Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>>[N+:14]([C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: O=[N+]([O-])c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 5 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 337. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) (d, 1H) 7.6-6.6 (m, 7H) 6.0 (d, 2H) 4.85 (s, 2H) 4.40 (d, 2H) 3.0 (m, 1H), 2.0 (m, 4H), 1.6 (m, 4H).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:17]=[CH:16][C:15]3[O:14][CH2:13][CH:12]([C:18](O)=[O:19])[CH2:11][C:10]=3[C:9]=2[CH:21]=1>>[CH3:1][NH:2][C:18]([CH:12]1[CH2:11][C:10]2[C:9]3[CH:21]=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][C:8]=3[CH:17]=[CH:16][C:15]=2[O:14][CH2:13]1)=[O:19]
Reactant: CN
Reactant: COc1ccc2ccc3c(c2c1)CC(C(=O)O)CO3
Product: CNC(=O)C1COc2ccc3ccc(OC)cc3c2C1

Procedure:
Methylamine, condensed with the acid obtained in Step B of Example 5, allows the title compound to be obtained.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([N+:21]([O-])=O)([CH3:20])[CH2:5][C:6]1[CH:19]=[CH:18][C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.[BH4-].[Na+]>CO>[CH3:20][C:4]([NH2:21])([CH3:3])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(Cc1ccc(Oc2ccc(O)cc2)cc1)[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(N)Cc1ccc(Oc2ccc(O)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of NiCl2.6H2O (1.40 g, 5.9 mmol) in MeOH (100 mL) was stirred at RT under a nitrogen atmosphere. Sodium borohydride (0.675 g, 17.9 mmol) was carefully added to the mixture in small portions. Twenty minutes after complete addition of the initial sodium borohydride 4-(4-(2-methyl-2-nitropropyl)phenoxy)phenol (3.20 g, 11 mmol) was added followed by the careful portionwise addition of more NaBH4 (1.58 g, 42 mmol) which caused a frothing exothermic reaction. All starting nitro compound had been consumed within 15 minutes of the last hydride addition as judged by TLC analysis. The mixture was then filtered through Celite and the filtrate concentrated in vacuo. The resulting residue was chromatographed over silica gel (MeOH/CHCl3) which allowed for isolation of both the incompletely reduced hydroxylamine product (0.675 g, 22%) and the desired amine product (0.94 g, 34%). MS (FD+): 258 (amine)
Reaction SMILES: [O:1]1[CH2:6][CH2:5]OCC1.[C:7]([CH2:9][C:10]1([C:15]#[N:16])CC(=C)[CH2:11]1)#[N:8].I([O-])(=O)(=O)=O.[Na+]>O.[Os](=O)(=O)(=O)=O>[C:7]([CH2:9][C:10]1([C:15]#[N:16])[CH2:5][C:6](=[O:1])[CH2:11]1)#[N:8]
Reactant: C1COCCO1
Reactant: C=C1CC(C#N)(CC#N)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: N#CCC1(C#N)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of water (2 mL, 0.1 mol) and 1,4-dioxane (6 mL, 0.08 mol), 1-(cyanomethyl)-3-methylenecyclobutanecarbonitrile (0.270 g, 0.00204 mol), and 0.2 M of osmium tetraoxide in water (0.04 mL) was stirred for 5 min, during which time the mixture became brown. While the temperature was maintained at room temperature, sodium periodate (0.919 g, 0.00430 mol) was added in portions over a period of 30 min. The mixture was stirred overnight. The mixture was extracted with EtOAc and the combined organic layers were dried over MgSO4. After removal of the solvents, the crude product was used directly in next step.
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9](Cl)=[N:10][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH2:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1>>[Br:1][C:2]1[C:7]2[NH:8][C:9]([NH:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][CH:23]=[N:24]4)=[CH:19][CH:18]=3)=[N:10][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: FC(F)(F)c1cc(Br)c2[nH]c(Cl)nc2c1
Product: FC(F)(F)c1cc(Br)c2[nH]c(Nc3ccc4cccnc4c3)nc2c1

Procedure:
The reaction of 7-bromo-2-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazole (135 mg, 0.45 mmol, prepared according to the procedures described in WO 2004/035549 A1) with 7-aminoquinoline (43 mg, 0.3 mmol, Synchem) under the condition of Example 2 afforded the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 407 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.Br[CH:28]([CH2:30][CH2:31][CH3:32])[CH3:29]>>[CH3:29][CH:28]([O:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:13][CH2:12][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])([CH2:14][CH2:15]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(O)c3)(CC1)OC2
Reactant: CCCC(C)Br
Product: CCCC(C)Oc1cccc(C23CCC(CCOCC(=O)O)(CC2)CO3)c1
Reaction time: 0.33 h
Yield: 88 %

Procedure:
The title compound was prepared by an analogous sequence to that used to synthesize Example 51 from 7F (tert-butyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate) except that 2-bromopentane instead of (bromomethyl)cyclobutane was used as the alkylating agent. The crude product was purified by preparative LC/MS (Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 MeCN:water with 10 mM NH4OAc; Mobile Phase B: 95:5 MeCN:water with 10 mM NH4OAc; Gradient: 30-70% B over 20 min, then a 5-min hold at 100% B; Flow rate: 20 mL/min) to give the title compound (11.5 mg, 88% yield; 96% purity by LC/MS) as a light yellow oil. LCMS, [M−H]−=375. 1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.96-6.83 (m, 2H), 6.74 (d, J=8.3 Hz, 1H), 4.41 (sxt, J=5.9 Hz, 1H), 3.95 (s, 2H), 3.76 (s, 2H), 3.50 (t, J=6.7 Hz, 3H), 2.09-1.96 (m, 2H), 1.87-1.75 (m, 2H), 1.71-1.57 (m, 5H), 1.56-1.47 (m, 1H), 1.46-1.32 (m, 3H), 1.21 (d, J=6.1 Hz, 3H), 0.90 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[N:13]=[CH:14][C:15]([NH:18][C:19](=[O:28])[C:20]2[C:25]([F:26])=[CH:24]C=[CH:22][C:21]=2F)=[N:16][CH:17]=1.FC1C=[N:37]C=CC=1C(Cl)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[C:12]1[N:13]=[CH:14][C:15]([NH:18][C:19](=[O:28])[C:20]2[CH:21]=[CH:22][N:37]=[CH:24][C:25]=2[F:26])=[N:16][CH:17]=1
Reactant: O=C(Nc1cnc(-c2cc(C(F)(F)F)ccc2Cl)cn1)c1c(F)cccc1F
Reactant: O=C(Cl)c1ccncc1F
Product: O=C(Nc1cnc(-c2cc(C(F)(F)F)ccc2Cl)cn1)c1ccncc1F

Procedure:
Compound 2 was prepared in an analogous fashion to Compound 1 except that 3-fluoro-isonicotinoyl chloride was used instead of 2,6-difluoro-benzoyl chloride.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:18]1[CH2:19][CH2:20][N:15]([CH2:13][CH3:14])[CH2:16][CH2:17]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CCN(C(=O)CCl)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 19 %

Procedure:
Chloroacetyl chloride (6.63 ml) and triethylamine (13.4 ml) in DCM (20 ml) was added dropwise to 1-ethylpiperazine (10 g) in DCM (60 ml) under nitrogen. The mixture was stirred at room temperature for 17 hours then partitioned between DCM and H2O (100 ml). The aqueous layer was neutralised using 1M NaOH before extracting into DCM. Organic layer dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (silica, 0 to 5% MeOH in DCM) gave the title compound as a pale oil (3.23 g, 19%). δH (CDCl3) 4.08 (2H, s), 3.65 (2H, m), 3.55 (2H, m), 2.52-2.40 (6H, m), 1.10 (3H, t, J 7.2 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.C(N(C(C)C)CC)(C)C.[CH3:26][N:27]([CH3:32])[CH2:28][C:29](Cl)=[O:30]>ClCCl>[CH3:26][N:27]([CH3:32])[CH2:28][C:29]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)=[O:30]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CN(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a 100 mL round bottom flask was placed 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine 65 (438 mg, 2 mmol), dichloromethane (30 mL), diisopropylethylamine (517 mg, 4 mmol), and 2-(dimethylamino)acetyl chloride (267 mg, 2.2 mmol). The reaction was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. Saturated aqueous sodium bicarbonate was added (20 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified on a silica-gel column using 0 to 20% methanol in dichloromethane as the solvent gradient. The product fractions were collected and concentrated to afford the title compound 66 as an orange oil. Mass found by LC-MS(+): 305 (M+H); calc. for C16H25BN2O3: 304.19.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>O1CCOCC1>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][C:3]([N:2]([CH3:1])[CH3:12])=[CH:4][CH:5]=2)[N:15]=1
Reactant: CN(C)c1ccc(CCO)cc1
Reactant: Clc1cncc(Cl)n1
Solvent: C1COCCO1
Product: CN(C)c1ccc(CCOc2cncc(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 0.2 h

Procedure:
K-t-BuO (2.27 g, 20.3 mmol) was added to a stirred solution of 4-(dimethylamino)phenethyl alcohol (3.55 g, 21.5 mmol) in dioxane (35 mL) at 0° C. (ice-bath). After being stirred for 5 min at 0° C. and 12 min at room temperature, the mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (2.62 g, 17.6 mmol) was added.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH3:16]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5]([OH:7])=[O:6]
Reactant: CCCCCBr
Reactant: O=C(O)c1ccc(O)c(Br)c1
Product: CCCCCOc1ccc(C(=O)O)cc1Br
Yield: 87.2 %

Procedure:
25.8 g (0.119 mol) of the 3-bromo-4-hydroxybenzoic acid was reacted with 36.0 g (0.238 mol) pentyl bromide to yield 29.8 g of purified 3-bromo-4-n-pentyloxybenzoic acid. The yield was calculated to be 87.2%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:50])[N:24]([CH:25]([CH2:42][CH2:43]O)[C:26]([NH:28][CH:29]([CH2:34][CH2:35][CH2:36][CH:37]([O:40][CH3:41])[O:38][CH3:39])[C:30]([O:32][CH3:33])=[O:31])=[O:27])[C:23](=[O:45])[C:22]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:21]12.[C:51]([OH:54])(=[S:53])[CH3:52]>O1CCCC1>[C:23]1(=[O:45])[N:24]([CH:25]([CH2:42][CH2:43][S:53][C:51](=[O:54])[CH3:52])[C:26]([NH:28][CH:29]([CH2:34][CH2:35][CH2:36][CH:37]([O:38][CH3:39])[O:40][CH3:41])[C:30]([O:32][CH3:33])=[O:31])=[O:27])[C:20](=[O:50])[C:21]2=[CH:49][CH:48]=[CH:47][CH:46]=[C:22]12
Reactant: COC(=O)C(CCCC(OC)OC)NC(=O)C(CCO)N1C(=O)c2ccccc2C1=O
Reactant: CC(O)=S
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(CCCC(OC)OC)NC(=O)C(CCSC(C)=O)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A cold (0° C.) solution of triphenylphosphine (1.143 g., 4.36 mmol.) in tetrahydrofuran (20 ml.) was treated with diisopropyl azidodicarboxylate (860 μl., 883 mg., 4.37 mmol.). Within 5 minutes a white slurry developed. After 30 minutes, a solution of [S-(R*,R*)-2-[(2-phthalimido-4-hydroxy-1-oxobutyl]-amino]-6,6-dimethoxyhexanoic acid, methyl ester [prepared as described in Example 1(f), 928 mg., 2.19 mmol.] in tetrahydrofuran (8 ml.) was added followed by neat thioacetic acid (312 μl., 332 mg., 4.36 mmol.). The mixture was stirred at 0° C. for 1.25 hours, then partitioned between 50% saturated sodium bicarbonate and ethyl acetate. The ethyl acetate extract was washed with brine, dried (sodium sulfate), filtered and stripped. The residue was redissolved in ethyl acetate and treated with a small amount of hexane to precipitate triphenylphosphine oxide. The mixture was filtered and the filtrate was flash chromatographed (Merck silica gel, 65:35-ethyl acetate:hexanes) to give 894 mg. of the title product as a colorless oil. TLC (75:25-ethyl acetate:hexanes) Rf =0.43.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([N:11]=[N:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:16]([O:28]CC)=[C:15](C(O)=O)[CH:14]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br.[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH2:42].N1C(C)=CC=CC=1C>O1CCCC1>[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][S:2]([C:5]1[CH:6]=[C:7]([N:11]=[N:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:16]([OH:28])=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCOc1c(C(=O)O)cc(N=Nc2cccc(S(=O)(=O)Cl)c2)c2c(NS(C)(=O)=O)cccc12
Reactant: NCCCCCCBr
Agent: Br
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)Nc1cccc2c(O)ccc(N=Nc3cccc(S(=O)(=O)NCCCCCCBr)c3)c12

Procedure:
A suspension of 4-[3-chlorosulfonylphenylazo]-1-ethoxycarboxy-5-methanesulfonamidonaphthalene (20.4 g), 6-bromohexylamine hydrobromide (14.4 g), 2,6-lutidine (600 ml) and tetrahydrofuran (30 ml) was reacted for one hour at 50°-55° C. The mixture was cooled and filtered; the filtrate was concentrated to an oil which was dissolved in a minimum amount of acetonitrile and chromatographed on silica gel using acetonitrile as the eluant. The orange colored eluate was concentrated and cooled to obtain the product; yield 7.3 g (32%), m.p. 163°-5° C.
Reaction SMILES: [C:1]1([C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([C@@H:7]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][CH:16]=2)[CH2:8][CH:9]=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc([C@@H](CCO)c2ccccc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-3-phenyl-3-(4-methanesulfonylphenyl)propan-1-ol (244 mg, 0.84 mmol) in DCM (5 mL) was added Dess-Martin periodinane (392 mg, 0.92 mmol) and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was washed with 2M aqueous sodium hydroxide (2×10 mL), dried and evaporated to give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=O)C.O.[NH2:21][NH2:22]>C(O)C>[CH2:16]([N:15]([CH2:18][CH3:19])[C:13]1[CH:12]=[CH:11][C:9]2[CH:10]=[C:6]([C:4]([NH:21][NH2:22])=[O:3])[O:7][C:8]=2[CH:14]=1)[CH3:17]
Reactant: NN
Reactant: CCOC(=O)c1cc2ccc(N(CC)CC)cc2o1
Solvent: CCO
Solvent: O
Product: CCN(CC)c1ccc2cc(C(=O)NN)oc2c1
Temperature: 25 °C
Yield: 97 %

Procedure:
Equimolar amounts of 6-diethylaminobenzofuran-2-carboxylic acid ethyl ester (Example 3) and hydrazine hydrate are boiled under reflux for three hours in solution in ethanol and after cooling to ambient temperature stirred for another twelve hours. The reaction mixture is poured into ice-water and the precipitate is suction filtered and washed with water. After recrystallization from alcohol the hydrazide is obtained in colorless crystals having a melting point of 127° to 129°C in a yield of 97%. (N: calculated 16.99, found 17.1). It dissolves in alcohol to give a colorless solution with a strong blue fluorescence.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[C:24]([NH2:25])=[C:23]2[O:26][CH2:27][O:28][C:22]2=[C:21]([I:29])[CH:20]=1>>[Cl:18][C:19]1[C:24]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[C:23]2[O:26][CH2:27][O:28][C:22]2=[C:21]([I:29])[CH:20]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Product: COc1cc2ncc(C#N)c(Nc3c(Cl)cc(I)c4c3OCO4)c2cc1OC
Yield: 72.6 %

Procedure:
Using an analogous procedure to that described in the portion of Example 1 that is concerned with the preparation of starting materials, 4-chloro-3-cyano-6,7-dimethoxyquinoline (1.74 g) was reacted with 6-chloro-4-iodo-2,3-methylenedioxyaniline (2.5 g) to give 4-(6-chloro-4-iodo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinoline as a solid (2.59 g) which gave the following characterising data; NMR Spectrum: (DMSOd6) 4.0 (s, 6H), 6.18 (s, 2H), 7.38 (s, 1H), 7.48 (s, 1H), 7.88 (s, 1H), 8.44 (s, 1H), 9.45 (s, 1H); Mass Spectrum: M+H+ 510.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH:10]([CH2:32][OH:33])[CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:16]=2[S:24]([N:27]=[CH:28][N:29]([CH3:31])[CH3:30])(=[O:26])=[O:25])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[NH2:21][C:19]1[CH:18]=[CH:17][C:16]([S:24]([N:27]=[CH:28][N:29]([CH3:30])[CH3:31])(=[O:26])=[O:25])=[C:15]([O:14][CH2:13][CH2:12][CH2:11][C@H:10]([NH:9][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)[CH2:32][OH:33])[CH:20]=1
Reactant: CN(C)C=NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCCCC(CO)Nc1nc(Cl)ncc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C=NS(=O)(=O)c1ccc(N)cc1OCCC[C@@H](CO)Nc1nc(Cl)ncc1Br
Reaction time: 2 h

Procedure:
A solution of 145 mg (0.30 mmol) of 2-[4-(5-bromo-2-chloro-pyrimidin-4-ylamino)-5-hydroxy-pentyloxy]-N-dimethylaminomethylene-4-nitro-benzenesulfonamide in 20 ml of THF is mixed under argon at room temperature with 2.0 ml of an approximately 10% solution of Ti(III)Cl in 20-30% hydrochloric acid. After 2 hours, the reaction solution is mixed again with 0.3 ml of Ti(III)Cl solution, and it is stirred for another 18 hours. The batch is diluted with ethyl acetate and made basic with 1N NaOH solution. The phases are separated, and the aqueous phase is extracted again from ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (DCM/methanol 9:1; Flashmaster II). 90 mg (0.17 mmol, corresponding to 56% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[S:23]([NH2:26])(=[O:25])=[O:24].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=2)=[CH:4][C:3]=1[S:23]([NH2:26])(=[O:25])=[O:24]
Reactant: CCCCCCOc1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Reaction time: 0.5 h

Procedure:
2-Chloro-5-[(4-hexyloxy-phenyl)-hydroxy-methyl]-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 25-75%) followed by recrystallization from ether affording 30 mg of the title compound. 1H NMR (DMSO) 0.88 (t, 3H, J=6.78 Hz), 1.28-1.45 (m, 6H), 1.70-1.79 (m, 2H), 4.09 (t, 2H, J=6.4 Hz), 7.10 (d, 2H, J=9.04 Hz), 7.75-7.90 (m, 4H), 8.24 (d, 1H, J=1.89). MS (m/z): 396 (M+1).
Reaction SMILES: Cl.[N:2]1[N:3]([C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[CH2:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]2)[N:4]=[CH:5][CH:6]=1.[N:20]1[N:21]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27](O)=[O:28])[N:22]=[CH:23][CH:24]=1>>[N:2]1[N:3]([C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[CH2:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:27]([C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[N:21]2[N:22]=[CH:23][CH:24]=[N:20]2)=[O:28])[N:4]=[CH:5][CH:6]=1
Reactant: c1cc(C[C@@H]2CCCCN2)cc(-n2nccn2)c1
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: Cl
Product: O=C(c1ccccc1-n1nccn1)N1CCCC[C@H]1Cc1cccc(-n2nccn2)c1

Procedure:
The title compound was prepared from (S)-2-(3-[1,2,3]triazol-2-yl-benzyl)-piperidine hydrochloride and 2-(2H-1,2,3-triazol-2-yl)benzoic acid E-2 following the procedure described for B-28. LC-MS D: tR=0.91 min; [M+H]+=414.05.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:6]([N+:18]([O-])=O)[CH:5]=1>C(OCC)(=O)C.CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[C:6]([NH2:18])[CH:5]=1
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reaction time: 8 h

Procedure:
4-tert-Butoxycarbonylamino-3-nitrobenzoic acid methyl ester (1.11 g, 3.75 mmol) was dissolved in ethyl acetate-methanol (1:1) (30 ml). Next, 10% palladium-carbon powder (200 mg, 5 mol %) was added to the aqueous solution under a nitrogen atmosphere, and the mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered with celite, and the filtrate was concentrated under reduced pressure to obtain 3-amino-4-tert-butoxycarbonylaminobenzoic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([O:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(F)(F)F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from step (ii) (2.3 g), benzyl bromide (1.44 ml) and potassium carbonate (1.67 g) in DMF (20 ml) was stirred at RT for 2 h. The mixture was partitioned between diethylether and water, the organic layer dried, and the solvent evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 40/60 pet. ether/diethylether 4:1, yield 2.83 g.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](C(O)=O)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[C:18]([OH:20])=[O:19].CO>O=[Pt]=O>[NH:2]1[CH2:3][CH2:4][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccccc1-c1ccncc1
Reactant: CC(=O)O
Agent: O=[Pt]=O
Agent: [Na]
Solvent: CO
Product: O=C(O)c1ccc(C2CCNCC2)cc1
Reaction time: 4 h

Procedure:
To the sodium salt of 4-pyridine benzoic acid (500 mg, 2.25 mmol) suspended in 20% AcOH/MeOH (20 ml) was added PtO2 (250 mg) and the mixture was hydrogenated at 50 psi with agitation (Parr) for 4 h. The solution was filtered through celite, washed with MeOH (3×5 ml), evaporated with hexane (4×) to azeotrope the acetic acid. TLC of the crude (EtOH/H2O/NH4OH 10:1:1) shows no starting material, but did show 2 more polar spots. After evaporation from hexane, the white solid (596 mg crude, still with residual HOAc) was dried in a vacuum overnight, and used without further purification in subsequent steps. MS m/z [M+H]+.