Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[N:9][CH2:10][C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=[C:4]([Cl:22])[C:3]=1[N:23]=[C:24]=[O:25].ClC1[C:32]2[C:33]([C:40]3C=CC=CC=3F)=[N:34][CH2:35][C:36](=O)[N:37](C)[C:31]=2C=C(Cl)C=1NC(=O)N(C)C.NC1C(Cl)=CC2N(C)C(=[O:66])CN=C(C3C=CC=CC=3F)C=2C=1Cl.C(=O)([O-])[O-].[Na+].[Na+]>OCCN1CCNCC1.C(Cl)Cl.ClCCCl>[Cl:1][C:2]1[C:7]2[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[N:9][CH2:10][C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=[C:4]([Cl:22])[C:3]=1[NH:23][C:24]([N:34]1[CH2:35][CH2:36][N:37]([CH2:31][CH2:32][OH:66])[CH2:40][CH2:33]1)=[O:25]
Reactant: CN(C)C(=O)Nc1c(Cl)cc2c(c1Cl)C(c1ccccc1F)=NCC(=O)N2C
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1cc(Cl)c(N)c2Cl
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1cc(Cl)c(N=C=O)c2Cl
Agent: O=C([O-])[O-]
Agent: OCCN1CCNCC1
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1C(=O)CN=C(c2ccccc2F)c2c1cc(Cl)c(NC(=O)N1CCN(CCO)CC1)c2Cl
Temperature: 25 °C
Reaction time: 138 h

Procedure:
A 1,2-dichloroethane solution of [6,8-dichloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate, prepared in analogy to the procedure described in paragraph (a) of Example 4 from 6 g (17.1 mmol) of 7-amino-6,8-dichloro-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one, is treated with a suspension of 6.11 g of sodium carbonate in 6.3 ml of N-(2-hydroxyethyl)piperazine and 40 ml of methylene chloride. The mixture is stirred at room temperature for 138 hours and concentrated in vacuo. The residue is taken up in 1.5 liter of methylene chloride/ethanol (4:1), the solution is washed with 300 ml of water, dried over magnesium sulphate and evaporated. The residue is chromatographed on 250 g of silica gel using chloroform for the elution, there being obtained N-[6,8-dichloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-4-(2-hydroxyethyl)-1-piperazinecarboxamide. After recrystallisation from methylene chloride/hexane, the product melts at 232°-233° C.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[C:34]1([S:40]([NH:1][C:2]2[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=2[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Nc1ccccc1CONC(=O)c1ccccc1NCc1ccncc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NOCc1ccccc1NS(=O)(=O)c1ccccc1)c1ccccc1NCc1ccncc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of N-(2-amino-benzyloxy)-2-[(pyridin-4-ylmethyl)-amino]-benzamide (see example 400) in dichloromethane at 0-5° C. was added triethylamine (1.2 eq.) followed by addition of benzensulfonyl chloride (1.1 eq.). The mixture was allowed to warm to room temperature and stirred for 20 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc, 2/1, v/v) and gave the title compound. 13C-NMR (DMSO-d6) δ 170.7, 149.6, 149.4, 149.1, 140.7, 138.3, 134.2, 132.5, 131.0, 130.7, 128.8, 127.4, 126.9, 125.3, 124.5, 123.0, 122.2, 115.7, 112.4, 111.1, 76.6, 46.0.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:17][C:11]1[N:10]=[C:9]([NH2:18])[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:26])[CH2:3][CH2:2]2)[N:12]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: O=C(Cl)c1ccccc1
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccccc4)CC3)cccc2n1
Yield: 31 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and benzoyl chloride (57.6 mg; 0.41 mmol) to obtain 21.3 mg. (31% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 7.46 (m, 5H), 7.39 (t, J=6.0 Hz, 1H), 7.14 (br s, 1H), 6.98 (d, J=6.4 Hz, 1H), 6.86 (d, J=5.6 Hz, 1H), 5.92 (br s, 2H), 4.59 (br s, 1H), 3.66 (br s, 1H), 3.44 (m, 1H), 3.13 (m, 3H), 2.77 (m, 2H).
Reaction SMILES: O1CCOCC1.C(=O)(O)[O-].[Na+].[NH2:12][C:13]1[N:17]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23]([CH3:25])=[N:24][C:20]=3[CH:19]=2)[N:16]=[CH:15][C:14]=1[C:28]([C:30]1[N:31]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:32]=[C:33](Br)[CH:34]=1)=[O:29].[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>O>[NH2:12][C:13]1[N:17]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23]([CH3:25])=[N:24][C:20]=3[CH:19]=2)[N:16]=[CH:15][C:14]=1[C:28]([C:30]1[N:31]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:32]=[C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:34]=1)=[O:29]
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)cc2C(=O)c2cnn(-c3ccc4[nH]c(C)nc4c3)c2N)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3)cc2C(=O)c2cnn(-c3ccc4[nH]c(C)nc4c3)c2N)cc1

Procedure:
Dioxane (1.5 ml) and an aqueous solution (1.5 ml) of 1 M sodium bicarbonate were added to [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[4-bromo-1-(toluene-4-sulfonyl)-1H-pyrrol-2-yl]-methanone (57 mg), palladium chloride bis-triphenylphosphine complex (10 mg), and phenylboronic acid (37 mg). The mixture was reacted at 140° C. in a microwave reactor for ten minutes. The reaction mixture was diluted with water (5 ml), and then extracted with ethyl acetate. The organic layers were combined, and concentrated under reduced pressure. After HPLC purification, the eluate was desalted using PLHCO3 cartridge (PolymerLabs), and then concentrated under reduced pressure. Thus, [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[4-phenyl-1-(toluene-4-sulfonyl)-1H-pyrrol-2-yl]-methanone was obtained as a yellow powder (15 mg, 26%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([Cl:11])=[O:10])[CH2:2]2.C([N:15](CC)[CH:16]([CH3:18])[CH3:17])(C)C.N[C:22]1C=CC=[C:27]2[C:23]=1[CH:24]=[N:25][NH:26]2>CN(C1C=CN=CC=1)C>[ClH:11].[NH:26]1[CH:27]2[CH:23]([CH:22]=[CH:18][C:16]([NH:15][C:9]([CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:10])=[CH:17]2)[CH:24]=[N:25]1
Reactant: O=C(Cl)C1CN2CCC1CC2
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1cccc2[nH]ncc12
Agent: CN(C)c1ccncc1
Product: Cl
Product: O=C(NC1=CC2NN=CC2C=C1)C1CN2CCC1CC2

Procedure:
In analogy to the method described in Example 2, 250 mg (2.57 mmol) of 3-quinuclidinecarbonyl chloride, 461 mg (3.57 mmol) of N,N-diisopropylethylamine, catalytic amounts of DMAP (approx. 1 mg) and 158 mg (1.19 mmol) of 4-aminoindazole are reacted.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>O.CC(C)=O>[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:5]2[C:4]([NH:15][C:14]3[CH:16]=[CH:17][C:11]([O:10][CH3:9])=[CH:12][CH:13]=3)=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(N)cc1
Reactant: Oc1cccnc1O
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(NC2=CC(=O)C(=O)N=C2Nc2ccc(OC)cc2)cc1
Reaction time: 2 h
Yield: 32 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), p-methoxyaniline (0.0054 mol); and NaIO3 (0.0009 mol) were dissolved in 160 ml of water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours, and maintained still overnight. It was then filtered, and recrystallized with chloroform. The final product was 5,6-di(p-methoxyphenylamino)-2,3-pyridindione in a red powder. The yield was 32%-50%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:24]([CH3:23])[CH2:25][CH2:26][CH3:27])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCNC
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A1) (4.00 g, 11.7 mmol), N-methyl-propylamine (1.89 ml, 17.6 mmol) and triethylamine (5.73 ml, 41.1 mmol) in DMSO (30 mL) at RT according to the general procedure C. Obtained as a yellow solid (4.04 g, 91%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][C@H:14]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.[C:50]([NH:60][C@H:61]([C:66](O)=[O:67])[CH2:62][CH2:63][S:64][CH3:65])([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]>CCOC(C)=O.CC#N>[CH2:53]([O:52][C:50]([NH:60][C@@H:61]([CH2:62][CH2:63][S:64][CH3:65])[C:66]([NH:12][C@H:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][C@H:14]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:67])=[O:51])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CCOC(=O)[C@@H]1CC2(CC[C@@H]1N)OCCO2
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CC2(CC[C@@H]1NC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Example 1, Alternative Step 9aii: Aminoester 1 (63 g, 0.16M, 1 eq.; the product of reductive deprotection of a known compound—(See e.g. R. J. Cherney, WO 2004/098516 and G. V. Delucca & S. S. Ko, WO 2004/110993) was placed in a round bottom flask and MeCN (500 mL) was added. EDAC (33.1 g, 0.17M, 1.1 eq), HOBt.H2O (21.2 g, 0.16M, 1.0 eq) and N-Cbz-L-methionine (46.7 g, 0.17M, 1.05 eq) were then added followed by TEA (48.0 mL, 0.35M, 2.2 eq). An exotherm to 38° C. was observed. The reaction mass was left to stir at RT. After 30 mins, HPLC indicated complete conversion. The reaction mass was diluted with EtOAc (2.5 L) and washed with KHCO3 (4×500 mL, 20 wt % aq. solution) and brine (500 mL). The organic phase was separated, dried over MgSO4 and concentrated. The residue was dissolved in TBME and reconcentrated to give ethyl (7R,8S)-8-{(2S)-2-benzyloxycarbonylamino-4-methylsulfanyl-butyr-yl-amino}-1,4-dioxa-spiro[4.5]decane-7-carboxylate 2 as a sticky semi-solid (76.2 g, 98% yield, 93 AP purity). 1H-NMR: (300 MHz, CDCl3) δ 7.36-7.30 (m, 5H), 7.03 (d, J 9.0 Hz, 1H), 5.66 (d, J 8.0 Hz, 1H), 5.10 (s, 2H), 4.35-4.25 (m, 2H), 4.19-4.04 (m, 2H,), 3.98-3.86 (m, 4H), 2.87-2.80 (m, 1H), 2.55-2.45 (m, 2H), 2.18 (dd, J 14.0 Hz, 7.0 Hz, 1H), 2.08 (s, 3H), 2.05-1.67 (m, 6H), 1.26 (t, J 7.0 Hz, 3H). HPLC: YMC-Pack Pro C18 5 μm 4.6×150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% 10 min gradient. 10.01 min (Compound 2, 93.1 AP). HRMS: m/z 495.2166 [Calc: C24H35N2O7S 495.2165].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](C(O)=O)([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.N1C=CC=CC=1.O.Cl>[Cu-]=O.C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C1(C(=O)O)CCOCC1
Agent: O=[Cu-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)C1CCOCC1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
In a flask made of glass equipped with a stirring device, a thermometer and a reflux condenser and having an inner volume of 50 ml were charged 1.0 g (5.74 mmol) of tetrahydropyran-4,4-dicarboxylic acid with purity of 100%, 21 mg (0.14 mmol) of copper(I) oxide and 3.0 ml of pyridine under nitrogen atmosphere, and the mixture was reacted at 110 to 120° C. for 1 hour under stirring. After completion of the reaction, the reaction mixture was cooled to room temperature, 5 ml of water, 5 ml (60 mmol) of conc. hydrochloric acid and 10 ml of ethyl acetate were successively added in this order to the reaction mixture. The aqueous layer and the organic layer (the ethyl acetate layer) were separated, the aqueous layer was extracted three times with each 10 ml of ethyl acetate, then, the organic layer and the ethyl acetate extracts were combined and the mixture was concentrated under reduced pressure to give 534 mg (Isolation yield: 72%) of tetrahydropyran-4-carboxylic acid with purity of 100% (analytical value by differential refractometry) as white crystals.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1Br)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:30]1[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1Br
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1-c1ccncc1
Yield: 65 %

Procedure:
By carrying out the operation analogously to example 1, starting from 2-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 4-pyridineboronic acid, the expected product is obtained in the form of a white powder with a yield of 65%.
Reaction SMILES: [CH2:1]([N:4]=[C:5]([NH2:21])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[NH:20])OC)[N:8]=1)[CH2:2][CH3:3].[Cl-:22].[NH4+:23]>CO>[ClH:22].[CH2:1]([N:4]=[C:5]([NH2:21])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH2:23])=[NH:20])[N:8]=1)[CH2:2][CH3:3]
Reactant: [Cl-]
Reactant: CCCN=C(N)Nc1ccnc(CCCCC(=N)OC)n1
Reactant: [NH4+]
Solvent: CO
Product: CCCN=C(N)Nc1ccnc(CCCCC(=N)N)n1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A mixture of methyl 5-(4-[2-propylguanidino]pyrimid-2-yl)valerimidate (0.4 g.) and ammonium chloride (0.076 g.) in MeOH (20 ml.) was stirred at ambient temperature for 1 hour and the solvent evaporated in vacuo to give 5-(4-[2-propylguanidino]pyrimid-2-yl)valeramidine hydrochloride (0.4 g.) as an oil which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][CH2:20][CH2:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26])=[CH:11]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:10][CH:11]=1)[CH3:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(CCCN)CCCc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CCCNC(=O)c1ccccc1)CCCc1c[nH]c2ccccc12
Reaction time: 2 h

Procedure:
A solution of 10.1 g benzoyl chloride in 15 ml anhydrous methylene chloride is added dropwise with stirring for 25 minutes between 0° and 10° to a solution of 14.5 g N-[3-(3-indolyl)propyl]-N-methyl-1,3-diaminopropane in 150 ml anhydrous pyridine and the reddish clear solution is stirred for 2 hours at 0°. The reaction mixture is divided between a 2 N sodium carbonate solution and methylene chloride, and the organic phase is washed, dried and evaporated. Chromatographic purification of the resinous product on aluminium oxide using methylene chloride with 0.1 to 0.3% of methanol yields the title compound. The naphthalene-2-sulfonate-dihydrate, obtained by conventional methods, melts at 73°-74° after crystallization from methanol/water/ethyl acetate (1:1:1).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([OH:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:16].[Na+].Cl[CH2:19][CH:20]([OH:29])[CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>C(O)C>[C:12]([OH:13])(=[O:29])[C:7]([OH:6])=[O:16].[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[O:15][CH2:19][CH:20]([OH:29])[CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(O)cc1OC1CCCC1
Reactant: OC(CCl)CCc1cccnc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(OCC(O)CCc2cccnc2)cc1OC1CCCC1
Product: O=C(O)C(=O)O

Procedure:
Prepared according to the method described in Example 24b) from 3-cyclopentyloxy-4-methoxyphenol (0.835 g), ethanol (10 ml), aqueous sodium hydroxide (2 M, 2.5 ml) and (±)-α-(chloromethyl)-3-pyridinepropanol (0.760 g, Example 24a) to give the title compound as a yellow oil. This was purified by column chromatography over silica eluting with dichloromethane:ethanol and further purified by preparative normal-phase HPLC on a Dynamax™ Silica column with dichloromethane:ethanol (19:1). The purified material was then converted to the oxalate salt by treatment with excess oxalic acid in diethyl ether to give the title compound as a white solid (0.197 g).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.[NH2:52][CH:53]([CH2:56][OH:57])[CH2:54][OH:55].OCCN1CCNCC1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](=[O:46])[NH:52][CH:53]([CH2:56][OH:57])[CH2:54][OH:55])([CH3:44])[CH3:43])=[CH:33][CH:32]=3)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NC(CO)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: OCCN1CCNCC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)NC(CO)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 48 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 2-amino-1,3-propanediol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)-piperazine, respectively.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18]C2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].BrCC[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4]
Reactant: BrCCCc1ccccc1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-bromo-3-phenylpropane and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:9]2=[O:13])=[CH:15][CH:16]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1NCCC1(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of the product from Example 25B (0.76 g, 2.5 mmol) in tetrahydrofuran (40 mL) was added a solution of potassium t-butoxide (1.0 M in tetrahydrofuran, 2.6 mL, 2.6 mmol). After stirring for 30 minutes at room temperature a pale yellow homogeneous solution resulted. To the reaction was added ethyl bromoacetate (0.42 g, 2.5 mmol) and stirring was continued overnight at room temperature. The reaction was concentrated, diluted with ethyl acetate (100 mL), washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in minimal amount of dichloromethane and loaded onto a silica gel column. The product was eluted with a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to afford the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1(=[O:17])=[O:16].[CH3:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][CH:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:25]2.[I-].[Na+].NC1C2C(=CC=CC=2)CCC1>CN(C)C=O.C(N(CC)CC)C>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][CH:27]([N:30]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[S:7]1(=[O:17])=[O:16])[CH2:31][CH2:32][CH3:33])[CH2:26][CH2:25]2
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: CCCNC1CCc2cccc(OC)c2C1
Agent: NC1CCCc2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN(CCCCN1C(=O)c2ccccc2S1(=O)=O)C1CCc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.6 %

Procedure:
1.9 g (6.0 mmol) of 2-(4-bromobutyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide were added dropwise to the solution of 1.3 g (6.0 mmol) of 8-methoxy-2-propylamino-1,2,3,4-tetrahydronaphthalene and 1.3 g (12 mmol) of triethylamine in 15 ml of dimethylformamide. After stirring for 15 hours at room temperature, a spatula tip of sodium iodide was added, and the mixture was heated to 60° C. After 4 hours at this temperature, 0.4 g of the above aminotetralin and 0.3 g of triethylamine were added. Chromatography on silica gel (toluene/ethyl acetate gradients) of the crude product, obtained after removal of the solvent in vacuo, yielded 0.70 g (25%) of the title compound as a yellowish oil.