Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C[CH2:15][CH2:14][CH2:13]1>>[C:2]1([CH2:1][O:8][CH2:9][C@@H:10]([OH:11])[CH2:15][CH:14]=[CH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCOCc1ccccc1
Reactant: C1CCOC1
Product: C=CC[C@H](O)COCc1ccccc1

Procedure:
The optically active tetrahydrofuran derivatives are prepared according to Scheme V. Benzyloxyacetaldehyde is reacted with optically active 2-allyl-1,3,2-dioxaborolane-4,5-dicarboxylic acid ester, XVII, to give optically pure (S)-1-phenylmethoxy-4-penten-2-ol, XVIII. Cyclization of alcohol, XVIII, with iodine in the presence of sodium bicarbonate gives a mixture of optically pure 2,5-anhydro-1,3-dideoxy-1-iodo-D-threopentitol, XIX, ##STR112## and 2,5-anhydro-1,3-dideoxy1-iodo-D-erythro-pentitol, XX, which is separated by flash chromatography using silica gel. ##STR113##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][C:13]=2Br)=[CH:8][CH:7]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][C:13]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)C=Cc1ccc(C2=C(Br)CCCc3ccccc32)cc1
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: COCCOC
Product: COC(=O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Yield: 62.3 %

Procedure:
To a solution of the bromide (2c) (6.85 g, 17.9 mmol) in DME (125 mL) was added benzene boronic acid (3.25 g, 26.8 mmol), tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol), and 2N aqueous sodium carbonate (13.5 mL). After refluxing overnight the solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 7.5 EtOAc/hexanes to 100% EtOAc) followed by recrystalization from EtOAc to give (2d) as a white solid (4.24 g, 62%): 1H NMR (CDCl3) δ 7.58 (d, J=16.1 Hz, 1H), 7.20 (m, 10H), 6.92 (d, J=8.1 Hz, 2H), 6.85 (dd, J=7.3, 1.1 Hz, 1H), 6.32 (d, J=16.1 Hz, 1H), 3.78 (s, 3H), 2.82 (t, J=7.0 Hz, 2H), 2.40 (t, J=7.0 Hz, 2H), 2.20 (m, 2H); APcI m/z: 422 (M+H+CH3CN+, 100%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][C:20]=2[C:29]([O:31]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[NH4+:35]>C1COCC1.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][C:20]=2[C:29](=[O:31])[NH2:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cc1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cc1ccccc1
Yield: 44 %

Procedure:
A solution of the 9-[(2-benzylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (166 mg, 0.39 mM) in 8 mL THF and 30 mL concentrated aqueous ammonium hydroxide was sonicated for 30 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 70 mg (44%) of the 9-[(2-benzylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (CDCl3) δ 8.0 (d, 1H, J=8 Hz), 7.4-7.0 (m, 12H), 6.8 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.5 (m, 1H), 6.4 (m, 1H), 5.8 (s, 1H), 5.4 (s, 2H), and 4.2 (s, 2H). MS (ES) m/e 405, 407.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:42].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:42][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: COCCOCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Yield: 77.6 %

Procedure:
This was prepared using the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), 5-chloro-7-[3-(2-methoxyethoxy)prop-1-yn-1-yl]-1,3-benzodioxol-4-amine (185 mg, 0.65 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 1.24 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (268 mg, 77%) as a pale yellow solid; NMR Spectrum: (DMSOd6) 1.99 (quintet, 2H), 2.40 (m, 4H), 2.49 (t, 2H), 3.30 (s,3H), 3.52 (m, 2H), 3.59 (m, 4H), 3.65 (m, 2H), 3.93 (s, 3H), 4.20 (t, 2H), 4.44 (s, 2H), 6.16 (s, 2H), 7.16 (s, 1H), 7.19 (s, 1H), 7.82 (s, 1H), 8.32 (s, 1H), 9.5 (s, 1H); Mass Spectrum: M+H+ 585/587.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:8]([CH2:9][C:10](=[O:25])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2].[CH:26](OCC)=[O:27].[O-]CC.[Na+]>C1COCC1.C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH:8]2[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:12]([CH2:11][C:10](=[O:25])[C:9]2=[CH:26][OH:27])[CH2:13]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC2CC(=O)CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1CC2CC(=O)C(=CO)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 94 %

Procedure:
9-(4-Chloro-benzenesulfonyl)-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester (2.49 g, 6.45 mmol) was dissolved in THF/ethanol (14 mL, 1/1, v/v). Ethyl formate (5.19 mL, 64.53 mmol) was added followed by sodium ethoxide (6.2 mL of 21% solution in ethanol). The resulting mixture was heated to 60° C. for 30 minutes after which the solution was cooled to room temperature and quenched by the addition of saturated aqueous NH4Cl (10 mL). The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated under vacuum to yield 2.51 g (94%) of 9-(4-chloro-benzenesulfonyl)-6-hydroxymethylene-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester as a yellow oil. Retention time (min)=2.017, method [1], MS (ESI) 414.0 (M+H).
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CO>[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36](=[O:37])[NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[CH:33][CH:34]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCOc1ccc(N=C=O)cc1
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCCCCCCOc1ccc(NC(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)cc1
Reaction time: 18 h

Procedure:
To a solution of (R)-aminocarnitine (16 mg, 0.10 mmol) and diisopropylethylamine (52 uL, 0.30 mmol) in MeOH (2 mL) was added 1-(heptyloxy)-4-isocyanatobenzene (46 uL, 0.20 mmol) and the reaction stirred for 18 h. The MeOH was removed in vacuo and the residue stirred with 1:1 ether/EtOAc. Impurities dissolved into the ether/EtOAc which were discarded and the remaining material taken up into 90:10 CH2Cl2/MeOH and then loaded onto a short SiOH plug. The title compound was eluted by increasing MeOH content in 10% steps to 60%. The compound was then taken up into 90:10 CH2Cl2/MeOH and filtered through a plug of celite which gave after drying the title compound as a white powder (9 mg, 23%). 1H NMR (400 MHz, CD3OD) δ 7.24 (d, 2H, J=9.2 Hz), 6.84 (d, 2H, J=8.8 Hz), 4.71-4.69 (m, 1H), 3.93 (t, 2H, J=6.4 Hz), 3.77-3.53 (m, 2H), 3.25 (s, 9H), 2.74-2.70 (m, 2H), 1.77-1.72 (m, 2H), 1.49-1.34 (m, 8H), 0.92 (t, 3H, J=6.8 Hz); MS ESI 394.3 [M+H]+, calcd for [C21H35N3O4+H]+ 394.52.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.OS(O)(=O)=O.[CH3:18][CH2:19]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:18][CH3:19])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCO
Reactant: Cc1cc(Cl)cc(CC(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(C)cc(Cl)c1
Yield: 85 %

Procedure:
A solution of 3-chloro-5-methylphenylacetic acid (5.0 g; 27.09 mmol; from step (iii) above) and H2SO4 (conc.; 0.1 mL) in EtOH (25 mL) was refluxed overnight. The solution was concentrated, and the resultant mixture digerated in Na2CO3 solution (75 mL). After extraction with ether (2×75 mL) the combined organic phases were washed with brine, dried (Na2SO4), and evaporated to yield 4.92 g (85%) of the sub-title compound.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)C=O)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].CO[CH:29]([O:32][CH3:33])[O:30][CH3:31].C(=O)(O)[O-].[Na+]>CO>[CH3:33][O:32][CH:29]([O:30][CH3:31])[C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][C:12](=[O:17])[C:13]([CH3:15])([CH3:14])[CH3:16])[CH:20]=1
Reactant: CC(C)(C)C(=O)Oc1cccc(C=O)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1cccc(OC(=O)C(C)(C)C)c1
Reaction time: 1 h

Procedure:
Four hundred mg of p-toluenesulfonic acid dissolved in 25 ml of methanol was added, with stirring, to the 3-pivaloyloxybenzaldehyde of Example I. Trimethylorthoformate (224 ml; 2.05 mol) was then added dropwise. The minor exotherm that resulted was allowed to proceed unchecked while the mixture was stirred for 1 hour. One half gram of sodium bicarbonate was added, and the flask was placed on the rotary evaporator (bath temperature40° C.) to remove all volatiles. The resulting oil was passed through a short silica gel column under nitrogen pressure to give an orange-brown oil which was pumped under vacuum (1.0 mm Hg) with stirring to yield 426 g of crude 3-pivaloyloxybenzaldehyde dimethyl acetal. Infrared analysis revealed no aldehyde carbonyl absorption (1695 cm-1).
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[Na+].[CH:13](=O)[CH3:14]>O.CO>[NH2:8][C:7]1[NH:6][C:4]([N:2]([CH3:3])[CH3:1])=[N:5][CH:13]([CH3:14])[N:9]=1
Reactant: CC=O
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1N=C(N)NC(N(C)C)=N1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 84 %

Procedure:
A 4 L two neck flask charged with 662 g (4 mol) metformin HCl and 1600 mL MeOH was stirred with a magnetic bar at 750 rpm at room temperature with a water bath. To this suspension was added sodium hydroxide 160 g (4 mol) in 200 mL water through one dropping funnel. At the same time acetaldehyde 226 mL (4 mol) in 400 mL of MeOH in another funnel was added to the mixture. The addition of NaOH solution finished in 70 minutes whereas the addition of acetaldehyde finished in 100 minutes. Then, the reaction mixture was filtered through celite to remove the sodium chloride. The solution was concentrated to give a white solid that was extracted with 1.2 L of hot ethanol to give a suspension. After filtration, the ethanol solution was concentrated to give a pale yellow solid, 520 g, yield is 84%.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10].[OH-].[Na+].Cl.O>CO>[N+:9]([CH:12]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:11])=[O:10]
Reactant: O=Cc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])C=Cc1ccccc1
Temperature: 0 °C

Procedure:
Benzaldehyde (2, 52.35 g, 0.493 mol) and nitromethane (30.11 g, 0.493 mol) were dissolved in methanol (100 mL) in a two-necked flask equipped with a thermometer and a pressure-equalizing dropping funnel. NaOH (25.6 g, 0.641 mol) in ice/water (50 mL) was added dropwise to the solution keeping the temperature below 15° C. A fine slurry formed during the addition and methanol was added to allow stirring. After the addition the slurry was diluted with ice/water and the resulting clear solution was added dropwise to a solution of conc. HCl/H2O (200/300 ml); a yellow precipitate was formed during the addition. The precipitate was filtered on a buchner funnel, washed with water and crystallized from methanol obtaining pure 3 (58.78 g, 80%). Yellow needles. M.p. 57-58° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (191 mg, 0.63 mmol) [prepared according to the procedure of Example 159], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (209 mg, 0.62 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (359 mg, 0.77 mmol) in chloroform (7 mL). DIEA (560 μL, 3.21 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (171 mg, 0.29 mmol, 46%): LC-MS (ES) m/z=583 (M+H)+.
Reaction SMILES: [CH2:1]([CH2:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>CC(OC)(C)C.C(#N)C>[CH2:1]([CH2:8][NH:9][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: OCCCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC#N
Product: OCCCCCCCCNCCc1ccccc1
Temperature: 80 °C
Reaction time: 25 h
Yield: 96.5 %

Procedure:
A 2-L flask was charged with benzylmethylamine (270 g, 2.23 mol), sodium carbonate (157 g, 1.48 mol), sodium iodide (11.1 g, 0.074 mol), 8-chlorooctanol (122 g, 0.74 mol) and ACN (1000 mL) and the resulting suspension was stirred at 80° C. for 20-30 hours. The reaction mixture was then concentrated to a volume of about 500 mL and water (600 mL) and MTBE (1000 mL) were added. The MTBE layer was then separated and washed with water (500 mL). The MTBE solution was concentrated under vacuum and the resulting oil was then further concentrated by distillation under high vacuum to remove excess benzylmethylamine. N-methyl-2-pyrrolidone (300 mL) was then added to the remaining oil and this solution concentrated by distillation under high vacuum to provide an oil. The oil was dissolved in MTBE (1000 mL) and the resulting solution was washed with water (2×500 mL), brine (500 mL), dried with sodium sulfate (100 g), filtered and concentrated by distillation to afford the title compound as an oil (178 g, 96% yield, >95% purity).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[O-:31][CH2:32][CH3:33].[Na+]>C(O)C.CS(C)=O>[CH2:32]([O:31][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])[CH3:33]
Reactant: CC[O-]
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CC1

Procedure:
3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide (60 mg, 0.129 mmol) was reacted with sodium ethoxide (0.5 M in ethanol, 0.5 mL, 0.25 mmol) in a mixture of ethanol (5 ml) and DMSO (0.2 mL) at reflux for 16 h to form the desired product which was purified by reverse phase HPLC eluting with 10% B to 70% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (10 mg, 17%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:5][CH:4]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Si:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([NH:2][CH3:1])=[CH:8][CH:7]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNc1ccc(CCCCOCCCCCCO)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNc1ccc(CCCCOCCCCCCO[Si](C)(C)C(C)(C)C)cc1

Procedure:
A solution of Intermediate 56 (0.92 g, 3.3 mmol) in dichloromethane was treated successively with tert-butyldimethylsilyl chloride (0.75 g, 5.0 mmol), DMAP (50 mg), and triethylamine (1.4 mL, 10 mmol). After a few minutes, additional quantities of tert-butyldimethylsilyl chloride (0.75 g, 5.0 mmol) and triethylamine (1 mL) were added. The mixture was filtered through a pad of Celite and concentrated. The residue was purified via automated flash silica gel chromatography, using a 40 g Silicycle SiliSep flash column (hexanes/ethyl acetate). Concentration of the desired fractions under reduced pressure provided the title compound as clear, colorless syrup (0.99 g, 76%). ES/MS calcd. for C23H44NO2Si+ 394.3. Found m/z=394.4 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[C:12]([O:29][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])=[N:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:20]=1OS(C(F)(F)F)(=O)=O)([O-:10])=[O:9].[NH2:37][CH2:38][C:39]([CH3:42])([CH3:41])[OH:40]>C(Cl)Cl>[F:36][C:33]([F:34])([F:35])[S:30]([O:29][C:12]1[C:11]([N+:8]([O-:10])=[O:9])=[C:20]([NH:37][CH2:38][C:39]([OH:40])([CH3:42])[CH3:41])[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]=1)(=[O:32])=[O:31]
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)nc2c(c1OS(=O)(=O)C(F)(F)F)CCCC2
Reactant: CC(C)(O)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)CNc1c2c(nc(OS(=O)(=O)C(F)(F)F)c1[N+](=O)[O-])CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Triethylamine (1.36 mL, 9.8 mmole) was added to a solution of 5,6,7,8-tetrahydro-3-nitro-2,4-bis[(trifluoromethyl)sulfonyloxy]quinoline (4.2 g, 9.4 mmole) in methylene chloride (180 mL). 2-Amino-α,α-dimethylethanol (0.88 g, 9.8 mmole) was added to the reaction mixture which was then stirred at ambient temperature overnight. The reaction mixture was evaporated to provide a residue which was purified by silica gel chromatography eluting with hexane: ethyl acetate 40:60 to provide 3.8 g of the desired product.
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2F)[CH2:5][CH2:4][N:3]([C:17]([C:19]2[C:24]3[NH:25][CH:26]=[C:27]([C:28]#[N:29])[C:23]=3[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:2]1.O.[ClH:31]>CC(C)=O>[ClH:31].[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][N:6]2[CH2:5][CH2:4][N:3]([C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:24]=3[NH:25][CH:26]=[C:27]4[C:28]#[N:29])=[O:18])[CH2:2][CH2:1]2)=[CH:10][CH:11]=1
Reactant: N#Cc1c[nH]c2c(C(=O)N3CCN(CCc4ccc(F)cc4F)CC3)cccc12
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1c[nH]c2c(C(=O)N3CCN(CCc4ccc(F)cc4)CC3)cccc12
Yield: 69 %

Procedure:
2.1 g of the free base of EMD281014 are heated in 50 ml of acetone, and water is added until a clear solution is formed. A mixture of 0.6 ml of hydrochloric acid (w=37%) and 1.2 ml of acetone is then stirred in. The mixture is subsequently evaporated to half the volume in a rotary evaporator. The precipitated hydrochloride is filtered off with suction, washed with acetone and diethyl ether and dried, giving 1.6 g of 7-{4-[2-(4-fluorophenyl)ethyl]-piperazine-1-carbonyl}-1H-indole-3-carbonitrile, hydrochloride (69% of theory), decomposition range 314-319°.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([S:18]([Cl:21])(=[O:20])=[O:19])=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[CH:10]3)[CH2:6]1)=[O:4].[N+:24]([O-])([OH:26])=[O:25]>>[N+:24]([C:10]1[C:11]2[C:12]3[C:7](=[CH:8][CH:9]=1)[CH2:6][N:5]([C:3](=[O:4])[C:2]([F:1])([F:22])[F:23])[CH2:14][C:13]=3[CH:15]=[CH:16][C:17]=2[S:18]([Cl:21])(=[O:19])=[O:20])([O-:26])=[O:25]
Reactant: O=C(N1Cc2cccc3c(S(=O)(=O)Cl)ccc(c23)C1)C(F)(F)F
Reactant: O=[N+]([O-])O
Product: O=C(N1Cc2ccc([N+](=O)[O-])c3c(S(=O)(=O)Cl)ccc(c23)C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Solid 2,3-dihydro-2-trifluoroacetyl-1H-Benz[de]isoquinoline-6-sulfonyl chloride (6 mmol) is added portionwise to cold (0° C.) 90% nitric acid (5 mL). The resulting mixture is stirred at 0° C. overnight then cautiously poured into ice-water. The precipitate is collected by filtration and washed with ice-water to give the title compound. The crude product can be purified by recrystallization or chromatography.