Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:49])[C@@H:7]([NH:39][S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:42])=[O:41])[CH2:8][NH:9][C:10]([NH:12][C:13]1[C:22](=[O:23])[N:21]2[C:16]([CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])=[CH:20]2)=[CH:15][CH:14]=1)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:43]1([S:40]([NH:39][C@@H:7]([CH2:8][NH:9][C:10]([NH:12][C:13]2[C:22](=[O:23])[N:21]3[C:16]([CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:30])=[CH:20]3)=[CH:15][CH:14]=2)=[O:11])[C:6]([OH:49])=[O:5])(=[O:41])=[O:42])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)Nc1ccc2ccc(OCCCNC(=O)OCc3ccccc3)cn2c1=O)NS(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)Nc1ccc2ccc(OCCCNC(=O)OCc3ccccc3)cn2c1=O
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of (S)-2-Benzenesulfonylamino-3-{3-[7-(3-benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-propionic acid tert-butyl ester (25 mg, 0.036 mmol) in dichloromethane (3 mL) was added TFA(3 ml) at room temperature. The reaction mixture was stirred overnight and then solvents were evaporated under reduced pressure. The residue was triturated with ether(2×5 ml) and dried. The resulting solid was purified by flash chromatography (10% methanol in ethyl acetate) to give 18 mg of compound VI which was characterized by 1HNMR (300 MHz) (CD3OD) δ: 8.56 (d, 1H, J=7 Hz), 8.40 (s, 1H), 7.92 (m, 2H), 7.42-7.60 (m, 4H), 7.25 (m, 5H), 6.91-7.04 (m, 2H), 5.12 (s, 2H), 4.19 (t, 2H), 3.63 (m, 1H), 3.50 (m, 2H), 3.20 (m, 2H), 2.02 (m, 2H)
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[O:4].C(=O)(O)[O-].[Na+].[CH2:12]([S:16](Cl)(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15].C(=O)=O>O.CO>[CH2:12]([S:16]([NH:1][NH:2][C:3]([NH:5][NH:6][S:16]([CH2:12][CH2:13][CH2:14][CH3:15])(=[O:18])=[O:17])=[O:4])(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15]
Reactant: NNC(=O)NN
Reactant: CCCCS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCS(=O)(=O)NNC(=O)NNS(=O)(=O)CCCC

Procedure:
A mixture of 11.25 g (0.125 mole) carbohydrazide, 25 g sodium bicarbonate, 200 ml methanol and 37 g (0.25 mole) 1-butanesulfonyl chloride was heated to 60° C until evolution of CO2 ceased. The mix was cooled and water was added to precipitate the product. The initial precipitate weighed 12 g (dry). This melted with decomposition at 195°-197° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([C:17]([O:19]CC)=[O:18])[N:16]=2)[N:13]=1.[OH-].[Na+].O.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=2)[N:13]=1
Reactant: CCOC(=O)c1cn2nc(OCc3cc(OC)c(OC)c(OC)c3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(COc2ccc3nc(C(=O)O)cn3n2)cc(OC)c1OC
Yield: 83.5 %

Procedure:
The product of stage (a) (1.94 g, 5 mmol) was heated under reflux with stirring with sodium hydroxide solution (1 ml, 10M, 10 mmol), water (9 ml) and methanol (5 ml) for 20 min. The mixture was cooled and acidified with dilute hydrochloric acid and filtered to give a solid which was dried at 60° in vacuo to give the title compound as a powder (1.5 g), m.p. 224°-226° (decomp), Nmr δH (d6 -DMSO) 8.56 (1H,s,3H), 8.07 (1H,JAB 8.8Hz, 8H), 7.05 (1H, JAB 8.8Hz, 7H) 6.88 (2H,s,ArH), 5.29 (2H,s,CH2Ar), 3.82 (6H, s, OCH3)3.68 (3H, s, OCH3) and 3.32 (1H, br.s, CO2H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([F:15])[C:9]=1[F:16]>C(O)(=O)C>[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[C:12]([N+:1]([O-:4])=[O:2])[C:11]([OH:14])=[C:10]([F:15])[C:9]=1[F:16]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(O)c(F)c1F
Solvent: CC(=O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(O)c(F)c1F
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Concentrated nitric acid (70% w/w) (0.72 mL, 11.2 mmol) in glacial acetic acid (2 mL) was added dropwise to a solution of 2,3-difluoro-4-hydroxy-benzoic acid methyl ester [Gonzales, Javier et al., PCT Int. Appl. (1999), 551 pp. WO 9901423 A1 19990114] (2 g, 10.6 mmol) in glacial acetic acid (28 mL). The mixture was stirred at 45° C. for 0.5 hour and then at room temperature overnight before it was evaporated to a quarter of the volume in vacuo. Water was added to the concentrate to give a solid precipitate which was filtered, washed with water twice and dried to give the title compound (2.2 g, 88%) as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[I:16]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]([I:16])=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(Br)cn1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(Br)cc1I
Temperature: 50 °C

Procedure:
To a solution of 2-amino-5-bromopyridine (2) in DMF was added trifluoroacetic acid (1.2 equiv). At room temperature, N-iodosuccinimide (1.1 equiv) was added and the reaction mixture was heated at 50° C. for 3 h. HPLC indicated complete conversion. After cooling to room temperature the product was precipitated by adding the reaction mixture to water. After neutralization with sodiumthiosulfate and 1N NaOH the title compound (II) was collected by filtration as a brown solid in 90% yield.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8](=[O:11])[C:9]#[CH:10])=[CH:4][CH:3]=1.C(=O)C.C(CN)O>>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([OH:11])[C:9]#[CH:10])=[CH:4][CH:3]=1
Reactant: C#CC(=O)COc1ccc(F)cc1
Agent: CC=O
Solvent: NCCO
Product: C#C[C@H](O)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.7 %

Procedure:
A solution of R-Alpine-Borane® (0.5 M in THF, 930 mL, 465 mmol) was evaporated to dryness under vacuum to get about 150 g of a thick syrup. 4-(4-Fluorophenoxy)-1-butyn-3-one (27.6 g, 155 mmol) was added and when an exothermic reaction was observed, the reaction mixture was cooled with an ice/water bath, then allowed to warm to ambient temperature. After two days, the reaction mixture was cooled to 0° C. and acetaldehyde (26 mL, 465 mmol) was added to quench the excess reagent. After stirring at ambient temperature for 2 hours the reaction mixture was placed under vacuum and stirred first at 0° C. for one hours, then at 65° C. for 2 hours. The reaction mixture was cooled to ambient temperature and ether (300 mL) was added under nitrogen. Ethanolamine (30 mL, 465 mmol) was added drop-wise at 0° C. and the resulting reaction mixture was stored in the freezer overnight. The resulting precipitate was removed by filtration and washed with cold ether. The combined filtrates were concentrated under vacuum. The crude product was purified by flash chromatography on a 2.5 L column of silica gel with 10–25% ethyl acetate in hexane as eluant to obtain 27 g of (3S)-4-(4-fluorophenoxy)-3-hydroxy-1-butyne, a compound of formula (BB), in quantitative yield; 1H NMR (CDCl3) δ 2.56 (s, 1H), 4.10 (m, 2H), 4.78 (m, 1H), 6.85 (m, 2H), 7.0 (m, 2H). This material was determined to be about 64% ee based on chiral HPLC of its 3,5-dinitrobenzoyl ester (see below).
Reaction SMILES: [C-:1]#[N:2].[K+].C1(C)C=CC(S([C:13]2[C:22]3[C:17](=[C:18]([CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=3)[N:16]=[N:15][CH:14]=2)(=O)=O)=CC=1>CN(C=O)C>[C:1]([C:13]1[C:22]2[C:17](=[C:18]([CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[N:15][CH:14]=1)#[N:2]
Reactant: CCc1cccc2c(S(=O)(=O)c3ccc(C)cc3)cnnc12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc2c(C#N)cnnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g of potassium cyanide was added to a stirred solution of 4.4 g of 53F in 60 ml of dry DMF at room temperature, under nitrogen. The mixture was stirred overnight at room temperature, under nitrogen, then 200 mg potassium cyanide was added and the mixture was stirred for 5 hours at room temperature. The mixture was quenched in water and filtered. The solid was dissolved in ethyl acetate, the solution was washed with water, dried (MgSO4), filtered and stripped of solvent, to give 4-cyano-8-ethylcinnoline (53G), as a yellow solid, m.p.: 102°-104° C., with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][OH:25])[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CN=C1.[C:31]([Si:35]([CH3:38])([CH3:37])Cl)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C.C(OCC)(=O)C>[Si:35]([O:25][CH2:24][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][C:10]1=[O:23])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)(c2ccc(Cl)c(Cl)c2)C(=O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOC(CO[Si](C)(C)C(C)(C)C)(c2ccc(Cl)c(Cl)c2)C(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution (20 mL) of tert-butyl 7-(3,4-dichlorophenyl)-7-(hydroxymethyl)-6-oxo-1,4-oxazepane-4-carboxylate (1.27 g) in DMF were added imidazole (266 mg) and tert-butyldimethylchlorosilane (540 mg), and the mixture was stirred at room temperature for 3 hr. The reaction solution was diluted with ethyl acetate, the mixture was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.35 g).
Reaction SMILES: [F:1][CH:2](F)[CH:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:17]([O:19][CH3:20])=[O:18])=[C:5]([C:21]([F:24])([F:23])[F:22])[NH:4]1.FC(F)C1NC(C(F)(F)F)C(C(OC)=O)=C(CC(C)C)C=1C(OC)=O.C1CCN2C(=NCCC2)CC1>CCOCC>[F:1][CH2:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:17]([O:19][CH3:20])=[O:18])=[C:5]([C:21]([F:24])([F:22])[F:23])[N:4]=1
Reactant: COC(=O)C1=C(C(F)(F)F)NC(C(F)F)C(C(=O)OC)=C1CC(C)C
Agent: COC(=O)C1=C(C(F)F)NC(C(F)(F)F)C(C(=O)OC)=C1CC(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: COC(=O)c1c(CF)nc(C(F)(F)F)c(C(=O)OC)c1CC(C)C
Yield: 19 %

Procedure:
To a solution of 50.3 g (0.136 mole) of product of example 14 in 200 ml of DMF is added 21.3 g (0.563 mole) of sodium borohydride. The reaction mixture becomes exothermic and the temperature of the reaction mixture rises to 65° C. and subsides to 40° C. after 40 min. of stirring. To the reaction mixture is added 15 ml of water. The exothermic reaction mixture is cooled by an ice-water bath to 40° C. The cooling bath is removed and the reaction mixture is stirred for 20 min. before being poured into 1 L of water. The organic is extracted into 500 ml of methylene chloride. The methylene chloride extract is dried over magnesium sulfate and concentrated. The residual oil (44.5 g) is purified by HPLC using 5% ethyl acetate in cyclohexane as eluent. The first 2.8 L of eluate gives 7.6 g of an oil which contains 56% of the desired product, 22% of the starting material, and 22% of an unidentified material. The second 2.5 L of eluate gives 24.6 g of an oil which contains a mixture of dimethyl 2-(difluoromethyl)-1,2-dihydro-4-isobutyl-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (E) and dimethyl 6-(difluoromethyl)-1,2-dihydro-4-isobutyl-2-(trifluoromethyl)-3,5-pyridinedicarboxylate (F) and other unidentified products. This oil is crystallized from ether-hexane to give 7.4 g (15%) of a solid, mp 82°-85° C., which is a 4.6:1 mixture of above mentioned (E) and (F). The mother liquor is concentrated to an oil (15.6 g) which contains (E), (F), and other unidentified products. A solution of above oil, 9.0 g (0.0568 mole) of DBU and 100 ml of ether is stirred for 18 hours and washed with 100 ml of 3N hydrochloric acid. The ether solution is dried over magnesium sulfate and concentrated. The residual oil (14.5 g) is purified by HPLC using 5% ethyl acetate in cyclohexane as eluent. The first 2.0 L of eluate gives 8.8 g (19%) of the desired product as an oil, n25D 1.4567. Anal. Calc'd. for C15H17F4NO4 : C, 51.28; H, 4.88; N, 3.99; Found: C, 51.39; H, 4.76; N, 3.85.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6](Cl)[C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)=[CH:2]1.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH:20]([CH3:33])[CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[CH2:16][CH2:15]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH:20]([CH3:33])[CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])[CH2:18][CH2:19]2)=[CH:2]1
Reactant: CC(CCOc1ccccc1[N+](=O)[O-])N1CCC(O)CC1
Reactant: ClC(c1ccsc1)c1ccsc1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: CC(CCOc1ccccc1[N+](=O)[O-])N1CCC(OC(c2ccsc2)c2ccsc2)CC1

Procedure:
The procedure of Example 36 (a) was repeated except for using di(3-thienyl)methyl chloride and 4-hydroxy-1-[1-methyl-3-(2-nitrophenoxy)propyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-di(3-thienyl)methoxy-1-[1-methyl-3-(2-nitrophenoxy)propyl]piperidine
Reaction SMILES: O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C)(C)[N:25]1[C:33]2[C:28](=[CH:29][C:30]([O:34][Si](C(C)(C)C)(C)C)=[CH:31][CH:32]=2)[C:27]([CH2:42][CH3:43])=[CH:26]1)(C)(C)C>C1COCC1.C(OCC)(=O)C>[CH2:42]([C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[NH:25][CH:26]=1)[CH3:43]
Reactant: CCc1cn([Si](C)(C)C(C)(C)C)c2ccc(O[Si](C)(C)C(C)(C)C)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1c[nH]c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72.7 %

Procedure:
Tetrabutylammonium fluoride hydrate (1.4 g, 4.3 mmol) was added to an ice-cooled solution of 1-(tert-butyl-dimethyl-silanyl)-5-(tert-butyl-dimethyl-silanyloxy)-3-ethyl-1H-indole (840 mg, 2.2 mmol) in THF (8 ml). The reaction mixture was stirred for 45 min at ambient temperature, diluted with ethyl acetate and washed with 1 N HCl and water. The organic phase was concentrated under reduced pressure and the crude product purified by column chromatography (silica gel, ethyl acetate/heptane 1:2) to give 258 mg (1.6 mmol, 74%) 3-ethyl-1H-indol-5-ol.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[C:19]([CH3:26])[CH:18]=1>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:15][NH:14][C:12](=[O:13])[CH2:11][C@@H:8]2[CH2:9][CH2:10][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:7]2)=[O:25])=[C:19]([CH3:26])[CH:18]=1
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Reactant: Cc1cc(Br)ccc1N=C=O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1NC(=O)NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (800 mg, 3.79 mmol) in dry dichloromethane (5 mL) was added 4-bromo-1-isocyanato-2-methylbenzene (803 mg, 3.79 mmol). The reaction was allowed to progress for 1 h at room temperature (became a thick suspension that could not be stirred). The reaction mixture was diluted with dichloromethane (10 mL) and the precipitate was collected by filtration. A second crop was obtained by filtration and the two crops were combined, rinsed with minimal dichloromethane and dried to constant weight under high vacuum to provide the title product (1.54 g, 3.64 mmol, 96% yield) as a white solid. MS(ES)+ m/e 422.9 [M+H]+. This material was 76% pure by LCMS (UV214) and was used as is in the next step.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:33])[CH2:12][CH2:13][N:14]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16](O)=[O:17])[CH2:7][CH2:6]1.Cl.[CH2:35]([O:42][NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.B(F)([O-])[O-].B(F)([O-])[O-].B(F)([O-])[O-].B(F)([O-])[O-].B(F)([O-])[O-].B(F)([O-])[O-].N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[CH2:35]([O:42][NH:43][C:16](=[O:17])[CH:15]([N:14]([CH2:13][CH2:12][C:11]([N:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][OH:2])[CH2:6][CH2:7]1)=[O:33])[S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[CH:19]([CH3:20])[CH3:21])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCN(CCO)CC2)C(C(=O)O)C(C)C)cc1
Reactant: NOCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: [O-]B([O-])F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCN(CCO)CC2)C(C(=O)NOCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To a solution of 2-[{3-[4-(2-hydroxyethyl)piperazin-1-yl]-3-oxopropyl}(4-methoxy-benzenesulfonyl)amino]-3-methylbutyric acid hydrochloride (1.10 grams, 2.17 mmol) in methylene chloride (50 mL) and N,N-dimethylformamide (0.5 mL) were added sequentially O-benzylhydroxylamine hydrochloride (0.41 grams, 2.60 mmol), triethylamine (0.91 mL, 6.5 mmol) and (benzotriazol-1-yloxy)tris-(dimethylamino)-phosphonium hexafluoroborate (1.20 grams, 2.71 mmol). The resulting mixture was stirred for 16 hours at room temperature and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and brine. The solution was dried over magnesium sulfate and concentrated to yield an oil which was chromatographed on silica gel eluting with 3% methanol in chloroform to afford N-benzyloxy-2-[{3-[4-(2-hydroxyethyl)piperazin-1-yl]-3-oxopropyl}(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide as a clear oil (0.85 grams, 68%). Conversion to the hydrochloride salt was subsequently carried out using anhydrous hydrochloric acid in cold (0° C.) methylene chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C1CCCCC=1.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: COc1ccc(S(=O)(=O)N2c3cc(F)ccc3-c3ccccc3C2C)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2ccccc2-c2ccc(F)cc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 30.7 %

Procedure:
To a stirred slurry of 3-fluoro-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (262 mg, 0.68 mmol) in cyclohexene (1.38 mL, 14 mmol) under an inert atmosphere of nitrogen was added a 1 M solution of boron tribromide in dichloromethane (4.1 mL). The progress of the reaction was monitored by thin-layered chromatography and after 2.5 hours the reaction was deemed complete. The reaction contents were cooled to 0° C. and methanol was added slowly. The volatile components were removed in vacuo and the crude residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane, to afford the title compound (77 mg, 30%) as a solid, m.p. 162-165° C.;
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:21]=[C:20]([CH3:22])[C:19]3[C:14](=[CH:15][C:16]([N:23]([S:30]([C:33]4[CH:34]=[CH:35][CH:36]=[C:37]5[C:42]=4[N:41]=[CH:40][CH:39]=[CH:38]5)(=[O:32])=[O:31])[CH2:24][C:25]([O:27]CC)=[O:26])=[CH:17][CH:18]=3)[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[OH-].[Na+]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:21]=[C:20]([CH3:22])[C:19]3[C:14](=[CH:15][C:16]([N:23]([S:30]([C:33]4[CH:34]=[CH:35][CH:36]=[C:37]5[C:42]=4[N:41]=[CH:40][CH:39]=[CH:38]5)(=[O:32])=[O:31])[CH2:24][C:25]([OH:27])=[O:26])=[CH:17][CH:18]=3)[N:13]=2)=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)CN(c1ccc2c(C)cc(CCc3ccc(C(=N)N)cc3)nc2c1)S(=O)(=O)c1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CCc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)S(=O)(=O)c3cccc4cccnc34)ccc12

Procedure:
Prepared analogously to Example 3 from 2-[2-(4-amidinophenyl)-ethyl]-4-methyl-7-[N-(ethoxycarbonylmethyl)-quinoline-8-sul-phonylamino]-quinoline and sodium hydroxide solution.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=[O:7])[C:4](O)=[O:5].O.OC1C2N=NNC=2C=CC=1.[N:20]1([C:26]2[N:34]=[C:33]([C:35]3[CH:36]=[N:37][C:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:39][CH:40]=3)[N:32]=[C:31]3[C:27]=2[N:28]=[C:29]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[N:30]3[CH2:49][C:50]([F:53])([F:52])[F:51])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1>[CH3:1][N:2]([C:3](=[O:7])[C:4]([N:57]1[CH2:56][CH2:55][N:54]([C:29]2[N:30]([CH2:49][C:50]([F:51])([F:52])[F:53])[C:31]3[C:27]([N:28]=2)=[C:26]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:34]=[C:33]([C:35]2[CH:40]=[N:39][C:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:37][CH:36]=2)[N:32]=3)[CH2:59][CH2:58]1)=[O:5])[CH3:8]
Reactant: CN(C)C(=O)C(=O)O
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC(F)(F)F)c3n2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(NC(=O)OC(C)(C)C)nc4)nc3n2CC(F)(F)F)CC1
Reaction time: 18 h
Yield: 82.6 %

Procedure:
N,N-Dimethyl-oxalamic acid (34 mg, 0.29 mmol), hydroxybenzotriazole hydrate (45 mg, 0.29 mmol), and tetrahydrofuran (5 ml) were added to tert-butyl {5-[6-morpholin-4-yl-8-piperazin-1-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-yl}carbamate (150 mg, 0.27 mmol). 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (56 mg, 0.29 mmol) and triethylamine (74 μl, 0.53 mmol) were added and the resulting mixture was stirred for 18 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel chromatography (chloroform:methanol=19:1) to give the title compound (148 mg, 84%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([CH2:34][OH:35])[CH2:29]1>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:28]2[CH2:33][CH2:32][CH2:31][CH:30]([CH2:34][OH:35])[CH2:29]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: OCC1CCCNC1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)N2CCCC(CO)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium 4-acetylbenzenesulfonate is added to a solution of 114 g. of 3-piperidinemethanol in 900 ml. of water. The mixture is stirred at room temperature for 16 hours, cooled, and the precipitate of 1-(4-acetylbenzenesulfonyl)-3-piperidinemethanol collected by filtration, washed with water and dried; m.p. 104°-106° C. after crystallization from aqueous ethanol.