added NaH (1.7 g, 42.7 mmol) portion wise over 20 min. The dark brown solution was allowed to stir for an additional 10 min. The aminating reagent ((aminooxy)(diphenyl)phosphine oxide) (10 g, 42.7 mmol) was added in one portion. The mixture was heated to 80° C. for 6 hours. The reaction was quenched with distilled water (100 mL). EtOAc (50 mL) was added to the reaction and the solution was transferred to a separatory funnel and the organic layer was isolated while the aqueous layer was back extracted with EtOAc (2×50 mL). The combined organic layers were collected, dried (MgSO4), filtered, and concentrated in vacuo to yield 3.4 g of the above compound (24.02 mmol, yield 84%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:21][C:20]=1[Pb+3:17]
Reactant: OB(O)c1cc(-c2ccc(Cl)cc2)ccc1Br
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Clc1ccc(-c2ccc(Br)c([Pb+3])c2)cc1
Temperature: 40 °C
Yield: 64.7 %

Procedure:
To a mixture of lead tetraacetate (3.76 g, 8.49 mmol) and mercuric diacetate (0.27 g, 0.85 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (25 ml). This mixture is warmed to 40° C., and 4-bromo-4′-chlorobiphenyl-3-yl-boronic acid (2.40 g, 7.72 mmol) is added in one portion, and the mixture is stirred and heated at this temperature for 4 hours. After cooling to room temperature, the mixture is diluted with chloroform (25 ml), cooled in an ice-bath, and powdered anhydrous potassium carbonate (2.75 g) is added rapidly, followed by rapid stirring for 5 minutes. The solids are removed by filtration, and the filtrate is concentrated to approximately a quarter of its volume. Hexane is added to induce crystallisation, and the solvents evaporated in vacuo. Trituration with hexane gives 4-bromo-4′-chlorobiphenyl-3-yllead triacetate (3.25 g), used without further purification in the next step.