Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:10](F)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1COCC1>[C:1]([C:4]1[CH:5]=[C:6]([S:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)c1cccc(S(=O)(=O)F)c1
Solvent: C1CCOC1
Product: CC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1

Procedure:
A solution of 20.02 g (0.1 mol) of 3-acetylbenzenesulfonyl fluoride and 29 ml of morpholine in 100 mL of THF is stirred at room temperature for 16 hours. The solvent is removed, the residue dissolved in CH2C2, and solution washed with H20 and 2N HCl. The organic layer is dried (MgSO4), the solvent removed, and the residue crystallized from CH2Cl2 -hexane to give 25.2 g (93%) of light yellow crystals, m.p. 144°-147° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH:6]=[C:7](SC)[C:8]=1[O:9][CH3:10].[Cl:29]C1C=C([N+]([O-])=O)C=C(OC)C=1OC>>[ClH:29].[Cl:29][C:7]1[CH:6]=[C:5]([NH:13][C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cccc(Nc2ccnc(Nc3cc(OC)c(OC)c(SC)c3)n2)c1
Reactant: COc1cc([N+](=O)[O-])cc(Cl)c1OC
Product: COc1cccc(Nc2ccnc(Nc3cc(Cl)c(OC)c(OC)c3)n2)c1
Product: Cl

Procedure:
The aniline starting material was prepared in a similar manner to the analogous aniline of Example 113, from 1-chloro-2,3-dimethoxy-5-nitrobenzene (1.08 g, 5.82 mmol), to give the desired product (0.85 g) as a white solid m.p. 66-68°. MS m/z 188 (M+H)+.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:40](=[O:41])[N:13]3[C:14]([C:37]([OH:39])=[O:38])=[C:15](OC(=O)C4C=CC=CC=4S(=O)(=O)NC(OCC)=O)[CH:16](C)[S:17][C@H:12]23)=[O:9])=[CH:4][S:3]1.[SH:42][C:43]1[N:47]([CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])[N:46]=[N:45][N:44]=1.[C:53](=O)([O-])O.[Na+]>O>[NH:1]=[C:2]1[NH:6][C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:40](=[O:41])[N:13]3[C:14]([C:37]([OH:39])=[O:38])=[C:15]([CH2:53][S:42][C:43]4[N:47]([CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])[N:46]=[N:45][N:44]=4)[CH2:16][S:17][C@H:12]23)=[O:9])=[CH:4][S:3]1
Reactant: CN(C)CCn1nnnc1S
Reactant: O=C([O-])O
Reactant: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(=N)[nH]3)[C@H]2SC1C
Agent: [Na+]
Solvent: O
Product: CN(C)CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(=N)[nH]3)[C@H]2SC1

Procedure:
In water (5 ml) are dissolved 7β-(2-imino-4-thiazolin-4-yl)acetamido-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]-methyl-3-cephem-4-carboxylic acid (313 mg), 5-mercapto-1-[2-(N,N-dimethylamino)ethyl]-1H-tetrazole (113 mg) and sodium hydrogen carbonate (42 mg) and the resultant solution is heated at 55° C. for 60 minutes. The reaction solution is adjusted its pH to 5.8 and purified by column chromatography on Amberlite XAD-2 and the fractions rich in the desired product are pooled and lyophilized. The procedure provides 7β-(2-imino-4-thiazolin-4-yl)acetamido-3-{1-[2-(N,N-dimethylamino)ethyl]-1H-tetrazol-5-yl}thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](O)=[O:7].S(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([Cl:17])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Product: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
A mixture of 3-methoxy-4-nitrobenzoic acid (2.01 g, 10.2 mmol) and thionyl chloride (2.3 mL, 31.5 mmol) was stirred at 80-90° C. for 1.5 h. The reaction was concentrated and the residue diluted with ether. The organic solution was washed with sat. aq. NaHCO3 (2×), H2O, then sat. aq. NaCl, dried (MgSO4) and concentrated to afford 3-methoxy-4-nitrobenzoyl chloride (1.92 g, 87%) as a white solid: 1H NMR (CDCl3, 300 MHz, ppm) 7.95-7.70 (m, 3H), 4.06 (s, 3H).
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[Cl:7][C:8]1[CH:23]=[CH:22][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20]Cl)[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:7].[ClH:5].[Cl:7][C:8]1[CH:23]=[CH:22][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][SH:3])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1
Reactant: NC(N)=S
Reactant: ClCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: SCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 97.8 %

Procedure:
The procedure described in Example 1(b) was followed, using 6.1 g of thiourea, 13.8 g of 1-(4-chlorobenzyl)-4-(2-chloroethyl)piperazine dihydrochloride, 4.1 g of triethylamine and 150 ml of reagent ethanol. The hydrolysis was effected with 7.0 g of sodium hydroxide and 50 ml of water. Work-up, as described above, gave 6.7 g (62% of theory) of 2-[4-(4-chlorobenzyl)piperazin-1-yl]ethanethiol dihydrochloride as a white crystalline solid, M.p. 244°-247° C.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>O.CC(O)C>[CH:12]1([NH:19][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCCCC1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(NC2CCCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 3.12 g (0.020 mol) of 4-fluoro-3-nitroaniline, 2.28 g (0.022 mol) of cycloheptylamine and 1.7 g (0.020 mol) of sodium hydrogen carbonate was refluxed for 3 hours in 5 ml of water and 5 ml of 2-propanol. After cooling to room temperature, the residues were filtered off and the filtrate was extracted with chloroform. The solvent was removed in vacuo and the residue was recrystallized from 20% hydrochloric acid. A green-brown solid melting at 153° C. was obtained.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([S:14][CH3:15])[S:13][C:6]=12.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.O>C(Cl)Cl>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([S:14]([CH3:15])=[O:31])[S:13][C:6]=12
Reactant: CSc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CS(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a solution of 230 (400 mg, 1.189 mmol, scheme 50) in DCM (12 mL) at 0° C. was added m-CPBA (77%, 272 mg, 1.189 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, water was added and the phases were separated. The organic phase was collected, washed with a 1% sodium hydroxide solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography, eluent DCM/MeOH (20:1), to afford title compound 233 (414 mg, 90% yield, crude), which was used in the next step without further purification. MS (m/z): 353.0 (M+1).
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:3].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][C:20](=[O:25])[CH:19]=[C:18]2[NH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][C:20](=[O:25])[CH:19]=[C:18]2[NH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH:2]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)[CH3:3])[CH2:29][CH2:28]1
Reactant: CC(Br)c1ccc2ncccc2c1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccc2ncccc2c1)N1CCC(Nc2cc(=O)oc3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
To a solution of 6-(1-bromoethyl)-quinoline (0.44 g, 1.86 mmol) and 6-chloro-4-(piperidin-4-ylamino)-chromen-2-one (0.35 g, 1.24 mmol) in DMF (10 mL) was added K2CO3 (0.26 g, 1.86 mmol). The reaction mixture was allowed to stir at room temperature for 12 h, and was then treated with H2O (100 mL) to provide 0.52 g (96%) of a white precipitate after filtration. MS (ESI(+)Q1MS) m/z 435 (M+H)+; 1H NMR (300 MHz, DMSO) δ ppm 8.82-8.88 (m, 1H), 8.30-8.37 (m, 2H), 7.97-8.02 (m, 1H), 7.76-7.89 (m, 2H), 7.58-7.64 (m, 1H), 7.47-7.55 (m, 1H), 7.22-7.34 (m, 2H), 5.23 (s, 1H), 3.76 (dt, 1H), 3.37-3.52 (m, 1H), 2.96-3.04 (m, 1H), 2.80-2.89 (m, 1H), 2.09-2.21 (m, 2H), 1.82-1.98 (m, 2H), 1.50-1.71 (m, 2H), 1.40 (d, 3H). The pure racemic mixture was separated into enantiomers by prep HPLC chiral chromatography using a CHIRALPAK AD column: 7.5/7.5/85 MeOH/EtOH/Hexane. Enantiomers had retention times of 4.1 and 6.3 minutes. The optical rotations of the enantiomers were [α]D (90:10 CH2Cl2:MeOH, 25° C.)=+19.2 and −14.7, respectively.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:15][S:14][C:9]2=[C:10]([C:12]#[CH:13])[N:11]=1)=[O:5])[CH3:2].[CH2:25]([N:32]=[N+:33]=[N-:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CCO.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)=[N:15][S:14][C:9]2=[C:10]([C:12]2[N:34]=[N:33][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:13]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: C#Cc1nc(C(=O)OCC)c(O)c2c(-c3ccc(Cl)cc3)nsc12
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2cn(Cc3ccccc3)nn2)c2snc(-c3ccc(Cl)cc3)c2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.7 %

Procedure:
To a mixture of 3-(4-chloro-phenyl)-7-ethynyl-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (0.106 mmol) and CH2Cl2/H2O (1/1, 0.70 mL) was added benzylazide (0.117 mmol), CuSO4.5H2O (0.0053 mmol) and sodium L-ascorbate (0.0159 mmol). The mixture was stirred at rt for 16 h before it was partitioned between H2O (20 mL) and CH2Cl2 (20 mL). The aqueous phase was then extracted with CH2Cl2 (2×15 mL). The combined organic layers were washed with brine and water, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 0-20% EtOAc/CH2Cl2, to give the title compound (40 mg) as a white solid: MS (m/z) 492.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:41])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35]C(OCC)=O)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([O:42][CH3:43])[CH:10]=1)#[N:2].[CH3:44][Mg]Br.C([O:50][CH2:51][CH3:52])(=O)C>O1CCCC1>[OH:50][C:51]([CH3:52])([CH3:44])[CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:41])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][C:11]=3[O:42][CH3:43])=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)[CH2:29][CH2:30]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2OC)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reactant: C[Mg]Br
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2OC)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Reaction time: 3 h

Procedure:
To a solution of ethyl [(trans-4-{6-[(2′-cyano-3-methoxybiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate (0.51 g) in tetrahydrofuran (5 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 3.5 mL) at 0° C., and the mixture was stirred for 3 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.44 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])=[CH:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:24]5[CH:25]=[CH:26][O:22][CH:23]=5)[CH:28]=4)[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1cccc(-c2ccoc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(-c3ccoc3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Yield: 79.6 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (48 mg, 0.17 mmol), 3-fur-3-ylbenzoic acid (32 mg, 0.17 mmol), HATU (65 mg, 0.17 mmol), HOBT (23 mg, 0.17 mmol) and DIPEA (88 μl) were stirred in DMF (1.5 ml) for 18 h at room temperature. The reaction was partitioned between ethyl acetate (100 ml) and hydrochloric acid (0.5M, 20 ml), the organic phase washed with aqueous sodium hydrogen carbonate (saturated) and dried (magnesium sulphate). The solvent was evaporated under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-fur-3-ylbenzamide (61 mg, 79%). NMR; δH [2H6]—DMSO 10.16,(1H, s), 8.35,(1H, t), 8.22,(1H, s), 7-89,(2H, d), 7.79,(2H, t), 7.69-7.65,(2H, m), 7.56,(1H, s), 7.45,(1H, t), 7.35,(2H, d), 7.19,(1H, d), 6.85,(1H, d), 6.49,(1H, m), 3.17,(2H, t), 2.18,(3H, s), 1.04,(1H, m), 0.42,(2H, m), 0.22,(2H, m). LCMS: retention time 3.75 min, MH+451.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Br:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.O>CN(C=O)C>[Br:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
2-Bromomethylnaphthalene (5.00 g, 22.6 mmol) was dissolved in N,N'-dimethylformamide (100 ml) and potassium carbonate (9.4 g, 68 mmol) and 3-bromophenol (3.91 g, 22.6 mmol) were added. The mixture was stirred vigorously for 16 h at room temperature and then poured into water (700 ml). The precipitate was filtered off, washed with water and dried in vacuo at 50° C. for 16 h to give 6.17 g (87%) of 2-(3-bromophenoxymethyl)naphthalene as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[NH:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][N:19]=C=S.O1CCC[CH2:23]1>>[CH2:1]([O:8][C:9]1[C:10]2[N:17]=[C:13]([NH:19][CH3:18])[N:12]([CH3:23])[C:11]=2[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN=C=S
Reactant: C1CCOC1
Reactant: CNc1cccc(OCc2ccccc2)c1N
Product: CNc1nc2c(OCc3ccccc3)cccc2n1C
Reaction time: 48 h

Procedure:
To a mixture of 3-benzyloxy-2-amino-N-methylaniline (200 mg) and methyl isothiocyanate (70.5 mg) was added tetrahydrofuran (2 ml) at ambient temperature, and the mixture was stirred for 2 days. The solvent was removed in vacuo, and the residue was dissolved in acetonitrile (2 ml). Methyl iodide (149 mg) was added thereto under ice-cooling, the mixture was stirred for 5 hours. The reaction mixture was concentrated in vacuo, and the residue was crystallized with ethyl acetate and recrystallized with acetonitrile to give 4-benzyloxy-1-methyl-2-methylamino-1H-benzimidazole (148 mg).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:8][C:9]1[CH:20]=[CH:19][CH2:18][C:17]2[C:10]=1[CH:11]=[C:12]1[C:16]=2[CH:15]=[N:14][N:13]1[CH2:21][CH:22](O)[CH3:23])[CH3:7].C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([CH:22]([CH3:23])[CH2:21][N:13]1[C:12]2=[CH:11][C:10]3[C:17]([CH2:18][CH:19]=[CH:20][C:9]=3[O:8][CH2:6][CH3:7])=[C:16]2[CH:15]=[N:14]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC1=C2C=c3c(cnn3CC(C)O)=C2CC=C1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2CC=C1
Yield: 94.4 %

Procedure:
1.2 ml (15.5 mmol) of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 2 g (7.7 mmol) of (RS)-1-(7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 4.3 ml (31 mmol) of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for a further 50 minutes. The reaction mixture was subsequently diluted with 130 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 1 g (15.5 mmol) of sodium azide and the reaction mixture was heated to 75° for 15 hours while stirring. After cooling the solution was poured into 80 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The is combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate). 2.06 g (94%) of (RS)-1-(2-azido-propyl)-7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a light yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([NH:13]S(C)(=O)=O)=[C:5](I)[CH:4]=1)#[N:2].[C:19]([Si:23]([O:26][C:27]([CH3:31])([CH3:30])[C:28]#[CH:29])([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].CCN(CC)CC.O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]([Si:23]([CH3:25])([CH3:24])[O:26][C:27]([C:28]1[NH:13][C:6]2[C:5]([CH:29]=1)=[CH:4][C:3]([C:1]#[N:2])=[C:8]([C:9]([F:12])([F:11])[F:10])[CH:7]=2)([CH3:30])[CH3:31])([CH3:22])([CH3:21])[CH3:20]
Reactant: C#CC(C)(C)O[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c(C#N)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O[Si](C)(C)C(C)(C)C)c1cc2cc(C#N)c(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
N-(4-Cyano-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide (1.95 g, 5.0 mmol), tert-Butyl-(1,1-dimethyl-prop-2-ynyloxy)-dimethyl-silane (992 mg, 5.0 mmol), PdCl2(PPh3)2, (175 mg, 0.25 mmol), Cul (95 mg, 0.5 mmol), NEt3 (1.4 mL, 10.0 mmol), was mixed in DMF (15 mL) and stirred at room temperature for 16 hours. Water was added and the mixture was extracted twice with ethyl acetate. The organic layers were washed with 10% LiCl solution, dried over magnesium sulfate, filtered, evaporated to a brown oil. The brown oil was purified by column chromatography eluting with 1, 3, and 10% ethyl acetate/hexanes. The product was obtained as a white solid (306 mg, 16%). 1H NMR (CDCl3) δ 8.75 (s, 1H), 7.92 S, 1H), 7.67 (s, 1H), 6.27 (d, J=1.2 Hz, 1H), 1.58 (s, 6H), 0.85 (s, 9H), 0.3 (s, 6H). MS (m/z): 405 (MNa+), 381 (MH−).
Reaction SMILES: C(NCCC1C=CC(S([NH:16][C:17]([NH:19][CH:20]2[CH2:25][CH2:24][CH:23]([Cl:26])[CH2:22][CH2:21]2)=[O:18])(=O)=O)=CC=1)(=O)C.[OH-].[Na+].O.COC1C=CC(Cl)=CC=1C(Cl)=O>CC(C)=O>[Cl:26][CH:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:17](=[O:18])[NH2:16])[CH2:25][CH2:24]1
Reactant: CC(=O)NCCc1ccc(S(=O)(=O)NC(=O)NC2CCC(Cl)CC2)cc1
Agent: COc1ccc(Cl)cc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)NC1CCC(Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.8 g of N-[4-(β-acetoamido-ethyl)-benzenesulfonyl]-N'-(4-chlorocyclohexyl)-urea (melting point 151° -153°C) are heated under reflux for 2 hours with 1.6 g of sodium hydroxide and 30 ml of water. Then the whole is cooled to room temperature, 20 ml of acetone are added and 1.2 g of glacial acetic -chlorobenzamido>-ethyl)-benzenesulfonyl] acid, and 4.1 g of 2-methoxy-5-chlorobenzoylchloride are added in portions and stirring is continued for 1 hour. The precipitate if filtered off with suction, stirred with bicarbonate solution and recrystallized from methanol/dimethylformamide. The N-[4-(β-<-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N'-(4-chlorocyclohexyl)-urea obtained melts at 178°-179°C.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[I:12].CO.[OH-].[K+]>O>[I:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1ccc(OC)cc1I
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)c(I)c1

Procedure:
205 G. of 2-iodo-4methoxy-benzoic acid methyl ester, 400 ml. of methanol, 390 ml. of water and 95 g. of potassium hydroxide are stirred at 48° C. for 30 minutes. The solution is then concentrated under reduced pressure and acidified with aqueous hydrochloric acid. The yellow crystalline 2-iodo-4-methoxy-benzoic acid obtained is removed by filtration, washed neutral with water and dried, melting point 185° C.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([CH:70](OC)[O:71]C)[CH2:67][CH:68]=[CH2:69])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C>FC(F)(F)C(O)=O.ClCCl.O>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:67][CH:68]=[CH2:69])[CH:70]=[O:71])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:52])([CH3:54])[CH3:53])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: C=CC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C)C(OC)OC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(C)(C)C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
50 mg (0.048 mmol) of N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N 1-[1(S)-(dimethoxymethyl)-3-butenyl]-L-leucinamide were dissolved in 4 ml of trifluoroacetic acid/dichloromethane (1:1) containing3 drops of water and the solution was stirred for 1 hour under nitrogen. The solution was evaporated to dryness under a vacuum and the residue was re-evaporated twice with toluene. The solid was triturated with 10 ml of diethyl ether to give 30 mg of 2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-pentenaldehyde; MS: m/e 831.5 [M+H]+.