Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:19])[N:12]([CH3:18])[NH:13]2.[H-].[Na+].Br[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:19])[N:12]([CH3:18])[N:13]2[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25]
Reactant: Cc1ccc(-c2cccc3[nH]n(C)c(=O)c23)c(C)c1
Reactant: CCC(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)n1c2cccc(-c3ccc(C)cc3C)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
To a solution containing 0.008 g (0.03 mmol) of 4-(2,4-dimethylphenyl)-2-methyl-1,2-dihydro-3H-indazol-3-one in 2 ml of N,N-dimethylformamide under a nitrogen atmosphere was added 0.001 g (0.038 mmol) of sodium hydride followed by 0.007 g (0.048 mmol) of 3-bromopentane. The reaction was allowed to stir at room temperature for 48 h, quenched with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 25% ethyl acetate/dichloromethane gave 0.003 g (30%) of compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[CH2:26]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Br)=[O:36])=[CH:33][CH:32]=1)[CH2:27][CH2:28][CH2:29][CH3:30]>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:31]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:32][CH:33]=4)=[CH:3][CH:4]=3)[CH:9]=2)[C:13]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: CCCCCc1ccc(C(=O)Br)cc1
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)CN([C@H](C(=O)OC)C(C)C)C4=O)cc2)cc1
Yield: 52 %

Procedure:
The compound of example 324 was prepared analogous to compound of example 304 by reaction of compound of example 223 with 4-(n-pentyl)benzoyl bromide. The compound of example 324 was used directly without isolation, for the preparation of compound of example 325.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[O:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:26][CH2:27]1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)NC2CCOCC2)cn1
Yield: 46 %

Procedure:
As described for example 2b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (125 mg, 0.40 mmol) was converted, using 4-aminotetrahydropyran instead of aminomethylcyclopropane to the title compound (SiO2, heptane:ethyl acetate=70:30 to 40:60, 73 mg, 46%) which was obtained as a white solid. MS: m/e=395.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH3:12][O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CO.C(Cl)(Cl)Cl>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([O:13][CH3:12])=[O:23])=[CH:20][CH:19]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(Cn2cnc3c(Cl)nc(N)nc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-amino-6-chloropurine (5 g, 0.029 mol), 4-(bromomethyl)benzoic acid methyl ester (6.7 g, 0.029 mol), and potassium carbonate (4.0 g, 0.029 mol) in dry DMF (75 ml) is stirred at room temperature for three days. The reaction mixture is filtered and the filtrate is evaporated to near dryness under vacuum. Water is added and the precipitate is collected by filtration to give a mixture of 7- and 9-substituted products (10.5 g). A sample of pure 9-isomer, i.e., 2-amino-9-[(4-carbomethoxyphenyl)methyl)-6-chloropurine, (mp=150°-155° C. softens, 183°-185° C. melts) is prepared by chromatography on silica gel with 5% methanol/chloroform as the eluting solvent to separate it from the slower moving 7-isomer.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][NH:19][NH2:20])[CH2:3]1.[CH3:21][N:22]=[C:23]=[S:24]>O1CCCC1>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][NH:19][NH:20][C:23](=[S:24])[NH:22][CH3:21])[CH2:3]1
Reactant: CN=C=S
Reactant: CN1C[C@H](CNN)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: C1CCOC1
Product: CNC(=S)NNC[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 0.5 °C
Yield: 74.5 %

Procedure:
1.2 g (0.0043 moles) of 6-methyl-8β-hydrazinomethyl-ergoline are dissolved in 120 ml of dry tetrahydrofuran, the solution is cooled to 0.5° C., and 0.38 g (0.0052 moles) of methyl isothiocyanate are added with stirring. The reaction mixture is stirred for one hour, and the solvent is distilled off in vacuo. The residue is subjected to chromatography on a column packed with 40 g of silica gel; a 100:0.3:20 mixture of chloroform, water and methanol is applied as eluting agent. The eluents which contain a single compound with an Rf value of 0.45 are combined and evaporated, and the dry residue is crystallized from ethanol. 1.1 g (76.8%) of 6-methyl-8β-([N'-methylthiocarbamoyl-hydrazino]-methyl)-ergoline are obtained; m.p.: 220°-221° C., [α]D20 =-45.7° (c=1, in 96% ethanol).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I-].[CH3:12][N:13]([CH3:36])[CH2:14][CH2:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:37][O:38][C:39](=[O:58])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[I:55])=[C:43]([CH:56]=O)[CH:42]=1.Cl>C1(C)C=CC=CC=1>[CH3:37][O:38][C:39](=[O:58])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[I:55])=[C:43]([CH:56]=[CH:16][CH2:15][CH2:14][N:13]([CH3:36])[CH3:12])[CH:42]=1
Reactant: COC(=O)Cc1ccc(OCc2ccccc2I)c(C=O)c1
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [I-]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(OCc2ccccc2I)c(C=CCCN(C)C)c1
Reaction time: 1 h
Yield: 81.1 %

Procedure:
Lithium bis(trimethylsilyl)amide (LiHMDS) (1M THF, 51.5 ml, 51.5 mmol) was added drop by drop to a dispersion of (3-Dimethylamino-propyl)-triphenyl-phosphonium iodide (24.33 g, 51.2 mmol) in anhydrous toluene (300 ml) at room temperature and in an inert atmosphere. The mixture was stirred at this temperature for 1 hour. Following this a solution of and [3-Formyl-4-(2-iodo-benzyloxy)-phenyl]-acetic acid methyl ester (5 g, 12.2 mmol) in anhydrous toluene was added to the mixture and they were stirred at room temperature for 2 h 30 min. Hydrochloric acid 2N was added to the mixture and organic layers were washed by HCl 2N. Aqueous layers were washed with toluene and then they were alkalized with K2CO3. Aqueous layers were extracted with ethyl acetate, filtered, dried and concentrated to dryness to obtain 4.74 g (83%) of [3-(4-Dimethylamino-but-1-enyl)-4-(2-iodo-benzyloxy)-phenyl]-acetic acid methyl ester, which was used, without having been purified in the following step.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[N:29][CH:30]=1)[CH2:8][NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH3:24])[S:22][CH:23]=2)=[CH:15][CH:14]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:6][C@H:7]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[N:29][CH:30]=1)[CH2:8][NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([CH3:24])[S:22][CH:23]=2)=[CH:17][CH:18]=1
Reactant: CC(=O)Nc1ccc([C@H](CNCCOc2ccc(-c3csc(C)n3)cc2)O[Si](C)(C)C(C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc([C@@H](O)CNCCOc2ccc(-c3csc(C)n3)cc2)cn1
Yield: 83.4 %

Procedure:
To a solution of (R)-N-[5-(1-(tert-butyl-dimethyl-silanyloxy)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-pyridin-2-yl]-acetamide (115 mg, 0.218 mmol) in tetrahydrofuran (1.5 mL) was added tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 0.65 mL, 0.65 mmol) at room temperature. The resulting solution was allowed to stir for about two and one-half hours, and the reaction mixture was then partitioned between ethyl acetate and water. The pH of the mixture was adjusted to about 10-11, and the aqueous phase was then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography (methylene chloride to 20% methanol/methylene chloride) to afford 75 mg (83%) of the desired product. LRMS ([M+1]+): 413.2.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.Cl.[SH:44][C@@H:45]1[CH2:49][N:48]([C:50]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=2)=[O:51])[C@H:47]([CH:63]2[CH2:66][N:65]([CH3:67])[CH2:64]2)[CH2:46]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=[C:18]([S:44][C@@H:45]3[CH2:49][N:48]([C:50]([O:52][CH2:53][C:54]4[CH:55]=[CH:56][C:57]([N+:60]([O-:62])=[O:61])=[CH:58][CH:59]=4)=[O:51])[C@H:47]([CH:63]4[CH2:64][N:65]([CH3:67])[CH2:66]4)[CH2:46]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: CN1CC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CN(C)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 80.5 %

Procedure:
The same procedure as in Example 49-1) was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (300 mg, 0.50 mmol) and (2S,4S)-4-mercapto-2-(N-methylazetidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride (195 mg, 0.50 mmol, compound of Reference Example 42) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(N-methylazetidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (280 mg, yield: 80% ).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[I:19]Cl.C(Cl)Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:7]=1[I:19]
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: ClI
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc2nc(-c3ccc(N)c(I)c3)sc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of 2-(4′-aminophenyl)-6-methoxy benzothiazole (22 mg, 0.09 mmol) in glacial acetic acid (2.0 mL) was injected 1 M iodochloride solution in CH2Cl2 (0.10 mL, 0.10 mmol, 1.2 eq.) under N2 atmosphere. The reaction mixture was stirred at room temperature for 16 hr. The glacial acetic acid was removed under reduced pressure and the residue was dissolved in CH2Cl2. After neutralizing the solution with NaHCO3, the aqueous layer was separated and extracted with CH2Cl2. The organic layers were combined and dried over MgSO4. Following the evaporation of the solvent, the residue was purified by preparative TLC(Hexanes:ethyl acetate=6:1) to give 2-(4′-amino-3′-iodophenyl)-6-methoxy benzothiazole (25 mg, 76%) as brown solid. 1HNMR (300 MHz, CDCl3) δ (ppm): 8.35 (d, J=2.0 Hz, 1H), 7.87 (dd, J1=2.0 Hz, J2=9.0 Hz, 1H), 7.31 (d, J=2.2 Hz, 1H), 7.04 (dd, J1=2.2 Hz, J2=9.0 Hz, 1H), 6.76 (d, J=9.0 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30](OC)=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:37])[CH3:36].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[C:35]([O:34][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][O:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:10][CH2:9]1)(=[O:37])[CH3:36]
Reactant: COc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1ccccc1CO2
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)OC1(c2ccc(Cl)cc2)CCN(CCC=C2c3ccccc3COc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-methoxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (Example 2)(200 mg) in dichloromethane (5 ml) were added acetyl chloride (0.06 ml), triethylamine (0.19 ml) and the mixture was stirred at room temperature for 1 hour. Aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:4) to give the titled compound (190 mg).
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Br:13]N1C(=O)CCC1=O>CN(C)C=O>[Br:13][C:7]1[C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:6]
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])cc(Cl)c(Cl)c1Br
Temperature: 100 °C
Yield: 85.9 %

Procedure:
4,5-Dichloro-2-nitroaniline (41.0 g, 198 mmol), N-bromosuccinimide (42.86 g, 241 mmol) and N,N-dimethylformamide were combined and heated to 100° C. for 1 h. The mixture was allowed to cool to room temperature and was poured into a flask containing ice water (1 L). The yellow solid was collected and was dissolved in dichloromethane (2 L), resulting in two phases. The organic layer was collected and was dried over magnesium sulfate, filtered and the solvents were removed under reduced pressure using a rotary evaporator to leave 48.62 g (86%) of a brown solid. Anal. Calcd for C6H3BrCl2N2O2: C, 25.21; H, 1.06; N, 9.80. Found: C, 25.32; H, 1.13; N, 9.68.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24](O)=[O:25])=[C:12]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].Cl>O1CCCC1.CN(C)C=O.COCCOC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:13]([CH2:24][OH:25])=[C:12]2[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Cn1c(C(=O)O)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: C1CCOC1
Product: CC(C)Cn1c(CO)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylic acid (3.42 g, 8 mmol) in tetrahydrofuran (30 mL) were added oxalyl chloride (0.84 mL, 9.6 mmol) and N,N-dimethylformamide (3 drops), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL). The obtained solution was added dropwise to a suspension of sodium tetrahydroborate (1.06 g, 28 mmol) in 1,2-dimethoxyethane (20 mL) at 0° C. The obtained mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give 6-benzyloxy-3-hydroxymethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (2.92 g, 88.5%) as crystals.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10]C(C=O)=[CH:6][CH:5]=1)(O)=[O:2].[CH3:12][O:13][C:14]([O:17][CH3:18])([CH3:16])C.CC1C=CC(S(O)(=O)=O)=CC=1.O.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC>CO.C1COCC1>[CH3:18][O:17][CH:14]([O:13][CH3:12])[C:16]1[CH:10]=[CH:11][C:4]([CH2:1][OH:2])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COC(OC)c1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a suspension of 4-carboxybenzaldehyde (7.51 g, 50 mmol) in dry MeOH (40 ml) was added 8 ml (65 mmol) of 2,2-dimethoxypropane and a catalytic amount of p-TsOH.H2O (190 mg, 1 mmol). The suspension cleared, then a colorless precipitate appeared (5 ml of dry MEOH added) and the thick suspension was stirred over night, before 100 mg of NaHCO5 were added and the mixture was concentrated in vacuo. The residue was tho roughly dried at high vacuum, dissolved in dry THF (50 ml) and added dropwise to an ice cooled slurry of LiAlH4 (1.71 g, 45 mmol) in 40 ml of dry THF. After the addition was complete (30 min), the cooling bath was removed and stirring was continued for 5 h, before the reaction mixture was treated with 1N HCl till Al-salts have precipitated (pH 9-10). The organic layer was decanted and the remaining salts were washed several times with Et2O, then treated with H2O/1N HCl and extracted several times with Et2O. All organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was chromatographed (500 g silica gel +0.5% Et3N, Hex/Et2O 2:3) to afford after crystallization from Hex/Et2O 5.66 g 31.1 mmol, 62%) of a colorless, fluffy powder (m.p. 43.5-45° C.). 1H NMR (400 MHz, CDCl3) d 7.44 (d, J=8.1, 2 H), 7.36 (d, J=m8.1, 2 H), 5.39 (s, 1 H), 4.69 (d, J=5.9, 2 H), 3.32 (s, 6 H), 1.92 (t, J=5.9, 1 H); 13C NMR (100 MHz, CDCl3) d 141.10, 137.31, 126.89, 126.73, 102.86, 64.91, 52.61; HRMS calcd for C10H14O3Na =(M+Na)+ 205.0841, found 205.0847.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH2:18][CH2:19][CH2:20][CH2:21]O)[C:16]2[C:23]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:24][CH:25]=[C:26]([Cl:27])[C:15]=2[N:14]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:13]2=[N:14][C:15]3[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:16]=3[N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(C(F)(F)F)cc3Br)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 863.4 %

Procedure:
To a solution of 4-[2-{[2-bromo-4-(trifluoromethyl)phenyl]amino}-4-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butan-1-ol (Reference Example 57; 109.2 mg, 0.205 mmol) in pyridine (0.5 mL) was added methanesulfonyl chloride (79.3 μL, 1.03 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting crude mesylate (MS Calcd.: 609; Found: 610 (M+H)) was subjected for the next step without further purification. To the crude material in N,N-dimethylformamide (1.0 mL) was added potassium carbonate (56.7 mg, 0.410 mmol). The reaction mixture was stirred at 80° C. for 4 hr. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×35) The combined organic layer was washed with water (×2) and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-20% ethyl acetate/n-hexane gradient mixture. The resulting solid was washed with n-hexane to give the title compound as a colorless powder (810.1 mg, 1.77 mmol, 71% (2 steps)).
Reaction SMILES: [F:1][C:2]([C:17]([F:20])([F:19])[F:18])([O:6][C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3](F)=[O:4].C[Si](C)(C)[O-:23].[K+:26]>CCOCC>[F:1][C:2]([C:17]([F:18])([F:19])[F:20])([O:6][C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:12])([F:10])[F:11])[C:3]([O-:4])=[O:23].[K+:26]
Reactant: C[Si](C)(C)[O-]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CCOCC
Product: O=C([O-])C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Yield: 72 %

Procedure:
The procedure of Example 1 was followed using perfluoro-2-methyl-3-oxahexanoyl fluoride (16.6 g, 50 mmol), potassium trimethylsilanolate (6.41 g, 50 mmol), and dry ether (300 mL). Potassium perfluoro-2-methyl-3-oxahexanoate (12.3 g initially and 0.9 g by concentrating the filtrate under vacuum; total: 13.2 g, 72% yield) was isolated as a white solid: 19F NMR (D2O) δ -81.0 ##STR12##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:6][C:7]1[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)[CH:9]=[CH:10][CH:11]=1.[H][H]>C(O)(=O)C.[Rh]>[CH3:33][O:32][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[O:30][CH3:31])[CH2:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[CH2:6][C:5]1[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(Cc2cccn2CCCCCCn2cccc2Cc2ccc(OC)c(OC)c2)cc1OC
Reactant: [H][H]
Agent: [Rh]
Solvent: CC(=O)O
Product: COc1ccc(CC2CCCN2CCCCCCN2CCCC2Cc2ccc(OC)c(OC)c2)cc1OC
Yield: 92 %

Procedure:
A solution of 1,6-bis[2-(3,4-dimethoxybenzyl)pyrrol-1-yl]hexane (2.5 g) in glacial acetic acid (30 mL) containing suspended 5% rhodium on alumina catalyst (1.87 g) was reduced at room temperature and an initial hydrogen pressure of 45 p.s.i.g. (3 hour reaction, followed by TLC). The mixture was filtered through Celite. The filtrate was dried at reduced pressure, and the residue dissolved in dichloromethane, washed with ammonium hydroxide solution and dried over sodium sulfate. The solvent was removed in vacuo, and the residue subjected to column chromatographic purification on silica gel (100 g) using dichloromethane, to elute 1,6-bis[2-(3,4-dimethoxybenzyl)pyrrolidin-1-yl]hexane, 2.5 g (92% yield) as an oil.