Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([C:18]([NH2:21])([CH3:20])[CH3:19])[CH:15]=[CH:16][CH:17]=3)[N:9]([CH3:22])[N:8]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH:32]1([NH:36][S:37](Cl)(=[O:39])=[O:38])[CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH:32]1([NH:36][S:37]([NH:21][C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:10]3[N:9]([CH3:22])[N:8]=[C:7]([CH2:6][C:5]4[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=4)[CH:11]=3)[CH:13]=2)([CH3:20])[CH3:19])(=[O:39])=[O:38])[CH2:35][CH2:34][CH2:33]1
Reactant: Cn1nc(Cc2ccc(F)cc2)cc1-c1cccc(C(C)(C)N)c1
Reactant: O=S(=O)(Cl)NC1CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc(Cc2ccc(F)cc2)cc1-c1cccc(C(C)(C)NS(=O)(=O)NC2CCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The crude amine was dissolved in CH2Cl2 (5 mL) and Et3N (222 μL, 1.6 mmol) and crude cyclobutylsulfamoyl chloride (136 mg, ca. 0.8 mmol) were added and the reaction was stirred at RT for 30 min. The reaction was evaporated under reduced pressure and diluted with MeCN:DMSO (1:1, 2 mL) and filtered. The filtrate was injected on to a reverse phase HPLC system and the title compound was isolated, after basic workup, as a yellow gum (4 mg, 1% over 2 steps). 1H NMR (CDCl3, 500 MHz) δ 7.52-7.48 (2H, m), 7.41 (1H, t, J=8.6 Hz), 7.31-7.23 (3H, m), 6.98 (2H, t, J=8.8 Hz), 6.02 (1H, s), 4.49 (1H, s), 4.10 (1H, d, J=8.4 Hz), 3.96 (2H, s), 3.85 (3H, s), 3.82-3.73 (1H, m), 2.30-2.21 (2H, m), 1.90-1.79 (2H, m), 1.73 (6H, s), 1.72-1.63 (2H, m). MS (ES+) C24H29FN4O2S requires 456: found: 457 (M+H+).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([NH:19]C(OC(C)(C)C)=O)[CH2:13]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:27].O1CCOCC1>C(O)(=O)C>[ClH:27].[C:1]1([NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([NH2:19])[CH2:13]3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)Nc3ccccc3)cc2C1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: NC1Cc2ccc(C(=O)Nc3ccccc3)cc2C1

Procedure:
Using N-phenyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (27 mg, 0.077 mmol), 4N hydrochloric acid-dioxane (2.0 ml) and acetic acid (6.0 ml), a similar procedure to Production Example 213 was carried out to obtain N-phenyl-2-amino-5-indan carboxamide hydrochloride. Then using ethanol (1 ml), triethylamine (0.50 ml, 3.6 mmol), 4-chloro-5-methylthieno[2,3-d]pyrimidine (18 mg, 1.0 mmol), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=4:1 to 1:1) to obtain the title compound (8 mg, 0.020 mmol) having the following physical properties:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]([NH:11][CH:12]1[C:28](=[O:29])[N:14]2[C:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:16]([CH3:20])[CH2:17][S:18](=[O:19])[C@H:13]12)=[O:10].C(O)(=O)C>[W].ClCCl>[Br:1][CH2:20][C:16]1[CH2:17][S:18](=[O:19])[C@@H:13]2[CH:12]([NH:11][CH:9]=[O:10])[C:28](=[O:29])[N:14]2[C:15]=1[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22]
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC=O)[C@H]2S(=O)C1
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC=O)C(=O)N12
Temperature: 0 °C
Yield: 28.5 %

Procedure:
27 g of N-bromosuccinimide were added portionwise to an ice-cold solution of 30 g of t-butyl 7-formamido-3-methyl-3-cephem-4-carboxylate-1-oxide in 1600 ml of a 1:1 mixture of acetic acid and dichloromethane under exposure to light of two tungsten lamps of 150 W over 3 hours. After a total exposure of 4 hours, the reaction mixture was then washed 3 times with water, a saturated solution of sodium bicarbonate and again with water. The organic phase was treated with activated carbon, dried over magnesium sulfate and evaporated to dryness after filtration. The residue was subjected to preparative high pressure chromatography using a 4:1 mixture of dichloromethane and acetone as eluent to obtain by evaporation to dryness of the suitable fractions 10.7 g of t-butyl 3-bromomethyl-7-formamido-3-cephem-4-carboxylate-1-oxide having the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([OH:26])=O.[C:27]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([N:36]1[CH2:37][CH2:38][CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:34][CH2:35]1)=[O:26]
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)O)cnc12
Reactant: c1ccc(C2CCNCC2)cc1
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 81.8 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2-chloro-5-methylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (72 mg, 0.17 mmol) obtained in step 2 and 4-phenylpiperidine (37 mg, 0.26 mmol), the title compound (72 mg, 84%) was obtained.
Reaction SMILES: [CH2:1]([C@@H:3]1[O:5][CH2:4]1)Cl.[C:6]1([S:12]([C:15]2[CH:16]=[CH:17][C:18]([OH:24])=[C:19]([C:21](=[O:23])[CH3:22])[CH:20]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:6]1([S:12]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH2:1][C@@H:3]3[CH2:4][O:5]3)=[C:19]([C:21](=[O:23])[CH3:22])[CH:20]=2)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1O
Reactant: ClC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1OC[C@@H]1CO1
Temperature: 25 °C

Procedure:
(R)-(−)Epichlorhydrin (1.93 g; 0.021 mol) was added to a suspension of 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone (1.92 g; 0.007 mol) and potassium carbonate (1.44 g; 0.011 mol) in acetonitrile (5 mL). The mixture was heated under reflux for 18 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate, filtered, washed with water and saturated sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (hexane-ethyl acetate; 7:3) to give 1-(5-benzene sulfonyl-2-(S)-oxiranylmethoxy-phenyl)-ethanone as a white solid (1.456 g; 63%). A sample was recrystallized from diethyl ether-hexane: M. p. 115.1-116.8° C. Similarly, but replacing (R)-(−)epichlorhydrin with (S)-(+)epichlorhydrin, 1-(5-benzene sulfonyl-2-(R)-oxiranylmethoxy-phenyl)-ethanone was prepared. M. p. 111.9-113.5° C. Similarly, but replacing 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone with 1-[5-(3-fluoro-benzenesulfonyl)-2-hydroxy-phenyl]-ethanone, the above procedure gave 1-[5-(3-fluoro-benzenesulfonyl)-2-(S)-oxiranylmethoxy-phenyl]-ethanone: M. p. 112.7-114.9° C. Replacing 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone with 1-[5-(3-Fluoro-benzenesulfonyl)-2-hydroxy-phenyl]-ethanone and replacing (R)-(−)epichlorhydrin with (S)-(+)epichlorhydrin gave 1-[5-(3-Fluoro-benzenesulfonyl)-2-(R)-oxiranylmethoxy-phenyl]-ethanone. M. p. 118.3-120.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]2)[CH:7]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[N:27][CH:28]=1>>[Cl:29][C:26]1[N:27]=[CH:28][C:23]([NH:22][C:2]2[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]3([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]3)[CH:7]=2)=[CH:24][CH:25]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(Br)ccc2F)C1(F)F
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(Nc3ccc(Cl)nc3)ccc2F)C1(F)F
Yield: 32.7 %

Procedure:
Prepared in an analogous manner as described for intermediate A9A or A13A from (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate A16B) (200 mg, 546 μmol) and commercially available 5-amino-2-chloropyridine [CAS no 5350-93-6] (140 mg, 1.09 mmol). The (R)-5-(5-(6-chloropyridin-3-ylamino)-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (74 mg, 32.7%) was obtained as a light brown foam. MS (ISP): m/z=414.2 [(M+H)+] and 416.2 [(M+2+H)+].
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[O-]CC.[Na+]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)C(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=O)C=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-fluorobenzaldehyde (12.13 ml, 110 mmol, Aldrich) and pinacolone (12.48 ml, 100 mmol, Aldrich) in absolute ethanol (120 ml) was treated with a solution of sodium ethoxide in ethanol (21% by weight solution; 3.72 ml, 10 mmol). The clear yellow reaction mixture was stirred at room temperature under argon for 24 hours. The reaction mixture was concentrated to 1/3 volume and partitioned between 50% saturated NH4 Cl and EtOAc. The layers were separated and the organic layer was washed twice with H2O and brine then dried (Na2SO4) and concentrated under reduced pressure. The oily residue was purified by flash chromatography (Merck Silica gel, 10% EtOAc/hexane), yielding the title compound as a colorless oil that slowly solidified. The white solid was recrystallized from hexane, yielding the title compound as white crystals (13.9 g, 67.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N.[CH:36]([O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43]O)=[CH2:37]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH:36]=[CH2:37])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=COCCOCCO
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=COCCOCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
In toluene (30 ml) was dissolved the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (520 mg, 1.72 mmol) obtained in Example 5. After addition of 2,2-(2-vinyloxyethoxy)ethanol (0.270 ml, 2.10 mmol) and cyanomethylenetri-n-butylphosphorane (500 mg, 2.07 mmol), the mixture was heated under reflux for 24 hours under an argon atmosphere. The reaction mixture was then allowed to cool down. After addition of 2-(2-vinyloxyethoxy)-ethanol (0.170 ml, 1.25 mmol) and cyanomethylenetri-n-butylphosphorane (300 mg, 1.24 mmol), the mixture was heated under reflux for 12 hours under an argon atmosphere. The reaction mixture was allowed to cool down and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=7:1) to yield a white solid. The resulting white solid was washed with hexane, whereby the title compound (140 mg, 20%) was obtained as a white powder.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Si:7]([O:14][CH2:15][C@H:16]1[NH:19][C:18](=[O:20])[C@H:17]1[NH:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].Br[CH2:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)=[O:44]>C(#N)C.CN(C)C=O>[Si:7]([O:14][CH2:15][C@H:16]1[N:19]([CH2:42][C:43]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=2)=[O:44])[C:18](=[O:20])[C@H:17]1[NH:21][C:22]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(COC(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(COC(=O)CN2C(=O)[C@@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 114.7 %

Procedure:
Cesium carbonate (1.58 g) was added to a stirred solution of(3S,4S)-4-t-butyldimethylsilyloxymethyl-3-tritylaminoazetidin-2-one (1.45 g) (IV) (H. Mastalerz et al., J. Med. Chem., 1988, 31, 1190-1196) in a mixture of acetonitrile (44 ml) and dimethylformamide (35 ml). 4-Methoxybenzyl bromoacetate (1.44 g) was then added and the mixture stirred at room temperature for 48 h. The mixture was then partitioned between ethyl acetate and water, the organic phase was washed four times with water, and then with brine. The solution was dried over magnesium sulphate and evaporated. The title compound (2.29 g) was isolated by column chromatography of the residue (Silica gel, 3:1 hexane:ethyl acetate as eluent). [α]D21 -9.0°; νmax (CHCl3) 3352, and 1755 cm-1 ; δ(CDCl3) -0.04 (3H, s), 0.00 (3H, s), 0.88 (9H, s), 1.69 (1H, br s), 2.54 (1H, dd, J 3.33 and 11.68 Hz), 3.19 (1H, dd, J 2.05 and 11.68 Hz), 3.38 (1H, m), 3.51 (1H, d, J 17.98 Hz), 3.90 (3H, s), 4.46 (1H, d, J 17.98 Hz), 4.54 (1H, m), 5.06 (1H, d, J 11.79 Hz), 5.15 (1H, d, J 11.81 Hz), 6.94 (2H, d, J 8.68 Hz), 7.2-7.65 (17H, m).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[NH4+].[Cl-].CCOC(C)=O>CN(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>[CH:22]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:23]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 20.7 %

Procedure:
To a degassed solution 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (22.2) (1.2 g, 3.52 mmol) in DMF (10 mL) was added Pd(PPh3)4 (610 mg, 0.528 mmol). The solution was stirred for 20 min, then tributyl(vinyl)stannane (1.227 g, 3.87 mmol) was added. The reaction mixture was heated at 120° C. for 5 h. Aqueous NH4Cl solution was added to quench the reaction, followed by addition of EtOAc. The mixture was filtered through celite and the filtrate was washed with saturated NaHCO3 and NH4Cl solutions. The organic layer was separated, dried over Na2SO4 and concentrated to give the crude product, which was purified with Analogix system on silica gel (hexanes:EtOAc) to afford 210 mg (20%) of the title compound. LCMS (method B): [MH]+=288, tR=2.05 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[S:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>CC(C)=O>[C:1]([O:5][C:6]([NH:7][C:8]1[S:9][C:10]2[CH:16]=[C:15]([O:17][S:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)(=[O:26])=[O:25])[CH:14]=[CH:13][C:11]=2[N:12]=1)=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(O)cc2s1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1nc2ccc(OS(=O)(=O)c3cccs3)cc2s1
Yield: 76.1 %

Procedure:
A solution of (6-hydroxybenzothiazol-2-yl)carbamic acid tert-butyl ester (intermediate 14) (527 mg, 1.979 mmol), 2-thiophenesulfonyl chloride (433 mg, 2.37 mmol) and triethylamine (677 μl, 4.75 mmol) in 10 ml of acetone is stirred overnight at room temperature. The reaction medium is concentrated to dryness. The residue obtained is washed with water, with acetone and then with ethyl ether to give 621 mg of thiophene-2-sulfonic acid 2-tert-butoxycarbonylaminobenzothiazol-6-yl ester (light gray powder) in a yield of 76%.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1.Cl.Cl.[F:13][C:14]([F:34])([F:33])[C:15]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([S:7]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:15]([OH:20])([C:14]([F:13])([F:34])[F:33])[C:16]([F:19])([F:17])[F:18])=[CH:26][CH:25]=3)[CH2:28][CH2:29]2)(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cscc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cscc1Br)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
To a 20 mL vial containing 4-bromothiophene-3-sulfonyl chloride (0.20 g, 0.77 mmol, ASDI, Newark, Del.) was added a solution of 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-yl)phenyl)-2-propanol dihydrochloride (0.31 g, 0.77 mmol, Example 91) and triethylamine (0.53 mL, 3.8 mmol) in CH2Cl2 (7 mL). The solution was stirred at room temperature for 16 h. To the vial was added saturated aqueous sodium bicarbonate (4 mL) and the solution was stirred for 15 min. The solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies, Essex, UK) with the organic phase being collected and passed through a plug of Na2SO4. The resulting solution was concentrated and purified by Prep-HPLC (Instrumentation: MS—Waters SQ; UV—Waters 2487 or Waters PD, Waters, Milford, Mass. Solvents: A: Water w/0.1% NH4OH B: Acetonitrile w/0.1% NH4OH. Column: Phenomenex Gemini-NX C18 110 Å 5 μm 21×100. Flow Rate: 44 mL/min. 10 min Method, variable gradient over 8 min. Mass spectral data were acquired from 100-850 amu in electrospray positive mode) to afford 2-(4-(4-(4-bromothiophen-3-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (81 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (br s, 1H), 8.08 (d, J=5.1 Hz, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.37 (d, J=5.1 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 3.31-3.35 (m, 4H), 3.26-3.29 (m, 4H). m/z (ESI, +ve ion) 552.8 (M+H)+. GK-GKRP IC50 (Binding)=0.816 μM.
Reaction SMILES: [CH2:1]([C:3]([NH:8][C:9]1[S:10][C:11]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]#[N:23])[CH:18]=3)[C:12]=2[N:13]=1)([CH2:6][OH:7])[CH2:4][CH3:5])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1([CH2:4][CH3:5])[CH2:6][O:7][C:34](=[O:36])[N:8]1[C:9]1[S:10][C:11]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]#[N:23])[CH:18]=3)[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCC(CC)(CO)Nc1nc2c(s1)CCc1cc(C#N)ccc1-2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(CC)COC(=O)N1c1nc2c(s1)CCc1cc(C#N)ccc1-2
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
2-{[1-Ethyl-1-(hydroxymethyl)propyl]amino}-4,5-dihydronaphtho[1,2-d][1,3]thiazole-7-carbonitrile (0.29 g, 0.89 mmol), prepared in the previous step, was dissolved in methylene chloride (10 mL) and diisopropylethyl amine (0.37 mL, 2.1 mmol) was added and the mixture was cooled to 0° C. Triphosgene (108 mg, 1.07 mmol) was added and the mixture was stirred for 2 h. The mixture was then diluted with methylene chloride and washed with 2N HCl, saturated NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10%-15% ethyl acetate in hexane) afforded the title compound (230 mg, 73%) as a white solid. HRMS: calcd for C19H19N3O2S+H+, 354.12707. Found (ESI-FT/MS, [M+H]1+), 354.127; Analytical HPLC: purity 98.1% at 210-370 nm, 10.7 min.; 98.8% at 316 nm, 10.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[N:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:30]=[CH:29][C:21]2[N:22]=[C:23]([NH:25][C:26]([NH2:28])=[NH:27])[NH:24][C:20]=2[CH:19]=1.[OH-].[Na+]>CO.O>[CH3:17][C:18]1[CH:30]=[CH:29][C:21]2[N:22]=[C:23]([N:25]=[C:26]3[NH:28][C:7]4([C:5]5[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=5)[NH:28][C:26](=[N:25][C:23]5[NH:24][C:20]6[CH:19]=[C:18]([CH3:17])[CH:30]=[CH:29][C:21]=6[N:22]=5)[NH:27][C:9]4([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][N:16]=4)[NH:27]3)[NH:24][C:20]=2[CH:19]=1
Reactant: Cc1ccc2nc(NC(=N)N)[nH]c2c1
Reactant: O=C(C(=O)c1ccccn1)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc2nc(N=C3NC4(c5ccccn5)NC(=Nc5nc6ccc(C)cc6[nH]5)NC4(c4ccccn4)N3)[nH]c2c1

Procedure:
A mixture of 2,2′-pyridil (603 mg, 2.84 mmol) and 5-methyl-2-guanidinobenzimidazole (489 mg, 2.58 mmol) in methanol (17 mL) was treated with a solution of sodium hydroxide (113.6 mg, 2.84 mmol) in 2.8 mL of water. The title compound was isolated as a grey powder (450 mg, 63% yield). mp: 290-291° C. (dec); HPLC retention time 7.1 min (reversed phase, Beckman ultrasphere ODS 4.6 mm×25 cm column, 20 min gradient elution with 20:80 to 60:40 acetonitrile:water containing 0.1% TFA@2 mL/min); 1H NMR (300 MHz, d6-DMSO) δ11.3 (br s, NH, 2 H), 10.0 (br s, NH, 2 H), 8.5 (br s, NH, 2 H), 8.32 (d, J=4.2 Hz, 2 H), 7.54 (t, J=7.6 Hz, 2 H), 7.31 (d, J=7.6 Hz, 2 H), 7.16 (d, J=7.8 Hz, 2 H), 7.16-7.09 (m, 2 H), 7.09 (s, 2 H), 7.14 (br s, 2 H), 6.86 (d, J=7.8, Hz, 2 H), 2.34 (s, 6 H); MS (ESI) m/z 555 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:33]=[CH:34][C:35]([NH2:38])=[CH:36][CH:37]=5)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(Cc3ccc(Cc4ccc(Cc5ccc([N+](=O)[O-])cc5)cc4)cc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Cc2ccc(Cc3ccc(Cc4ccc(Cc5ccc(N)cc5)cc4)cc3)cc2)cc1

Procedure:
In a 1-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 25.00 g of 1,4-bis(4-(4-nitrophenylmethyl)phenylmethyl)benzene was dissolved in 400 milliliters of tetrahydrofuran, 2.5 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) was added and contacted with hydrogen gas while cooled with water at a normal pressure and then stirred. By recrystallizing the concentrate from a tetrahydrofuran solvent, 21.13 g of a diamino compound according to the invention, that is, 1,4-bis(4-(4-aminophenylmethyl)phenylmethyl)benzene was obtained. Melting point was from 177.9° to 179.7° C.