Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:19]=[N:20][C:21](OC)=[CH:22][CH:23]=1)([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])[NH:28][NH2:29]>>[C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:19]=[N:20][C:21]([NH:29][NH:28][C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:22][CH:23]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1ccc(-c2ccc(OC)nn2)c(OCC(O)CNC(C)(C)C)c1
Product: COc1ccc(-c2ccc(NNC(=O)OC(C)(C)C)nn2)c(OCC(O)CNC(C)(C)C)c1

Procedure:
3-[2-(3-t-Butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-6-methoxypyridazine was heated with t-butyl carbazate to give 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-6-(2-t-butyloxycarbonylhydrazino)pyridazine.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14](F)[C:13]=1[N+:21]([O-:23])=[O:22])[CH3:11]>>[CH2:10]([C:12]1[C:13]([N+:21]([O-:23])=[O:22])=[C:14]([C:15]([F:19])=[C:16]([F:18])[CH:17]=1)[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1])[CH3:11]
Reactant: CCc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Reactant: Nc1ccc(I)cc1F
Product: CCc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Yield: 58.5 %

Procedure:
2-Fluoro-4-iodoaniline (2.05 g, 10 mmol) and 1-ethyl-3,4,5-trifluoro-2-nitrobenzene (2.37 g, 10 mmol) were reacted using the condition described in example 1 (Step A) to form the title compound (2.47 g, 60%); m/z=407 [M−1]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[Br:14][C:15]1[C:16]([F:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19]>O1CCCC1>[Br:14][C:15]1[C:16]([F:23])=[C:17]([CH:18]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[OH:19])[CH:20]=[CH:21][CH:22]=1
Reactant: Clc1ccccc1I
Reactant: O=Cc1cccc(Br)c1F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1ccccc1Cl)c1cccc(Br)c1F
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a stirring solution of 1-chloro-2-iodobenzene (7.05 g, 29.6 mmol) in tetrahydrofuran (Volume: 15 mL) at −15° C. was added isopropylmagnesium chloride (17.24 mL, 34.5 mmol). The mixture was allowed to stir for 30 minutes, at which time 3-bromo-2-fluorobenzaldehyde (5 g, 24.63 mmol) was added. The reaction mixture was stirred overnight. The reaction was quenched with saturated aqueous NH4Cl. The reaction mixture was extracted with EtOAc (3×). The organics were combined, rinsed with brine, dried over Na2SO4, filtered, and concentrated to afford the title compound (7.5 g, 96%).
Reaction SMILES: [C:1]1(C)C=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[C:12]([NH:31][C:32]1[S:33][CH:34]=[C:35]([C:37](=[N:43][OH:44])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC=CC=1.[OH2:51]>O1C=CCCC1.C(N(CC)CC)C>[C:12]([NH:31][C:32]1[S:33][CH:34]=[C:35]([C:37](=[N:43][O:44][CH:5]2[CH2:4][CH2:3][CH2:2][CH2:1][O:51]2)[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O
Agent: C1=COCCC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C(=NOC1CCCCO1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 8 h

Procedure:
2.4 g of p-toluene sulfonic acid were added to a mixture of 5.6 g of the product of Step A in 56 ml of redistilled dihydropyran in an ice bath and the mixture was then stirred for an hour while the temperature returned to room temperature. The mixture was poured into a mixture of 100 ml of benzene, 100 ml of water and 2 ml of triethylamine and the organic phase was decanted, was washed with water, dried and vacuum filtered. The filter was rinsed with benzene and the filtrate was evaporated to dryness. The residue was taken up in isopropyl ether and crystallization was induced. The mixture was stored overnight in a refrigerator and was then vacuum filtered. The product was rinsed with isopropyl ether to obtain 4.42 g of the syn isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-tetrahydropyranyloxyimino-acetate melting at 184° C.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]2[CH2:19][CH2:18][CH:17]([C:20]#[N:21])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[CH2:18][CH2:19]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCCc1ccc(C=CC2CCC(C#N)CC2)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(CCC2CCC(C#N)CC2)cc1
Yield: 81.8 %

Procedure:
956 mg of the 4-[2-(p-pentylphenyl)ethenyl]cyclohexanecarbonitrile obtained were dissolved in 50 ml of toluene in a sulphonation flask, treated with 150 mg of palladium/carbon (10%) and hydrogenated at normal pressure and room temperature until the hydrogen uptake came to a standstill (about 30 minutes). Filtration of the mixture (rinsing with toluene), concentration of the filtrate and low-pressure chromatography (0.4 bar) of the residue (890 mg) on silica gel with 5% ethyl acetate/petroleum ether gave 788 mg (82%) of 4-[2-(p-pentylphenyl)ethyl]cyclohexanecarbonitrile as a viscous colourless oil. Although in the thin-layer chromatogram using different solvent systems as the eluant only a single spot appeared, according to gas chromatographic and NMR spectroscopic analysis this material was a cis/trans isomer mixture (about 1:3). Two-fold crystallization of this material from pentane at -20° C. finally yielded trans-4-[2-(p-pentylphenyl)ethyl]cyclohexanecarbonitrile of sufficient purity (according to gas chromatographic analysis 98.8% of trans compound and 1.2% of cis compound); m.p. 22.4° C., cl.p. (N-I) -14.1° C.
Reaction SMILES: [CH2:1]([O:3][Si:4]([C:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]=[CH:12]2)([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].C([SiH]([CH2:23][CH3:24])CC)C.[CH2:25](O)[CH3:26]>ClCCl.C1COCC1.C1(C)C=CC=CC=1>[CH2:25]([C:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]=[CH:12]2)[CH2:26][CH2:23][CH3:24].[CH2:6]([O:5][Si:4]([C:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]=[CH:12]2)([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CC[SiH](CC)CC
Reactant: CCO
Agent: CCO[Si](OCC)(OCC)C12C=CC(CC1)C2
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCC12C=CC(CC1)C2
Temperature: 80 °C

Procedure:
BuNB (25.22 g, 0.168 mol), Triethoxysilyl Norbornene (TESNB, CAS 18401-43-9) (4.78 g, 0.019 mol), triethyl silane (0.011 g, 9.32E-05 mol), ethanol (0.10 g, 2.24E-03 mol) and toluene (170.0 g) were combined in a 500 mL serum bottle and heated to 80° C. in an oil bath to form a solution. To this solution were injected Pd1206 (0.018 g, 1.49E-05 mol) in the form of a concentrated solution in dichloromethane. After addition, the resulting mixture was maintained at 80° C. for 9 hours. The copolymer was precipitated by adding methanol drop wise into the vigorously stirred reaction mixture. The precipitated copolymer was collected by filtration and dried in an oven at 60° C. under vacuum. After drying, 20.58 g was obtained (69%). The molecular weight of the copolymer was determined by GPC in THF solvent (polystyrene standard) to be Mw=238,000 and Mn=96,000. The composition of the copolymer was determined by 1H-NMR to be (85/15) BuNB/TESNB copolymer. The refractive indices of this polymer were measured by prism coupling method and determined to be 1.5061 in TE mode and 1.5041 in TM mode at a wavelength of 633 nm. The Tg (based on thermomechanical analysis (TMA) measurement) of this polymer was 276° C. The dried copolymer was dissolved in sufficient toluene to result in a 30 wt % copolymer solution.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34][C:35](OCC)=[O:36])=[CH:20][CH:19]=3)[N:15]=2)=[CH:5][CH:4]=1.[CH3:42][NH2:43]>C(O)C>[CH3:42][NH:43][C:35](=[O:36])[CH2:34][CH2:33][C:29]1[N:28]([CH2:27][CH2:26][CH2:25][CH2:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][C:14]3[N:15]=[C:11](/[CH:10]=[CH:9]/[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:40])([F:41])[F:1])=[CH:8][CH:7]=4)[O:12][CH:13]=3)=[CH:23][CH:22]=2)[CH:32]=[CH:31][N:30]=1
Reactant: CCOC(=O)CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: CN
Solvent: CCO
Product: CNC(=O)CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1

Procedure:
A mixture of ethyl 3-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]propionate (180 mg) and a solution (3 ml) of 30% methylamine in ethanol in sealed tube was heated at 120° C. for 12 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent; dichloromethane to dichloromethane:methanol=30:1) and recrystallized from ethyl acetate-hexane to give the titled compound (43 mg) as a colorless crystal powder.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[O:22]1[CH2:23][CH2:24][N:19]([CH2:2][CH2:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:6])[CH3:5])[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: CC(O)(CCCl)c1ccccc1-c1ccccc1
Product: CC(O)(CCN1CCOCC1)c1ccccc1-c1ccccc1

Procedure:
2.6 g of 1-chloro-3-p-biphenylyl-butan-3-ol are boiled with 30 ml of morpholine for 1.5 hours and the mixture is cooled and worked up in the customary manner to give 1-morpholino-3-p-biphenylyl-butan-3-ol, m.p. 116°-118°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1COCC1>[Br-:15].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N+:10]2[CH:14]=[CH:13][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Reactant: CCCCCCCBr
Solvent: C1CCOC1
Product: CCCCCCCn1cc[n+](-c2ccc([N+](=O)[O-])cc2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 5.3 mmol (1.00 g) 1-(4-nitrophenyl)imidazole and 6.3 mmol (1.14 g, 1.0 ml) 1-bromoheptane are dissolved in 5 ml THF and heated for 48 h to 90° C.
Reaction SMILES: [C:1]1([CH:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([CH:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11][CH2:10]2)[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCc1ccccc1
Reactant: OC(c1ccccc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1ccccc1)C1CCN(CCc2ccccc2)CC1
Temperature: 80 °C

Procedure:
A mixture of alpha-phenyl-4-piperidinemethanol (1.5 g, 7.8 mmol), 2-bromoethyl benzene (1.1 ml, 8.0 mmol) and potassium carbonate (1.1 g, 8.0 mmol) in dry DMF (20 ml) was heated at 80° C. over the weekend (60 h). The excess DMF was distilled off at reduced pressure and the residue was dissolved in ethyl acetate. The organic phase was washed with H2O (3×100 ml), saturated aqueous NaCl (1×100 ml), dried (MgSO4), filtered and evaporated to give a pale yellow oil which eventually crystallized. After recrystallization from ethyl acetate-hexane, a white crystalline solid was obtained, mp 125°-128° C.
Reaction SMILES: [Cl-].[CH3:2][C:3]1([CH3:16])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH2:11][CH2:12][NH2+:13][CH2:14][CH:15]=2)[O:4]1.C(N(C(C)C)C(C)C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([N:13]1[CH2:12][CH:11]=[C:10]([B:5]2[O:4][C:3]([CH3:16])([CH3:2])[C:7]([CH3:8])([CH3:9])[O:6]2)[CH2:15][CH2:14]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OB(C2=CC[NH2+]CC2)OC1(C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a cooled (0° C.) solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinium chloride (8 g) and N-ethyldiisopropylamine (12 mL) in dichloromethane (100 mL) is added dropwise methanesulfonyl chloride (3 mL). The mixture is stirred for 12 hours at room temperature. The mixture is partitioned between dichloromethane and 0.1 M hydrochloric acid. The organic phase is separated, washed with brine and dried (MgSO4). The solvent is evaporated and the residue is crystallized from diethylether to give the title compound. Yield: 7.4 g; LC (method 15): tR=0.98 min; Mass spectrum (ESI+): m/z=288 [M+H]+.
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH2:7]Cl)=[O:4].C(OC)(=O)[CH2:13][OH:14].C(C1C=CC=CC=1)(C)(C)C.C([O:30]CC)C>>[OH:1][C:2]([CH3:11])([CH2:9][CH3:10])[C:3]([O:5][CH2:6][C:7]([O:14][CH3:13])=[O:30])=[O:4]
Reactant: COC(=O)CO
Reactant: CCOCC
Reactant: CCC(C)(O)C(=O)OCCCl
Solvent: CC(C)(C)c1ccccc1
Product: CCC(C)(O)C(=O)OCC(=O)OC

Procedure:
A 6 mL aliquot of an ethyl ether solution containing 0.25 M 2-chloroethyl 2-hydroxy-2-methylbutyrate, 0.25 M methyl glycolate, and 1.0% tert-butylbenzene was added to 0.4 g Lipase P30. After mixing for 7 d at room temperature, the conversion of 2-chloroethyl 2-hydroxy-2-methylbutyrate to the title compound was estimated (by GC, Method A) to be approximately 10%. The GC peak assigned to the title compound was confirmed by HRMS: calcd for C7H10O5Tms (M--CH3) 247.1001, obsd 247.0998. In identical reactions substituting Lipase MAP10, Lipase G, Lipase AK, or porcine pancreatic lipase for Lipase P30, the relative values for conversions at 7 d (Lipase P30 =100) were 73, 21, 16, and 0, respectively.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7]1([B:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[B:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)O)[OH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:30]1([B:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[B:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:14][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN(C)CCO
Reactant: OB(c1ccccc1)c1ccccc1Oc1ccccc1B(O)c1ccccc1
Product: CN(C)CCOB(c1ccccc1)c1ccccc1Oc1ccccc1B(OCCN(C)C)c1ccccc1

Procedure:
The entitled compound (60 mg) was obtained by allowing 50 mg of dimethylethanolamine to act on 95 mg of bis(4,4′-(phenylhydroxyboryl)phenyl) ether.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:17]=[C:18]3[C:26]4[C:25]([Cl:27])=[N:24][CH:23]=[N:22][C:21]=4[NH:20][C:19]3=[O:28])=[CH:15][CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:29]([N:36]1[C:44]2[C:39](=[CH:40][C:41]([NH2:45])=[CH:42][CH:43]=2)[CH:38]=[CH:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCOCCOC>[ClH:27].[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:17]=[C:18]3[C:26]4[C:25]([NH:45][C:41]5[CH:40]=[C:39]6[C:44](=[CH:43][CH:42]=5)[N:36]([CH2:29][C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:37]=[CH:38]6)=[N:24][CH:23]=[N:22][C:21]=4[NH:20][C:19]3=[O:28])=[CH:15][CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2ncnc(Cl)c2C1=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Reactant: Nc1ccc2c(ccn2Cc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCOCCOC
Product: Cl
Product: O=C1Nc2ncnc(Nc3ccc4c(ccn4Cc4ccccc4)c3)c2C1=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Temperature: 177.5 °C
Yield: 42 %

Procedure:
A mixture of 5-(4-chloro-6-oxo-6.7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide, 1-benzyl-1H-indol-5-ylamine and p-toluenesulfonic acid (5 mg) in 2 mL of 1-methyl-2-pyrrodinone and 2-methoxyethyl ether (1:3) was heated at 170-185° C. for 7 to 15 hours. The reaction mixture was evaporated to dryness and purified by reversed phase HPLC, then dissolved in 2N HCl and acetontrile and freeze-dried to give 13.5 mg (42%) of the title compound. MS 589.3 [M++1].
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N2CCN(C(C3C=C4C(=CC=3)NC(C(N3CCS(=O)(=O)CC3)=O)=C4)=O)CC2)CCCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:80][C:81]1[CH:87]=[C:86]([CH3:88])[CH:85]=[C:84]([CH3:89])[C:82]=1[NH2:83].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:80][C:81]1[CH:87]=[C:86]([CH3:88])[CH:85]=[C:84]([CH3:89])[C:82]=1[NH:83][C:23]([C:18]1[NH:19][C:20]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:12]([N:9]1[CH2:8][CH2:7][N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:11][CH2:10]1)=[O:13])=[CH:22][CH:21]=2)=[O:24]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(NC(=O)c2cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc3[nH]2)c(C)c1
Yield: 7 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride (example 34, intermediate b), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2,4,6-trimethylaniline (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow solid (7%).
Reaction SMILES: C(C1C=CC=CC=1N[C@@H](CC1C=CC(C2C=CC=C(N(C)C(NCCCCCCC)=O)C=2)=CC=1)C(O)=O)(=O)C1C=CC=CC=1.[C:45]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C@@H:60]([CH2:66][C:67]1[CH:72]=[CH:71][C:70]([C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([N:79]([CH3:92])[C:80]([NH:82][C:83]3[CH:88]=[CH:87][C:86]([N:89]([CH3:91])[CH3:90])=[CH:85][CH:84]=3)=[O:81])[CH:74]=2)=[CH:69][CH:68]=1)[C:61]([O:63]CC)=[O:62])(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[OH-].[Li+]>>[C:45]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C@@H:60]([CH2:66][C:67]1[CH:72]=[CH:71][C:70]([C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([N:79]([CH3:92])[C:80]([NH:82][C:83]3[CH:84]=[CH:85][C:86]([N:89]([CH3:91])[CH3:90])=[CH:87][CH:88]=3)=[O:81])[CH:74]=2)=[CH:69][CH:68]=1)[C:61]([OH:63])=[O:62])(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2cccc(N(C)C(=O)Nc3ccc(N(C)C)cc3)c2)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc2)c1
Agent: [Li+]
Agent: [OH-]
Product: CN(C)c1ccc(NC(=O)N(C)c2cccc(-c3ccc(C[C@H](Nc4ccccc4C(=O)c4ccccc4)C(=O)O)cc3)c2)cc1
Yield: 74.4 %

Procedure:
In a manner similar to the preparation of the (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionic acid (Example 2), using 0.60 g (0.9 mmol) of ethyl (S)-2-(2-benzoylphenylamino)-3-{3′-[3-(4-dimethylaminophenyl)-1-methylureido]biphenyl-4-yl}propionate (Example 4) and 43 mg (1.02 mmol) of lithium hydroxide, 0.41 g of (S)-2-(2-benzoylphenylamino)-3-{3′-[3-(4-dimethylaminophenyl)-1-methylureido]biphenyl-4-yl}propionic acid is obtained with an 89% yield. Melting point: 130° C.
Reaction SMILES: [ClH:1].[C:2]([CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]1[O:15][C:14]([C:16]([O:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:29](=[NH:31])[NH2:30])[CH:25]=3)[CH:20]=2)=[O:17])=[CH:13][CH:12]=1)=[O:8])([OH:4])=[O:3].CC(C)[O-:34].[Al+3:36].CC(C)[O-:39].CC(C)[O-]>C(O)C.C1(C)C=CC=CC=1>[ClH:1].[OH-:3].[Al+3:36].[C:2]([CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]1[O:15][C:14]([C:16]([O:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:29](=[NH:30])[NH2:31])[CH:25]=3)[CH:20]=2)=[O:17])=[CH:13][CH:12]=1)=[O:8])([OH:4])=[O:3].[OH-:34].[OH-:39]
Reactant: CC(C)[O-]
Agent: Cl
Agent: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)CCC(=O)O)o3)ccc2c1
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: CCO
Product: [OH-]
Reaction time: 3 h

Procedure:
In 1.84 l of 95% ethanol was dissolved 18.4 g of 6-amidino-2-naphthyl 5-(3-carboxypropionylaminomethyl)furan-2-carboxylate hydrochloride, and a solution of 8.42 g of aluminium isopropoxide in 670 ml of toluene was added dropwise thereto at room temperature. After completion of the addition, the reaction mixture was stirred for 3 hours and allowed to stand overnight. The crystals thus precipitated were collected by filtration to obtain 19.1 g of the intended product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=CC=CC=2)[N+:5]([O-:12])=[CH:4][CH:3]=1.N(OS(=O)(=O)O)=O.O.FC(F)(F)[C:23](O)=[O:24]>COCCO>[NH2:1][C:2]1[CH:3]=[CH:4][N+:5]([O-:12])=[CH:6][C:11]=1[O:24][CH3:23]
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1cc[n+]([O-])c2ccccc12
Agent: O=NOS(=O)(=O)O
Solvent: O
Solvent: COCCO
Product: COc1c[n+]([O-])ccc1N
Reaction time: 1 h

Procedure:
A solution of 4.8 g of 4-aminoquinoline-N-oxide (Amine 6) in 40 ml of trifluoroacetic acid is diazotised at 0° C. with 4.8 ml of 40% nitrosyl sulphuric acid. After one hour. the diazonium salt solution is added dropwise at 0° C. to a solution of 22.2 g of 2,3-dimethyl-5-propyl-6-α-3-(N-5-hydroxy-1-naphthylsulphamoyl)-phenylsulphonyl]-tetradecyl-1,4-quinone (the method of preparation is described in DE-A- No. 3 344 295) in 200 ml of methyl glycol and stirring is then continued for 5 hours at 0° C. The reaction mixture is then stirred into 1000 ml of water and decanted and the smeary residue is again stirred up with 1000 ml of water. After one hour, the reaction mixture is suction filtered and washed with water. 21 g of crude dye are obtained. The dye is chromatographed on a Jobin Yvon Chromatospac Prep. 100 medium pressure-liquid chromatograph C, Instruments SA GmbH, Unterhaching, using an 80 mm×1000 mm column packed with 1.5 kg of silica gel Woelm (ICN) 32-63 nm. Detection is carried out with a preparative LC-UV Detector GOW-MAC 80-800 at a wavelength of 310 nm. A Gilson M 201 is used as fraction collector. A mixture of methylene chloride and ethyl acetate 10/1 is used for elution and working up the fractions yields 2.8 g of an isomeric reddish violet dye and 8.3 g of the desired dye in the form of a dark powder.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:22][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[N+:19]([O-])=O)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1.[H][H]>CO.C1COCC1.[Pd]>[OH:1][CH2:2][C@H:3]1[CH2:22][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[NH2:19])[CH2:11][C@@H:6]2[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(F)ccc1N1CCN2C[C@H](CO)CC[C@H]2C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(F)ccc1N1CCN2C[C@H](CO)CC[C@H]2C1
Yield: 97.8 %

Procedure:
A solution of 3.0 g (9.7 mmol) of (7R,9aS)-7-hydroxymethyl-2-(4-fluoro-2-nitrophenyl)-2,3,4,6,7,8,9,9a-octahydro-1 H-pyrido[1,2-a]pyrazine in 50 mL of methanol and 50 mL of THF was treated with 0.30 g of 10% Pd/C and treated with 30 psi of hydrogen in a Parr apparatus for 1.5 h. The catalyst was removed by filtration and the red solution concentrated to give 2.65 g (98%) of (7R,9aS)-7-hydroxymethyl-2-(2-amino-4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.