Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:22]=[C:21]3[C:13]([C:14]4[C:15](B5OC(C)(C)C(C)(C)O5)=[CH:16][CH:17]=[C:18]([C:23]([NH2:25])=[O:24])[C:19]=4[NH:20]3)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.Br[C:36]1[C:44]([F:45])=[C:43]2[C:39]([CH:40]=[CH:41][NH:42]2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:45][C:44]1[C:36]([C:15]2[C:14]3[C:13]4[C:21](=[CH:22][C:10]([C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[O:9])=[CH:11][CH:12]=4)[NH:20][C:19]=3[C:18]([C:23]([NH2:25])=[O:24])=[CH:17][CH:16]=2)=[CH:37][CH:38]=[C:39]2[C:43]=1[NH:42][CH:41]=[CH:40]2
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(B4OC(C)(C)C(C)(C)O4)c23)CC1
Reactant: Fc1c(Br)ccc2cc[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4ccc5cc[nH]c5c4F)c23)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
A mixture of 7-(4-methylpiperazine-1-carbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole-1-carboxamide (prepared according to the procedure of Step 1 of Example 2-1, 75 mg, 0.065 mmol), 6-bromo-7-fluoro-1H-indole (prepared according to U.S. pat. appl. 2007/112005, 18.7 mg, 0.087 mmol), and 2 M aqueous sodium carbonate (0.081 mL, 0.162 mmol) in toluene (0.8 mL) and ethanol (0.2 mL) was purged with argon, treated with tetrakis(triphenylphosphine)palladium (7.5 mg, 0.007 mmol) and heated at 90° C. After 16 h, the mixture was cooled to rt. The residue was purified by preparative HPLC. The resulting TFA salt was partitioned between NaHCO3 (aq) and EtOAc, and the organic extracts were dried and concentrated to provide 4-(7-fluoro-1H-indol-6-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as an off-white solid (9 mg, 30%). 1H NMR (400 MHz, methanol-d4) δ 7.99 (d, J=7.5 Hz, 1H) 7.68 (d, J=0.9 Hz, 1H) 7.52 (d, J=7.9 Hz, 1H) 7.39 (d, J=3.5 Hz, 1H) 7.25 (dd, J=8.1, 1.1 Hz, 1H) 7.21 (d, J=7.5 Hz, 1H) 7.08 (dd, J=8.1, 6.4 Hz, 1H) 6.92 (dd, J=8.1, 1.5 Hz, 1H) 6.63 (t, J=3.3 Hz, 1H) 3.77 (br. s., 2H) 3.49 (br. s., 2H) 2.51 (br. s., 2H) 2.39 (br. s., 2H) 2.30 (s, 3H). Mass spectrum m/z 470.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH:13]([CH2:15][CH2:16][CH:17]([CH3:21])[CH:18]([CH3:20])[CH3:19])[CH3:14]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:13]([CH3:14])[CH2:15][CH2:16][CH:17]([CH3:21])[CH:18]([CH3:20])[CH3:19])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(Br)CCC(C)C(C)C
Product: COC(=O)c1ccc(OC(C)CCC(C)C(C)C)cc1

Procedure:
By utilizing the procedure of Example 19, by reacting p-hydroxybenzoic acid methyl ester with 2-bromo-5,6-dimethyl heptane, there is obtained p-[(1,4,5-trimethylhexyl)oxy]benzoic acid methyl ester; nD25 = 1.4938.
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9]O)=[O:8])=[CH:5][CH:4]=[C:3]([F:11])[CH:2]=1.CI.[H-].[Na+].CN(C)[CH:18]=[O:19]>>[CH3:9][C:7]([C:6]1[CH:5]=[CH:4][C:3]([F:11])=[CH:2][C:1]=1[O:19][CH3:18])=[O:8]
Reactant: O=C(CO)c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COc1cc(F)ccc1C(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 13.9 g. of 2-hydroxy-4-fluoroacetophenone and 75 ml. of dried dimethylformamide were added 30 ml. of methyl iodide. The solution was cooled to 0° C. and 4.1 g. of a 50% oil dispersion of sodium hydride were carefully added. After stirring for 1 hour at 0° C., the reaction was extracted with ethyl acetate. The organic extract was washed three times with 200 ml. each of 1N hydrochloric acid. The ethyl acetate solution was then dried and removed in vacuo. This reaction and a subsequent identical reaction provided a total of 28 g. of 2-methoxy-4-fluoroacetophenone as an oil which was used in the subsequent step without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=[N:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)N
Reactant: O=Cc1ccccc1CCCCCCCCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)N=Cc1ccccc1CCCCCCCCc1ccccc1
Yield: 93.4 %

Procedure:
A stirred solution of 2-(8-phenyloctyl)benzaldehyde (10 g, 0.034 mol), and t-butylamine (4.96 g, 0.068 mol) in toluene (100 mL) was refluxed under standard Dean-Stark conditions for 16 h. The solution was evaporated to an oil which was vacuum distilled (bp 260° C., 0.15 mm Hg) to afford the titled product (11.1 g, 94%): GC RT 19.8 min (DB-1, 30 m×0.53 mm, program, 100° C. for 5 min, 100°-260° C. at 15° C./min, hold at 260° C. for 12 min.); 1H NMR (CDCl3, 400 MHz) δ 8.58 (s, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.29-7.13 (m, 8H), 2.79 (t, J=7.5 Hz, 2H), 2.58 (t, J=7.5 Hz, 2H), 1.59-1.51 (m, 12H), 1.30 (s, 9H).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]([CH2:20][C:21]([CH3:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[CH2:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[OH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]([CH2:20][C:21]([CH3:29])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])[CH2:11]1
Reactant: COC(=O)N1CCC(CO[Si](C)(C)C(C)(C)C)CC1CC(C)(C)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COC(=O)N1CCC(CO)CC1CC(C)(C)c1ccccc1

Procedure:
The compound was prepared as described in Reference Compound 4, Step 4 starting from crude methyl 4-((tert-butyldimethylsilyloxy)methyl)-2-(2-methyl-2-phenylpropyl)piperidine-1-carboxylate (16.5 g) and TBAF (46.5 mL, 46.6 mmol, 1 M in THF). The residue was purified by column chromatography (Biotage 40-65% gradient EtOAc in heptane, 340 snap column, 2 runs), which resulted in the titled compound. MS m/z 306 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[C:22]([O:26][C:27]([NH:29][CH:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36]2[N:40]([CH2:41][C:42]#[C:43][CH3:44])[C:39]([C:45](O)=[O:46])=[CH:38][N:37]=2)[CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:41]([N:40]1[C:39]([C:45]([NH:1][CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)=[O:46])=[CH:38][N:37]=[C:36]1[N:32]1[CH2:33][CH2:34][CH2:35][CH:30]([NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:31]1)[C:42]#[C:43][CH3:44]
Reactant: CC#CCn1c(C(=O)O)cnc1N1CCCC(NC(=O)OC(C)(C)C)C1
Reactant: NCc1cccc2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCn1c(C(=O)NCc2cccc3ccccc23)cnc1N1CCCC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.09 ml 1-aminomethylnaphthalene and 0.28 ml ethyldiisopropylamine are added to a solution of 0.20 g 2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-3-(but-2-ynyl)-3H-imidazole-4-carboxylic acid and 0.19 g O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate in 5 ml of dimethylformamide. The solution is stirred for 3 h at ambient temperature and then combined with saturated aqueous potassium carbonate solution. Then the mixture is extracted with ethyl acetate, the organic extracts are dried over sodium sulphate, and the solvent is removed. The residue is purified on silica gel (dichloromethane/methanol 1:0->7:3).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][N:25]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCNC2)c2cnccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCN(S(C)(=O)=O)C2)c2cnccc12
Reaction time: 2 h

Procedure:
To a solution of 1-({5-chloro-1-[(3R)-(pyrrolidin-3-yl)]-1H-benzo[d]imidazol-2-yl}methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (200 mg, 0.46 mmol) and Et3N (0.2 mL) in 8 mL of DCM was added 80 mg of methanesulfonyl chloride. The mixture was stirred for 2 hours. The mixture was then purified by preparative-HPLC to give the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([OH:30])=O)[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:31][N:32]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([NH:32][OH:31])=[O:30])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)c3cccs3)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(C(=O)c3cccs3)CC2)cc1

Procedure:
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(2-thienylcarbonyl)-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)-4-piperidinecarboxylic acid (335 mg, 0.75 mmol) in dimethylformamide (7 ml), 1-hydroxybenzotriazole(121 mg, 0.90 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (201 mg, 1.05 mmol), N-methylmorpholine (0.124 ml, 1.13 mmol), and hydroxylamine (0.229 ml, 3.75 mmol), 216 mg (62%) of the product was isolated as a solid. HR—MS: m/z Calculated for C21H22N2O6S2 463.0992; Found 463.0988.
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].Cl>O1CCOCC1>[Br:1][C:2]1[N:3]=[N:4][C:5]([NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:10]([Cl:9])[CH:11]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nn1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1cccc(Nc2ccc(Br)nn2)c1
Yield: 25.1 %

Procedure:
3,6-Dibromopyridazine (1 g, 4.20 mmol) was added to a solution of 3-chloroaniline (0.536 g, 4.20 mmol) in 1,4-dioxane (10 mL) followed by 4M HCl in 1,4-dioxane (6 mL, 24 mmol). The mixture was refluxed for 3 h. The slurry obtained was filtered, and the crude product was purified by preparative HPLC to afford the title compound 21D (0.3 g, 23%) as a solid. 1H NMR (300 MHz, DMSO-d6): δ 9.67 (s, 1H), 8.09 (t, J=1.8 Hz, 1H), 7.7 (d, J=9.0 Hz, 1H), 7.5 (dd, J1=9.0 Hz, J2=0.9 Hz, 1H), 7.35 (t, J=8.1 Hz, 1H), 7.12 (d, J=9.6 Hz, 1H), 7.05 (dd, J1=8.1 Hz, J2=0.9 Hz, 1H). ESI-MS m/z: 284 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70]>CN(C=O)C.ClCCl.C1(C)C=CC=CC=1.C(O)C>[OH:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH3:60])=[CH:3][CH:4]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1
Reactant: CCCCCCCCCCCBr
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reaction time: 1.5 h

Procedure:
To a vigorously-stirred suspension of 5,10,15,20-tetrakis-(4-hydroxy-phenyl)-porphyrin (400 mg, 0.59 mmol) and K2CO3 (1.0 g, 7.1 mmol) in DMF (75 mL), a solution of 1-bromoundecane (0.1 mL, 0.45 mmol) in DMF (10 mL) is added dropwise at 50° C. during 30 mins and the mixture is stirred at the same temperature for 1.5 h. After removal by filtration of K2CO3 and removal under reduced pressure of DMF, the residue obtained is dissolved in dichloromethane (200 mL), washed with water (3×150 mL) and the solution dried (Na2SO4). The solvent is evaporated under reduced pressure and the residue obtained is dissolved in toluene:ethanol (5:1 by vol., ca. 10 mL) and purified by chromatography using a column (5×50 cm) of silica gel (Merck 60). The column is eluted with toluene followed by toluene:ethyl acetate (2:1 by vol.) and the desired material recovered by evaporation of solvent from the appropriate fractions is dried under high vacuum. The product is obtained as violet crystals.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]1[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:16]=1[NH2:17]>>[Br:22][C:20]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([F:10])[CH:5]=[C:6]([F:9])[C:7]=2[F:8])=[C:15]([F:14])[CH:21]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Product: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(Br)cc1F
Yield: 0.1 %

Procedure:
Intermediate I-2a was prepared from 2,3,4,6-tetrafluoronitrobenzene (25 g, 128 mol) and 2-fluoro-4-bromoaniline (24.36 g, 128 mol) using procedures analogous to those described above for the preparation of Intermediate (I-1a) to afford 25 g of the product (64% yield). H1NMR (DMSO-d6, 300 MHz): δ 8.84 (s, 1H), 7.70-7.60 (m, 1H), 7.56 (dd, 1H), 7.29 (d, 1H), 7.04 (t, 1H). LCMS: 99.02%, m/z=366.9 (M+2).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:37]=[CH:36][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]([NH:31][CH2:32][C@H:33](O)[CH3:34])=[O:30])=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:38])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[N:1]1([C:5]([C:7]2[CH:37]=[CH:36][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]5[O:30][C@@H:33]([CH3:34])[CH2:32][N:31]=5)=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:38])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.9 %

Procedure:
5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-N-[(2R)-2-hydroxypropyl]-1H-pyrrole-2-carboxamide (464 mg, 0.883 mmol) synthesized in Example (69a) was dissolved in tetrahydrofuran (17 mL), and anhydrous methanesulfonic acid (558 mg, 3.20 mmol) and triethylamine (860 μL, 6.20 mmol) were added, followed by stirring at room temperature for 3 days under nitrogen atmosphere. To the reaction solution, saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/dichloromethane=3%-9%) to afford the desired compound (228 mg, yield 51%) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[C:12]([O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH3:2][O:3][C:4](=[O:11])[CH:5]1[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6]1.[C:20]([O:19][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21]
Reactant: COC(=O)C1CCNCC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h

Procedure:
To a solution of isonipecotic acid methyl ester HCl (2-3b) (34 g, 0.19 mol), and di-tert-butyl dicarbonate (43.5 g, 0.2 mol) in THF (300 mL) and H2O (150 mL) was added-K2CO3 (28.8 g, 0.21 mol). After 4 hours, the mixture was poured into water, extracted with EtOAc then washed with brine, dried (MgSO4) and evaporated to give the title compound 2-3c as an oil with a small amount of di-tert-butyl dicarbonate.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[I-:20].[NH4+]>C1C=CC=CC=1>[I-:20].[C:1]1([S+:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 70 °C
Yield: 145.1 %

Procedure:
50 g of diphenyl sulfoxide was dissolved in 800 ml of benzene and thereto, 200 g of aluminum chloride was added and refluxed for 24 hours. The reaction solution was gradually poured into 2 L of ice and thereto, 400 ml of concentrated hydrochloric acid was added and heated at 70° C. for 10 minutes. This aqueous solution was washed with 500 ml of ethyl acetate and filtered. Thus, a solution obtained by dissolving 200 g of ammonium iodide was added thereto. The powder precipitated was collected by filtration, washed with water, washed with ethyl acetate and then dried. Thus, 70 g of triphenylsulfonium iodide was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:15](=[O:16])[N:14](CC2C=CC(OC)=CC=2OC)[C@@H:13]1[CH2:28][N:29]1[C:33](=[O:34])[CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:30]1=[O:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OP([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:28][N:29]1[C:33](=[O:34])[CH2:32][N:31]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[C:30]1=[O:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CN2C(=O)CN(C(=O)OC(C)(C)C)C2=O)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(=O)N(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)C1=O
Temperature: 90 °C
Yield: 23.1 %

Procedure:
Prepared in an analogous manner to example 4, step 2 using tert-butyl 3-(((2R,3S)-3-(((benzyloxy)carbonyl)amino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-2-yl)methyl)-2,4-dioxoimidazolidine-1-carboxylate (900 mg, 1.70 mmol) K2S2O8 (280 mg, 2.89 mmol), and K2HPO4 (680 mg, 2.91 mmol) in ACN:water (2:1, 30 mL) while heating at 90° C. for 4 h. After cooling to rt, the mixture was filtered and the filtrate was concentrated in vacuo, removing most of the ACN. The mixture was diluted with water/EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 2-6%) to afford the title compound (170 mg, 23%). LCMS: m/z=431.0 (M−1).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[CH2:30]([C:32]1[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)[CH3:31]>CCCCCCC>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:3])[N:38]([C:35]3[CH:36]=[N:37][C:32]([CH2:30][CH3:31])=[CH:33][CH:34]=3)[CH2:23][CH2:22]2)[CH2:7][CH2:8]1)(=[O:13])=[O:14]
Reactant: CCc1ccc(N)cn1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cn1

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in heptane and 6-Ethyl-pyridin-3-ylamine. MS (ESI): 434.3 (MH+).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:10](=[O:11])[C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[C:6](=[O:7])[C:5]=1[CH2:16]/[CH:17]=[C:18](/[CH2:20][CH2:21]/[CH:22]=[C:23](/[CH2:25]C/C=C(/CC/C=C(/CC/C=C(/CC/C=C(/CC/C=C(/CC/C=C(/CC/C=C(/CCC=C(C)C)\C)\C)\C)\C)\C)\C)\C)\[CH3:24])\[CH3:19]>>[CH3:3][C:4]1[C:10]([OH:11])=[C:9]([O:12][CH3:13])[C:8]([O:14][CH3:15])=[C:6]([OH:7])[C:5]=1[CH2:16]/[CH:17]=[C:18](/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])\[CH3:19]
Reactant: COC1=C(OC)C(=O)C(C/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C)=C(C)C1=O
Agent: [BH4-]
Agent: [Na+]
Product: COc1c(O)c(C)c(C/C=C(\C)CCC=C(C)C)c(O)c1OC

Procedure:
Methanolic solution of coenzyme Q10 (1 mg/ml) was reduced by NaBH4 to pH 8 when the yellow solution became colorless. About 1 mg of 3,8-(OH)2-DBP was added to the solution and the mixture was analyzed by HPLC at different time intervals (0-80 min). A control CoQ10, without 3,8-(OH)2-DBP, was prepared similarly and analyzed at different time intervals (0-80 min).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:52])=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]5[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[C@@H:40]([CH3:51])[CH2:39]5)[CH:32]=4)[CH:30]=3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)C.[H-].[Na+].Br[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]>CN(C=O)C>[F:52][C:28]1[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][NH:41][C@@H:40]([CH3:51])[CH2:39]3)[CH:32]=2)=[CH:30][C:25]([CH2:24][N:23]([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[C:21](=[O:22])[C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:16]=2)=[CH:26][CH:27]=1
Reactant: CCCCCCBr
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN(Cc1ccc(F)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1)C(=O)c1cccc(CC2CCNCC2)c1
Yield: 26.1 %

Procedure:
Following the general procedure outlined in Example 66, 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]phenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (75.4 mg, 0.105 mmol), NaH (5.37 mg, 0.243 mmol) and 1-bromohexane (0.020 mL, 0.142 mmol) in DMF (0.5 mL) were reacted to give the desired product (16.4 mg, 24.0%). EI-MS m/z 599(M−H)+.