Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>CCOCC>[C:11]1([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCc2ccccc21
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C1=CC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.82 %

Procedure:
To a solution of 1-indanone (23.78 g, 0.18 mol) in 250 ml of ether at 0° C. was added dropwise over 30 min., 100 ml of phenyllithium in ether (1.8M in ether) and the mixture was allowed to warm to room temperature and stirred 1 h. The reaction mixture was poured into a cold saturated ammonium chloride solution, extracted with ether (2×200 ml), and the combined organic layer was washed with brine and dried over sodium sulfate. The organic solvent was removed under reduced pressure, 70 ml of 20% sulfuric acid in acetic acid was added to the residue and stirred 2 min. To the above solution water (100 ml) and ether (3×200 ml) were added, The organic layer was washed with sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated. Toluene (300 ml ) was added to the residue and the mixture was distilled (azeotropic removal of acetic acid) to afford a brown oil. The brown oil was purified by chromatography (silica; (2:1 hexane/methylene chloride)) to afford 15.58 g (45.82%) of 1-phenyl-indene as a colorless oil. In addition 11 g of 1-phenyl-1-acetoxy-indane was isolated as a by-product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].C=O.[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:23])[CH2:17][CH2:16]2)[C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)c1cc(Cl)cc(OC2CCNCC2)c1C
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(OC2CCN(C)CC2)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of methyl 5-chloro-2-methyl-3-(piperidin-4-yloxy)benzoate, hydrochloride (140 mg, 0.437 mmol) and formaldehyde (195 μl, 2.62 mmol) in methanol (3580 μl) and acetic acid (597 μl) was added portion wise sodium triacetoxyborohydride (278 mg, 1.312 mmol). The reaction was stirred for 18 h at RT, at which time it was concentrated. The residue was dissolved in water, neutralized with saturated sodium bicarbonate solution, and extracted with EtOAc (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated, and dried under high vacuum to give methyl 5-chloro-2-methyl-3-((1-methylpiperidin-4-yl)oxy)benzoate (0.130 g, 0.437 mmol, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.61-1.73 (m, 2 H) 1.84-1.94 (m, 2 H) 2.18 (s, 3 H) 2.21-2.27 (m, 2 H) 2.28 (s, 3 H) 3.83 (s, 3 H) 4.54 (dt, J=7.14, 3.63 Hz, 1 H) 7.29 (d, J=2.02 Hz, 1 H) 7.32 (d, J=2.02 Hz, 1 H). MS(ES) [M+H]+ 298.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12](=[S:15])[NH:13][N:14]=1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:14][N:13]=[C:12]([S:15][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[N:11]=1
Reactant: Cc1ccc(CCl)nc1
Reactant: COc1cc(C)ccc1-c1n[nH]c(=S)[nH]1
Product: COc1cc(C)ccc1-c1nc(SCc2ccc(C)cn2)n[nH]1
Yield: 14 %

Procedure:
Prepared in a similar manner to example 1 using 5-(2-methoxy-4-methylphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 1a) and 2-(chloromethyl)-5-methylpyridine (example 2a). Yield 14%. 1H NMR (500 MHz, CDCl3): δ2.29 (s, 3H), 2.41 (s, 3H), 4.00 (s, 3H), 4.51 (s, 2H), 6.75 (s, 1H), 6.90 (s, 1H), 7.40 (s, 1H), 8.1 (d, 1H), 8.4 (s, 1H), 11.5-11.7 (bs, 1H). MS(M+H, 327.1).
Reaction SMILES: Br[C:2]1[N+:3]([O-:8])=[N:4][CH:5]=[CH:6][N:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:20])([CH3:19])[CH2:17][NH2:18])=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C>CC#N>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([CH3:20])([CH3:19])[CH2:17][NH:18][C:2]2[N+:3]([O-:8])=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(CN)c1ccc(F)cc1
Reactant: [O-][n+]1nccnc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(CNc1nccn[n+]1[O-])c1ccc(F)cc1
Yield: 41.6 %

Procedure:
A solution of 3-bromo-1,2,4-triazin-2-oxide (2.0 g, 11 mmol), (2-(4-fluorophenyl)-2-methylpropan-1-amine (3.0 g, 17 mmol), and diisopropylethylamine (3.0 mL, 17 mmol) in CH3CN (20 mL) was stirred at rt for 24 h. The solvents were removed and the residue dissolved in EtOAc. The solution was washed with saturated NaHCO3, dried over Na2SO4, and evaporated to dryness. The residue was mixed with ether and then filtered to give the desired product (1.2 g) as a yellow solid.
Reaction SMILES: [C:1]1([O:7][CH:8]([CH2:10][O:11][CH:12]([CH2:14][OH:15])C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCCC>S(=O)(=O)(O)O.O>[C:16]([O:15][CH2:14][CH2:12][O:11][CH2:10][CH2:8][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(CO)OCC(C)Oc1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: O
Product: O=C(OCCOCCOc1ccccc1)c1ccccc1
Temperature: 115 °C

Procedure:
In a 2-L one-neck flask equipped with a magnetic stirrer, a heating mantle, and a Dean-Stark trap connected to a nitrogen purged condenser were placed 517.5 g dipropylene glycol phenyl ether technical grade containing a total hydroxyl content of 3.0 moles, 363.3 g (2.97 mole) benzoic acid, 300 ml heptane, and 20 drops concentrated sulfuric acid. The flask was heated to 115° C. to establish a constant heptane reflux through the trap where the water of esterification was collected. The reaction was allowed to continue for a total of 48 hours, at which point the theoretical amount of water was collected. The reaction mixture was cooled to 25° C. and then filtered through a small bed of activated basic alumina to neutralize the catalyst. The filtrate was placed in a boiling flask and the heptane removed at low pressure in a Büchi rotary evaporator. The residue was flash distilled under vacuum to isolate the diethylene glycol phenyl ether benzoate boiling at 165° C. @ 0.1 mmHg. The boiling point at reduced pressure was corrected to the normal boiling by means of a computer program that fits vapor pressure data to an Antoine equation of the form log P=A−B/(T+C). The normal boiling point was calculated at approximately 440° C. A sample of the product was then tested as specified by EPA Method 24 and found to contain only 0.7 percent volatiles.
Reaction SMILES: NC1C([N+]([O-])=O)=C(N2CCN(CC(NC3SC=CN=3)=O)CC2)C(Cl)=CN=1.[NH2:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32](Cl)[C:31]([Cl:38])=[CH:30][N:29]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[O:48])=[CH:43][CH:42]=1>C(O)(C)C>[NH2:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32]([N:52]2[CH2:51][CH2:50][N:49]([C:47]([C:44]3[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][CH:43]=3)=[O:48])[CH2:54][CH2:53]2)[C:31]([Cl:38])=[CH:30][N:29]=1
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Agent: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Solvent: CC(C)O
Product: COc1ccc(C(=O)N2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)cc1
Yield: 60.6 %

Procedure:
The method followed that used to prepare 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (Example 1, step 5), but using 2-amino-4,5-dichloro-3-nitropyridine (0.034 g, 0.16 mmol), isopropanol (3.0 ml), and (4-methoxyphenyl)(piperazin-1-yl)methanone (0.055 g, 0.25 mmol). Purification of the crude product on an isolute silica column using a gradient of ethyl acetate in dichloromethane as eluant (10 to 30%) afforded the title compound as a yellow solid (0.038 g, 61%). 1H-NMR (500 Mz, DMSO-d6) 3.13 (br s, 4H, piperazine N(CH2)2), 3.65 (br s, 4H, piperazine N(CH2)2), 3.86 (s, 3H, OCH3), 7.06 (d, J=8.27 Hz, 2H) and 7.47 (d, J=8.21 Hz, 2H) (2,6-C6H4—OMe and 3,5-C6H4—OMe), 7.14 (s, 2H, 2-NH2), 8.19 (s, 1H, 6-H);
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:21])[CH:12]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[N:11]=1.[I-].[Na+].Cl[CH2:36][C:37]1[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][N:38]=1>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH2:36][C:37]2[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][N:38]=2)[C:13](=[O:21])[CH:12]([N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[N:11]=1
Reactant: O=C1Nc2ccccc2C(c2ccccc2F)=NC1N1C(=O)c2ccccc2C1=O
Reactant: Cc1cccnc1CCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccnc1CN1C(=O)C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2F)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a suspension of sodium hydride (0.11 g of a 64% dispersion in mineral oil) in dry N,N-dimethylformamide (10 ml) was added (3RS)-2,3-dihydro-5-(2-fluorophenyl)-3-phthalimido-1H-1,4-benzodiazepin-2-one (1.00 g) under stirring for 2 hours at ambient temperature. To the mixture was added sodium iodide (0.42 g) and followed dropwise a solution of 2-chloromethyl-3-methyl-pyridine (0.389 g) in dry N,N-dimethylformamide (3 ml) at ambient temperature. The mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo, and the residue was taken up with ethyl acetate. The organic layer was washed with saturated sodium carbonate aqueous solution, dried over sodium sulfate, filtered and concentrated in vacuo to give (3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(3-methylpyridin-2-yl)methyl-3-phtalimido-1H-1,4-benzodiazepin-2-one (1.24 g). The product was used in a following reaction step without further purification.
Reaction SMILES: [C:1]([O:4][CH:5]1[O:27][C@H:26]([CH2:28]Br)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[P:30]([O:37]CC)([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33]>>[C:1]([O:4][CH:5]1[O:27][C@H:26]([CH2:28][P:30]([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:37])[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1O[C@H](CBr)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(C[C@H]1OC(OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)OCC
Yield: 78 %

Procedure:
2,3-Di-O-benzoyl-5-bromo-5-deoxyribofuranosyl acetate (68.0 g, 0.143 mol) was dissolved in triethyl phosphite (205 mL) and the solution was heated under reflux for 30 h. The volatiles were removed under reduced pressure and the resulting oil was dissolved in ether (780 mL). The organic solution was washed with brine (2×100 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (EtOAc:Hexanes=80:20) yielded 59.4 g of the target compound (78%).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[C:21]([O:24]C(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[C:21]([O-:24])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Solvent: c1ccncc1
Product: CC(=O)[O-]

Procedure:
A mixture of oestrone (10 g, 36.82 mmol), acetic anhydride (17.5 ml) and pyridine (75 ml) was heated under reflux for 2 h. The cooled reaction mixture was concentrated in vacuo and then quenched with ice-water. The precipitate that formed was filtered off, washed with water, dried, and recrystallised from aqueous ethanol (95%) to give 1 as white crystals (11.2 g, 97%); mp 115-118° C.; TLC (chloroform/acetone, 8:1): Rf 83; νmax (KBr) 1770, 1720 (C═O) cm−1; δH (400 MHz, CDCl3) 0.91 (3H, S, C-18-CH3), 1.42-2.19 (11H, m), 2.29 (3H, s, CH3CO), 2.38-2.54 (2H, m), 2.9 (2H, t, J=4.43 Hz, C-6-CH2), 6.81 (1H, d, JC-2-H, C-4-H=2.14 Hz, C-4-H), 6.86 (1H, dd, JC-4-H, C-2-H=2.44 Hz and JC-1-H, C-2-H=8.54 Hz, C-2-H) and 7.28 (1H, d, JC-2-H, C-1-H=8.24 Hz, C-1-H); MS m/z (FAB+) 466.2 [10, (M+H+NBA)+], 313.2 [65, (M+H)+], 270.2 [100, (M+H−CH3CO)+]; MS m/z (FAB−) 269.2 [100, (M−CH3CO)−]. Found C, 76.9; H, 7.83 C20H24O3 requires C, 76.89; H, 7.74%.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]1[NH:24][C:23]([C@@H:25]3[CH2:29][C@H:28]([CH3:30])[CH2:27][N:26]3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:22][CH:21]=1)[CH:14]=[CH:13]2>CN(C=O)C>[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]1[N:24]=[C:23]([C@@H:25]3[CH2:29][C@H:28]([CH3:30])[CH2:27][N:26]3[C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[NH:22][C:21]=1[Cl:8])[CH:14]=[CH:13]2
Reactant: C[C@H]1C[C@@H](c2ncc(-c3ccc4cc(Br)ccc4c3)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](c2nc(-c3ccc4cc(Br)ccc4c3)c(Cl)[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Yield: 37.4 %

Procedure:
NCS (203 mg, 1.52 mmol) was added to a solution of (2S,4S)-tert-butyl 2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (560 mg, 1.39 mmol) in dry DMF (15 mL) and the mixture was heated at 50° C. for 16 h. The solvent was removed by nitrogen purge and the residue was purified with a Thompson 90 g silica gel cartridge (gradient elution 5%-100% B over 2 L; Solvent B=ethyl acetate and Solvent A=hexanes) to yield (2S,4S)-tert-butyl 2-(4-(6-bromonaphthalen-2-yl)-5-chloro-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (255 mg) as a tan foam. For purpose of characterization, approximately 20 mg was dissolved in methanol (2 mL) and subject to prep HPLC (gradient 0-100% B over a 25 min at 40 ml/min) on a PHENOMENEX® Luna column (30×100 mm, 10u); Solvent B=95% CH3CN-5% H2O-10 mM NH4OAc and A=5% CH3CN-95% H2O-10 mM NH4OAc. LC-MS retention time 2.61 min; calcd. for C23H26BrClN3O2: 492.09 m/z. found 492.03 [M+H]. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.18 (s, 1H), 8.09 (s, 1H), 7.91 (br. s, 2H), 7.83 (d, J=8.6 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 4.79-4.75 (m, 1H), 3.78 (t, J=8.9 Hz, 1H), 3.19 (t, J=10.4 Hz, 1H), 2.49 (quin, J=6.1 Hz, 1H), 2.36-2.32 (m, 1H), 1.78 (q, J=11.9 Hz, 1H), 1.45/1.24 (s, 9H), 1.15 (d, J=6.1 Hz, 3H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].ClCCl.[F:10][C:11]1[CH:12]=[C:13]([C@H:19]2[NH:23][C@@H:22]([C:24]([OH:27])([CH3:26])[CH3:25])[CH2:21][CH2:20]2)[CH:14]=[C:15]([F:18])[C:16]=1[F:17].N1C=CC=CC=1>O>[CH3:26][C:24]1([CH3:25])[C@H:22]2[CH2:21][CH2:20][C@@H:19]([C:13]3[CH:12]=[C:11]([F:10])[C:16]([F:17])=[C:15]([F:18])[CH:14]=3)[N:23]2[C:2](=[O:3])[C:1](=[O:5])[O:27]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(O)[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC1(C)OC(=O)C(=O)N2[C@H](c3cc(F)c(F)c(F)c3)CC[C@@H]21

Procedure:
Under ice-cooling, oxalyl chloride (320 μL) was added dropwise into a dichloromethane (30 mL) solution containing 2-[(2R,5S)-5-(3,4,5-trifluorophenyl)pyrrolidine-2-yl]propan-2-ol (745 mg) and pyridine (5 mL). After stirring for 30 minutes at the same temperature, water was added to the reaction solution, and the organic layer was partitioned. After washing the organic layer with brine, the resultant was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the residue was purified by silica gel column chromatography (heptane/ethyl acetate→ethyl acetate), and the title compound (580 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1>>[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:13]=1
Reactant: Brc1cncc(Br)c1
Reactant: OCC(F)(F)F
Product: FC(F)(F)COc1cncc(Br)c1
Reaction time: 20 h
Yield: 70 %

Procedure:
2,2,2-Trifluoroethanol and 3,5-dibromopyridine were processed as described in Example 7A except that the heating time was extended to 20 hours at 100° C. The reaction was quenched onto ice/water, extracted with ethyl ether, and concentrated. The residue was purified on silica gel (hexanes:ethyl acetate, 8:2) to provide the title compound as a colorless oil (70% yield). MS (DCI/NH3) m/z 256/258 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:12]2=[O:29])=[CH:6][C:3]=1[C:4]#[N:5].Cl[CH2:31]I.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O1CCCC1>[OH:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]2[C:11]3([CH2:31][O:10][C:8]=2[CH:9]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C:12]3=[O:29]
Reactant: COc1ccc(CN2C(=O)C(c3cc(C#N)c(O)cc3O)c3ccccc32)cc1
Reactant: ClCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C3(COc4cc(O)c(C#N)cc43)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 26.5 %

Procedure:
To a stirred solution of 2,4-dihydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (9.40 g, 24.3 mmol) and chloroiodomethane (4.40 mL, 60.4 mmol) in tetrahydrofuran (250 mL) was added cesium carbonate (23.8 g, 73.0 mmol) under nitrogen. The reaction mixture was stirred at ambient temperature for 20 h and 5% w/v hydrochloric acid was added. The mixture was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water and brine, and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate to afford 6-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (2.57 g, 26%): mp 112-114° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.29-7.16 (m, 4H), 7.02-6.97 (m, 2H), 6.89-6.85 (m, 3H), 6.54 (s, 1H), 4.93-4.77 (m, 4H), 3.68 (s, 3H); MS (ES+) m/z 398.8 (M+1).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[F:42][C:43]1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:44]=1[CH2:45][NH2:46]>C1COCC1>[F:42][C:43]1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:44]=1[CH2:45][NH:46][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=3)[C:9]([CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][C:11]=2[CH:29]=1)=[O:31]
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Reactant: NCc1ccc(F)cc1F
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1F)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of 2,4-difluoro-benzylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 568.3 (M+H)+.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:14]=1[O:21][CH3:22])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[I-:23].[CH3:24][N+:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH3:35].C([O-])(=O)C.[NH4+].C(Cl)(Cl)Cl.CO>C(O)C>[I-:23].[C@@H:2]1([O:1][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:35][C:26]3[CH:27]=[CH:28][C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N+:25]=3[CH3:24])=[CH:15][C:14]=2[O:21][CH3:22])[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: Cc1ccc2ccccc2[n+]1C
Reactant: COc1cc(C=O)ccc1O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC(=O)[O-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(C=Cc2ccc3ccccc3[n+]2C)ccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 74.4 %

Procedure:
A stirred suspension of 4-formyl-2-methoxyphenyl β-D-galactopyranoside (1c)(0.12 g, 0.37 mmol), 1,2-dimethylquinolinium iodide (0.10 g, 0.37 mmol) and ammonium acetate (0.06 g, 0.8 mmol) in ethanol (10 ml) was heated under reflux to give a heterogeneous mixture which soon turned orange. After 1 h, t.l.c. (chloroform-methanol 5:4) indicated that the aldehyde had been fully converted into an almost non-mobile orange product. The solution was cooled, filtered and the collected material was washed thoroughly with ethanol to give (21c)(0.16 g, 72%) as an orange crystalline solid, m.p. 225° C., [α]D -18° (c1, DMSO).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].CN(C=O)C.[CH3:12][O:13][C:14]1[C:15]([N+:23]([O-:25])=[O:24])=C([CH:20]=[CH:21][CH:22]=1)C(O)=O>ClCCl>[CH3:12][O:13][C:14]1[C:15]([N+:23]([O-:25])=[O:24])=[C:1]([CH:20]=[CH:21][CH:22]=1)[C:2]([Cl:4])=[O:3]
Reactant: COc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(C(=O)Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
Oxalyl chloride (2 mL, 24 mmol) and DMF (0.4 mL) are added to a suspension of 3-methoxy-2-nitro benzoic acid (4 g, 20 mmol) in 200 mL of dichloromethane. The reaction mixture is stirred for 3 hours at 25° C. under nitrogen. The reaction solvents are removed under reduced pressure to yield 3-methoxy-2-nitrobenzoyl chloride (4.3 g, quant.) as a yellow solid. 1H NMR (DMSO): δ7.80 (1H, d, J=8 Hz), 7.65 (1H, t, J=9 Hz), 7.42 (1H, d, J=10 Hz).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:20])[NH:4][C:5](=[O:19])[N:6]([CH:18]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[C@H:8]1[N:15]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[I:1][C:2]1[C:3](=[O:20])[NH:4][C:5](=[O:19])[N:6]([CH:18]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[C@H:8]1[NH2:15]
Reactant: [N-]=[N+]=N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c(=O)[nH]c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 5-iodo,2'-azido,2'-deoxyuridine (2.48 g, 6.3 mmoles) in dioxane (33 ml) is added triphenylphosphine (5.8 g, 22 mmoles, 3.5 eq.) and the mixture is stirred at room temperature for 1 h, during which time a white precipitate forms. The precipitate is collected and washed three times with diethyl ether (3×50 ml). The filtrate is evaporated to dryness, taken up in a minimum amount of dioxane, and stored at -20° C. for 48 h. The precipitate is collected and washed with diethyl ether. The combined precipitates gave 1.81 g of 5-iodo,2'-amino,2'-deoxyuridine (78% yield). The spectral properties agreed with those reported in the literature (Verheyden et al. (1971) supra).