Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=O)[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].O.[NH2:26][NH2:27]>C(O)C>[O:1]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:26][NH2:27])=[O:23])[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]
Reactant: NN
Reactant: COC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Solvent: CCO
Solvent: O
Product: NNC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 92 %

Procedure:
Compound 1 (1 g) was dissolved in a mixture of ethanol (5 ml) and 85% hydrazine hydrate (2 ml). After 24 h the solvent was evaporated and residual traces of hydrazine removed by co-evaporation with toluene to give 8-hydrazinocarbonyloctyl β-D-galactopyranoside as a white solid which was recrystallized from ethanol, mp 194°, [α]D18 - 2.16° (c 1.1, water) 92% yield.
Reaction SMILES: O[N:2]1[C:10]2[C:5](=[C:6]([I:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:12].C(N(S(F)(F)[F:19])CC)C>ClCCl.C(OCC)(=O)C.ClCCl>[F:19][C:7]1[C:6]([I:11])=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:2][C:3](=[O:12])[CH2:4]2
Reactant: O=C1Cc2c(I)cccc2N1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1Cc2c(ccc(F)c2I)N1
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1,3-dihydro-1-hydroxy-4-iodo-2H-indol-2-one, (2.43 g, 9 mmol) (see below) in dry dichloromethane (500 mL) was cooled to −25° C. under an argon atmosphere with magnetic stirring. A solution of (diethylamino)sulfur trifluoride (DAST, 1.35 mL) (Aldrich) in dry dichloromethane (40 mL) was added dropwise at such a rate that the reaction temperature did not rise above −25° C. (about 15 min.). After stirring for an additional 30 min. at −25° C., the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (180 mL) and allowed to warm to room temperature. The mixture was then filtered through Celite® (Fisher Scientific) and the layers separated. The aqueous layer was extracted with dichloromethane (2×300 mL). The dichloromethane layers were washed with saturated aqueous sodium chloride solution (200 mL), combined, dried (magnesium sulfate) and concentrated. Residue was purified by flash chromatography on sitics get using ethyl acetate-dichloromethane (1:7, V/V) as solvent to give 1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one. (Yield 1.08 g, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:28]([O:30]C)=[O:29])=[C:20]([C:22]4[N:26]([CH3:27])[N:25]=[CH:24][N:23]=4)[N:21]=3)[CH2:13][C@@H:12]2[O:32][CH2:33][CH2:34][CH3:35])=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:28]([OH:30])=[O:29])=[C:20]([C:22]4[N:26]([CH3:27])[N:25]=[CH:24][N:23]=4)[N:21]=3)[CH2:13][C@H:12]2[O:32][CH2:33][CH2:34][CH3:35])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CCCO[C@H]1CN(c2nc(-c3ncnn3C)c(C(=O)OC)s2)CC[C@H]1NC(=O)c1cc(Cl)c(C)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCO[C@@H]1CN(c2nc(-c3ncnn3C)c(C(=O)O)s2)CC[C@@H]1NC(=O)c1cc(Cl)c(C)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
Methyl 2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate (Example 196, 80 mg, 0.153 mmol) was dissolved in methanol (30 mL), and 2N sodium hydroxide (6 mL) was added and stirred at room temperature for 4 h. The methanol was completely evaporated and water (20 mL) was added. The aqueous layer was washed with diethyl ether (2×20 mL) and the aqueous layer was acidified to pH 3 with 2N hydrochloric acid (2.0 mL). The obtained solid was filtered and dried to afford 2-[(3R,4S)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylic acid 60 mg (75%) as solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH2:20])[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH:20][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(Br)ccc1Oc1ccccc1
Product: Cc1ccc2c(Nc3cc(Br)ccc3Oc3ccccc3)ccnc2n1

Procedure:
The product from Example 1d (278 mg, 1.56 mmol) was reacted with the product from Example 124b (412 mg, 1.56 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (206 mg, 25%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.73 (s, 3 H) 6.69 (d, J=7.35 Hz, 2 H) 6.96 (d, J=7.72 Hz, 2 H) 7.05-7.15 (m, 3 H) 7.24-7.36 (m, 2 H) 7.68 (dd, J=8.82, 2.57 Hz, 1 H) 7.75 (d, J=8.46 Hz, 1 H) 7.82 (d, J=2.21 Hz, 1 H) 8.52 (d, J=6.99 Hz, 1 H) 8.86 (d, J=8.82 Hz, 1 H) 10.93 (s, 1 H) 14.49 (s, 1 H); MS (ESI+) m/z 408 (M+H−TFA)+.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].CN(C)[CH:15]=[O:16]>>[O:16]1[CH:15]=[CH:1][CH:2]=[C:10]1[CH2:9][CH2:8][CH2:7][CH2:3][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: CN(C)C=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1CCCCc1ccco1
Temperature: 0 °C

Procedure:
2[1-(4-bromobutyl)]furan (406 mg) and potassium phthalimide (370 mg) were stirred together at room temperature in dry dimethylformamide overnight. The solution was poured into ice-water and the resulting white solid filtered, dried and recrystallised from chloroform/petroleum ether (b.p. 60°-80°) to give 2-[4-(2-Furanyl)butyl]-1H-isoindole-1,3-(2H)-dione as white microcrystals (430 mg) m.p. 61°-63°.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:26]=[CH:25][C:24]3[CH2:23][CH2:22][C:21]4[C:27]([C:31]([NH:33][C:34]5[C:39]([CH2:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=5[CH2:42][CH3:43])=[O:32])=[N:28][N:29]([CH3:30])[C:20]=4[C:19]=3[N:18]=2)=[C:12]([O:44][CH3:45])[CH:11]=1)(C(C)(C)C)(C)C>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH2:40]([C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:42][CH3:43])[C:34]=1[NH:33][C:31]([C:27]1[C:21]2[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][C:12]=4[O:44][CH3:45])=[N:18][C:19]=3[C:20]=2[N:29]([CH3:30])[N:28]=1)=[O:32])[CH3:41]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(CO[Si](C)(C)C(C)(C)C)cc3OC)nc1-2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(CO)cc3OC)nc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 8-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methoxyphenyl]amino}-N-(2,6-diethylphenyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (300 mg, 0.48 mmol) in 6 ml of dry THF, 800 μl of commercial TBAF solution in THF were added. The mixture was stirred at room temperature for 1 h and the to solvent removed in vacuo. The crude was washed with water, extracted with ethyl acetate, dried on anhydrous Na2SO4 and evaporated to dryness affording the title compound in 85% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl.O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(NC2CCNCC2)cc1
Yield: 67.2 %

Procedure:
A solution of 1,1-dimethylethyl 4-[(4-fluorophenyl)amino]-1-piperidinecarboxylate (D1) (1.6 g) in 2M HCl (5 ml) and 1,4-dioxane (20 ml) was heated at 60° C. for 24 h. On cooling, the solution was diluted with water, basified with 2M NaOH solution and extracted with EtOAc (×3). The combined organics were dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow oil (0.71 g). δH (CDCl3, 250 MHz) 6.88 (2H, t), 6.54 (2H, dd), 3.30 (1H, m), 3.20 (2H, m), 2.70 (2H, m), 2.05 (2H, m), 1.69 (2H, br), 1.29 (2H, m).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].C(#N)C>O.C(O)CCC>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCCCO
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in water (0.5 ml) and butan-1-ol (8 ml). The mixture was stirred at about 80EC for 4 h, after which the starting material was not detected by HPLC. Then, acetonitrile (40 ml) was dripped into the solution and the mixture was cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (15 ml) and dried at 50EC in a vacuum oven for 24 h to obtain fluvastatin sodium Form VI (1.65 g, 81%).
Reaction SMILES: [F:1][C:2]([F:59])([F:58])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]([CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:20][C@H:21]([OH:50])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:26]([N:38](C(OC(C)(C)C)=O)[S:39]([CH3:42])(=[O:41])=[O:40])[CH:25]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].ClCCl>FC(F)(F)C(O)=O>[F:58][C:2]([F:1])([F:59])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:14][CH2:15][C@H:16]([N:19]([CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[CH2:20][C@H:21]([OH:50])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:26]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:25]=3)[CH2:17][CH2:18]2)=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: CC(C)(C)OC(=O)N(c1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)CC2)ccc1OCc1ccccc1)S(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)CC2)ccc1OCc1ccccc1

Procedure:
A solution of 1.4 g of trans-4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(tert-butoxycarbonyl)(methylsulfonyl)amino]phenoxy)-2-hydroxy-propyl)amino]cyclohexyl}phenyl trifluoromethanesulfonate (1.62 mmol) in a mixture of trifluoroacetic acid (5 ml) and of dichloromethane (45 mol) is stirred for 3 h 20. The solvents are evaporated under reduced pressure and then water, ethyl acetate and an aqueous ammonium solution are added. The organic phase is washed once with water and dried over sodium sulfate. trans-4-{4-[Benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenyl trifluoromethanesulfonate is obtained in the form of an oil (1.27 g, 98%) after evaporation of the solvents under reduced pressure. [M+H+]=763.5.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]2[N:6]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:21])[C:7](=[O:18])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:50]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[N:49]=1.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O.O>[F:1][C:2]1[CH:35]=[CH:34][C:5]2[N:6]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[O:21])[C:7](=[O:18])[CH:8]([CH2:47][C:48]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[N:50]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[N:49]=3)[C:9](=[O:17])[N:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccnc3)c3cc(F)ccc32)C(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3cccnc3)c3cc(F)ccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 65.4 %

Procedure:
To a solution of 0.400 g of 2-(7-fluoro-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part E, (0.839 mmol) in 5 mL dimethylformamide at 0° C. under nitrogen is added 2.01 mL (1.01 mmol, 1.2 equiv) potassium bis(trimethylsilyl)amide (0.5M in toluene) dropwise over 5 min. After stirring 10 min., 287 mg of 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole (0.923 mmol, 1.1 equiv) is added. After 15 min., the reaction is added to a mixture of ethyl acetate, saturated aqueous brine, and water with vigorous agitation. The mixture is transferred to a separatory funnel and the layers were separated. The organic layer is washed with 1:1 water/saturated aqueous brine, saturated aqueous brine, and then dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue. The residue is purified on flash grade silica with 2:3 ethyl acetate/hexane (500 mL) followed by 3:2 ethyl acetate/hexane (1000 mL). The appropriate fractions were combined, evaporated in vacuo to a residue, and triturated with hexane. Hexane is removed in vacuo to provide 388 mg of the title compound as a white solid: 1H NMR (300 MHz, CDCl3) δ8.69 (s, br, 1H), 8.58 (d, 1H, J=4.6), 8.20 (s, br, 1H), 8.02 (d, 1H, J=8.2), 7.84 (d, 1H, J=7.9), 7.57 (s, 1H), 7.50 (m, 1H), 7.32 (m, 2H), 7.14 (d, 2H, J=8.8), 7.05 (m, 1H), 6.97 (m, 2H), 6.61 (dd, 1H, J=2.8, 9.2), 4.92 (m, 1H), 4.52 (d, 1H, J=18.4), 4.40 (dd, 1H, J=5.1, 8.7), 4.04 (d, 1H, J=18.4), 3.85 (s, 3H), 3.81 (m, 1H), 3.53 (dd, 1H, J=5.2, 16.7), 1.66 (s, 9H), 1.03 (m, 6H). TLC Rf =0.50 (ethyl acetate/hexane 7/3).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[Br:16]Br.O>C(O)(=O)C>[NH2:1][C:2]1[C:3]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][C:10]=1[Br:16]
Reactant: BrBr
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(Br)cc(C(=O)O)cc1OC(F)(F)F
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of 4-amino-3-trifluoromethoxybenzoic acid (5 g, 22.6 mmoles) in acetic acid (50 mL), bromine (3.98 g, 24.9 mmoles) in acetic acid (10 mL) was added dropwise at room temperature. After the reaction mixture was kept stirring for one hour, water was added into the mixture. The solid was filtered and washed with water to give 4-amino-3-bromo-5-trifluoromethoxybenzoic acid (3.9 g, 54.9%).
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[CH3:31][NH:30][S:29]([C:26]1[CH:27]=[CH:28][C:20]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])(=[O:33])=[O:32]
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: C1COCCN1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: CNS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Yield: 40 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-methylsulfamoyl-benzoic acid and morpholine and obtained in 40% yield. MS (m/e): 299.2 (MH−, 100%).
Reaction SMILES: [Li+].C[Si]([N-:6][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>CCCCCC.C(OCC)C>[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]([NH2:6])=[NH:17])=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOCC
Product: N=C(N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
380 mL 1N LiHMDS-solution in n-hexane was added to 20 g 4-fluoro-benzonitrile in 1 L diethylether. The reaction was stirred 2 h at RT and 4N HCL solution was added at 0° C. until pH=12. The water layer was extracted with chloroform. The organic layer was dried and evaporated to give 6.64 g of the desired product. Rt: 2.28 min (method K), (M+H)+: 139
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([CH2:11][CH2:12][CH2:13][NH:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([O-])=O)([O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O)=O>CO>[CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([CH2:11][CH2:12][CH2:13][N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2C[C@@H]3CCCN[C@@H]3C2)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(=O)[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
The preparation comprises stirring [1S,6S]-8-benzyl-2,8-diazabicyclo[4,3,0]nonane (5.0 g, 23.1 mmol) in methanol (50 mL) at room temperature, adding batchwise tertbutyloxycarbonyl dicarbonate (5.1 g, 23.4 mmol), stirring for 0.5 h, vacuum distilling to remove solvent, and column chromatographing with petroleum ether and ethyl, acetate at the ratio of 10:1 to give [1S,6S]-8-benzyl-2-tertbutyloxycarbonyl-2,8-diazabicyclo[4,3,0]nonane (7.1 g, 97.2%), [α]20D=−72.4° (CHCl3, C=5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18]C2CCN(C3CCCN(CC4C=CC=CC=4)C3)CC2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH2:18])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Fc1ccc(Cn2c(NC3CCN(C4CCCN(Cc5ccccc5)C4)CC3)nc3ccccc32)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1nc2ccccc2n1Cc1ccc(F)cc1
Yield: 91.5 %

Procedure:
A mixture of 11.3 parts of 1-[(4-fluorophenyl)methyl]-N-[1'-(phenylmethyl) -[1,3'-bipiperidin]-4-yl]-1H-benzimidazol-2-amine and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 8.5 parts (91.5%) of N-([1,3'-bipiteridin]-4-yl)-1-[(4-fluorophenylmethyl]-1H-benzimidazol-2-amine (57).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:11]=[CH:12][C:13]=2[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[CH:26]=[CH:27][N:28](S(C3C=CC(C)=CC=3)(=O)=O)[C:4]=2[C:3]1=[O:39].[C:40](=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:40][N:21]([C:10]1[CH:11]=[CH:12][C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([C:6]2[C:5]3[CH:26]=[CH:27][NH:28][C:4]=3[C:3](=[O:39])[N:2]([CH3:1])[CH:7]=2)[CH:9]=1)[S:22]([CH3:25])(=[O:23])=[O:24]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(NS(C)(=O)=O)ccc4Oc4ccccc4)cn(C)c(=O)c32)cc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(c1ccc(Oc2ccccc2)c(-c2cn(C)c(=O)c3[nH]ccc23)c1)S(C)(=O)=O
Yield: 14.2 %

Procedure:
A mixture of Example 7d (0.113 g, 0.2 mmol) and potassium carbonate (0.111 g, 0.800 mmol) in methanol (0.9 mL) and water (0.1 mL) was heated at 100° C. for 1 hour. The reaction was partitioned between ethyl acetate and water adjusting the pH to 7. The organic layer was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by reverse phase HPLC (C18, 10-100% CH3CN/water (0.1% TFA)) to afford the title compound (0.012 g, 14%). 1H NMR (300 MHz, DMSO-d6) δ 2.99 (s, 3H) 3.27 (s, 3H) 3.51 (s, 3H) 6.27-6.32 (m, 1H) 6.93 (d, J=7.80 Hz, 2H) 6.99 (d, J=8.82 Hz, 1H) 7.03-7.10 (m, 1H) 7.25-7.34 (m, 4H) 7.40 (dd, J=8.65, 2.88 Hz, 1H) 7.55 (d, J=2.71 Hz, 1H) 12.01 (s, 1H). MS (ESI+) m/z 424 [M+H]+.
Reaction SMILES: Cl[CH:2]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:34][CH:33]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:5][CH:4]=1.[CH2:61]([NH2:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[CH2:61]([NH:68][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:34][CH:33]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:5][CH:4]=1)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: NCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(Cl)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(NCc2ccccc2)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To chloro-bis(4-docosyloxyphenyl)methane (75.9 mg, 89.1 μmol) were added chloroform (1 ml), benzylamine (29.1 μl, 267 μmol), and N-ethyldiisopropylamine (45.7 μl, 267 μmol), and the mixture was stirred at room temperature overnight. The reaction mixture was warmed to 50° C. and stirred for 1 hour. The mixture was cooled to room temperature again, and washed successively with 0.5N hydrochloric acid, 10% aqueous sodium hydrogen carbonate and 20% brine. The organic layer was dehydrated with anhydrous sodium sulfate, chloroform was evaporated, and the residue was precipitated with methanol to give N-benzyl-[bis(4-docosyloxyphenyl)]methylamine (72 mg, 87%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1N.[N+]([NH:12][C:13]1C=CC=[CH:15][CH:14]=1)([O-])=O.S(=O)(=O)(O)O.[As](=O)(O)(O)O.[N+](C1C=C(S(O)(=O)=O)C=CC=1)([O-])=O>OCC(CO)O>[NH2:12][C:13]1[CH:14]=[CH:15][C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=1
Reactant: Nc1ccccc1N
Reactant: O=[N+]([O-])Nc1ccccc1
Agent: O=S(=O)(O)O
Agent: O=[As](O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Solvent: OCC(O)CO
Product: Nc1ccc2ccccc2n1

Procedure:
In a Skraup synthesis, a phenylene diamine (148) or a nitroaniline is reacted with glycerine (149) and sulfuric acid or arsenic acid and an oxidizing agent, such as m-nitrobenzene sulfonic acid (Scheme 66). ##STR86## An intermediate amino- or nitro-guinoline or isoguinoline is produced. In the case of the amino-quinoline, it is not isolated, as it reacts immediately with excess reagents to yield the phenanthroline. If a nitro-aniline has been used to produce a nitroguinoline, it is isolated and purified if necessary. This often removes large amounts of tars produced by the Skraup synthesis. The nitro group is then reduced by standard conditions to yield an aminoquinoline. The aminoquinoline is then subjected to another Skraup reaction (sulfuric or arsenic acid, or both, glycerins and m-nitrobenzenesulfonic acid) to yield the phenanthroline.