Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([C:10]1[N:11]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:12]2[C:17]([CH3:18])=[C:16]([CH3:19])[N:15]=[C:14](OC3C=CC=CC=3)[C:13]=2[N:27]=1)[CH2:7][CH2:8][CH3:9]>C(OCC)(=O)C>[CH2:6]([C:10]1[N:11]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:12]2[C:17]([CH3:18])=[C:16]([CH3:19])[N:15]=[C:14]([NH2:5])[C:13]=2[N:27]=1)[CH2:7][CH2:8][CH3:9]
Reactant: [NH4+]
Reactant: CCCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCOc1ccccc1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCOc1ccccc1
Temperature: 150 °C

Procedure:
A sealed tube containing ammonium acetate (7.5 g) and 2-butyl-6,7-dimethyl-4-phenoxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridine (0.75 g) from Part C was heated in an oil bath to 150° C. for 48 hours. The reaction reached 70% completion and was allowed to cool to room temperature. The reaction mixture was then dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The product was passed through a silica gel column using 10/90 methanol/ethyl acetate as the eluant. To remove impurities, the product was recrystallized twice from acetonitrile with charcoal. The resulting white crystals were crushed and dried to yield 2-butyl-6,7-dimethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 130.0–132.0° C.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]1>CN(C=O)C.O>[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC1CCCCN1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCCCC2C)c([N+](=O)[O-])c1
Temperature: 50 °C

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Clontech 01072, 1 g; 4.69 mmol; 1 eq.) and 2-methylpiperidine (1.395 g; 14.07 mmol; 3 eq.) in DMF (4 mL) was heated to 50° C. for 3 hours. The reaction was then allowed to return to RT and diluted with water. It was extracted with EtOAc and the organic phase was dried over sodium sulfate and concentrated in vacuo, affording ethyl 4-(2-methylpiperidin-1-yl)-3-nitrobenzoate as a yellow oil. The residue was taken up in THF (10 mL) and lithium hydroxide (561.73 mg; 23.46 mmol; 5 eq.) was added followed by water (10 mL). The reaction mixture was stirred at RT for 16 hours. It was concentrated and the residue was diluted with water and washed with Et2O. The aqueous layer was acidified to pH 5 with acetic acid. It was extracted with Et2O and the organic phase was dried over magnesium sulfate and concentrated, affording the title compound as a yellow solid (1.17 g, 94%). 1H NMR: (DMSO-d6, 300 MHz) δ 13.07 (s, 1H), 8.23-8.22 (d, J=2.13 Hz, 1H), 8.04-8 (dd, J=8.96 Hz, J=2.28 Hz, 1H), 7.44-7.41 (d, J=8.88 Hz, 1H), 3.64-3.60 (m, 1H), 3.25-3.17 (m, 1H), 2.90-2.84 (m, 1H), 1.82-1.43 (m, 6H), 1.06-1.04 (d, J=6.43 Hz, 3H). LC/MS (Method A): 265.0 (M+H)+; 263.0 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13](Cl)(=[O:17])[CH2:14][CH2:15][CH3:16]>>[C:13]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])(=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)Nc1ccc(C(=O)OC)cc1C

Procedure:
In J. Med. Chem. 1993, 4040 a synthesis of the antagonist is described which starts from methyl 4-amino-3-methylbenzoate (I) and reacts it with butyryl chloride to give methyl N-butyryl-4-amino-3-methylbenzoate (II) (see the following reaction scheme (1)).
Reaction SMILES: [K].[C:2]([NH:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:10])([CH3:5])([CH3:4])[CH3:3].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[C:16]([CH3:24])=[CH:15][N:14]=1>C(O)(C)(C)C>[OH:11][CH:8]([CH2:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:9][O:10][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[C:16]([CH3:24])=[CH:15][N:14]=1
Reactant: CC(C)(C)NCC(O)CO
Reactant: Cc1cnc(Cl)c2cc(Cl)ccc12
Agent: [K]
Solvent: CC(C)(C)O
Product: Cc1cnc(OCC(O)CNC(C)(C)C)c2cc(Cl)ccc12
Reaction time: 24 h

Procedure:
0.74 g of Potassium is dissolved in 40 ml of tert.-butylalcohol and 3.0 g of 1-tert.butylamino-2,3-dihydroxypropane and subsequently 4 g of 1,7-dichloro-4-methylisoquinoline are added. After stirring for one day, heating up to 50° is effected for a further day. The reaction solution is concentrated by evaporation under vacuum. The residue is taken up with 1N hydrochloric acid and ether, the aqueous phase neutralised with 2N caustic soda solution and extracted with methylene chloride. After drying over magnesium sulphate and concentration by evaporation the title compound is obtained in free base form. M.p. 116°-117°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br-].[CH2:13]([Zn+])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccccc2)c1
Temperature: 60 °C

Procedure:
Methyl 2-chloroisonicotinate (4.29 g, 25 mmol) and Pd(PPh3)4 (1.156 g, 1.00 mmol) were dissolved in THF (60 mL) to give a yellow solution. Then benzylzinc(II) bromide (0.5 M in THF) (75 mL, 37.50 mmol) was added. The resulting brown mixture was warmed to 60° C. in an oil-bath for 18 h. The reaction mixture was quenched by addition of methanol, then diluted with ethyl acetate and washed with satd NH4Cl and water. The combined organic layers were dried over MgSO4 and evaporated. The residue was purified via Biotage, Thompsson 160 g Silica, eluent isocratic heptanes/ethyl acetate 9:1 over 1 CV, then linear gradient 9:1-75:25 over 6 CV. Product containing fractions were evaporated to give methyl 2-benzylisonicotinate as an orange liquid. 1H NMR (400 MHz, cdcl3) δ 3.91 (s, 3H), 4.22 (s, 2H), 7.19-7.34 (m, 5H), 7.66 (dd, 1H), 7.69 (d, 1H), 8.70 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:3][C:2]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[CH:25]=[O:26])=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CN1CCN(Cc2cc3nc(-c4cccc(C=O)c4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 3-formyl phenyl boronic acid in General Procedure A. Purification on silica yielded 3-[6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-benzaldehyde. This was then treated with sodium borohydride in methanol to give the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][NH:10][C:11](=[O:12])[C:3]=12.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:11](=[O:12])[C:3]=12
Reactant: COC(=O)CBr
Reactant: Cc1cc(C)c2c(=O)[nH]sc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cn1sc2nc(C)cc(C)c2c1=O
Reaction time: 5 h
Yield: 51.5 %

Procedure:
To enhance the selectivity of N-alkylation over O-alkylation, pyridinothiazolone 4 (500 mg, 2.77 mmol) was suspended in CH2Cl2 (20 mL) containing of diisopropylethylamine (DIEA, 1.5 mL, 8.61 mmol) and Cs2CO3 (700 mg, 3.07 mmol). Methyl 2-bromoacetate (900 mg, 5.88 mmol) was then added at room temperature. The mixture was stirred for 5 h, concentrated under reduced pressure, and purified by chromatography on a silica gel column with elution of EtOAc/hexane (1:4) to give the title compound 7 (360 mg, 55% yield) accompanied by an O-alkylation side product (7%). Compound 7: C11H12N2O3S; white solid; mp 89-91° C.; IR vmax (neat) 2928, 1766, 1728, 1664, 1561, 1523, 1435, 1375, 1324, 1210 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.92 (1H, s), 4.54 (2H, s), 3.76 (3H, s), 2.70 (3H, s), 2.57 (3H, s); 13C NMR (100 MHz, CDCl3) δ 167.4, 164.3, 162.6, 162.3, 149.6, 122.4, 113.8, 52.8, 44.2, 24.9, 17.8; ESI-HRMS calcd for C11H13N2O3S: 253.0647. found: m/z 253.0657 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:17]3[N:18]=[C:19]([CH:21]4[CH2:23][CH2:22]4)[O:20][C:16]=3[C:15]([C:24]([O:26]C)=O)=[CH:14][C:13]=2[N:28]=1.[F:29][C:30]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:31]=1[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:17]3[N:18]=[C:19]([CH:21]4[CH2:23][CH2:22]4)[O:20][C:16]=3[C:15]([C:24]([NH:32][C:31]3[CH:33]=[C:34]([C:37]([F:38])([F:39])[F:40])[CH:35]=[CH:36][C:30]=3[F:29])=[O:26])=[CH:14][C:13]=2[N:28]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2nc(C3CC3)oc12
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2nc(C3CC3)oc12
Yield: 17.5 %

Procedure:
To a solution of methyl 7-((2-chloro-6-fluorophenyl)amino)-2-cyclopropyl-8H-imidazo[4′,5′:5,6]-benzo[1,2-d]oxazole-4-carboxylate (Intermediate-59, 0.050 g, 0.125 mmol) in dry toluene (5.0 mL) was added 2-fluoro-5-trifluoromethylaniline (0.022 g, 0.125 mmol) and trimethyl aluminium (2M solution in toluene) (0.009 g, 0.125 mmol). The reaction mass was refluxed for 1 h. The reaction mass was quenched with water and extracted with 10% DCM: MeOH. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography to afford 0.012 g of the desired product. 1HNMR (DMSO-d6): δ 1.23 (m, 4H), 2.33 (m, 1H), 7.40-7.47 (m, 3H), 7.62 (m, 2H), 7.75 (s, 1H), 8.68 (s, 1H), 9.42 (s, 1H), 9.89 (s, 1H), 11.69 (s, 1H); MS [M+H]+: 547.81.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1[NH:16][N:17]=[CH:18][C:13]=1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1=[N:16][N:17]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[C:13]1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: BrCc1ccccc1
Reactant: Nc1c2c(nc3ccccc13)CCc1cn[nH]c1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1c2c(nc3ccccc13)CCc1cn(Cc3ccccc3)nc1-2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 11-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine (2.36 g) in dry DMF (90 ml) was added NaH (60%)(0.50 g) slowly. The reaction was stirred at room temperature for 15 minutes and then benzyl bromide (1.88 g) was added and the reaction was stirred an additional 15 minutes. At the end of this time the product was precipitated with water, filtered off, washed well with water, and air dried to yield a product which was further purified by flash chromatography (5% Et3N-EtOAc). The product-containing fractions were combined, concentrated, and recrystallized from EtOAc to give 2.35 g, mp 206°-207°.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:10])[NH2:9])=[CH:4][CH:3]=1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)[N:10]=1
Reactant: N=C(N)c1ccncc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(-c2ccncc2)ns1
Temperature: 25 °C
Yield: 6 %

Procedure:
To a solution of pyridine-4-carboximidamide hydrochloride (2.00 g, 12.7 mmol) and perchloromethyl mercaptan (1.75 ml, 16.3 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (3.26 g, 81.5 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to give 150 mg (5.98%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([SH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)([O-:20])=[O:19].N1C=CC=CC=1>C(#N)C>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:29])[S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCCCCCS
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCSC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and a reflux condenser, n-hexadecanethiol (165 g) was dissolved in acetonitrile (1000 ml). To the solution, p-nitrophenyl isocyanate (100 g) was gradually added, then pyridine (4 ml) was added dropwise, and the mixture was stirred at room temperature for 10 minutes, and then heat-refluxed for 30 minutes. When the reaction mixture was cooled to room temperature, crystals precipitated. The crystals were collected by filtering and washed with acetonitrile. S-n-hexadecyl p-nitrophenylthiocarbamate (250 g) was obtained at a yield of 97%.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[CH2:17]1[CH2:23][S:20](=[O:22])(=[O:21])[O:19][CH2:18]1.O1CCCC1>CN1CCCC1=O>[CH3:1][N:2]([CH3:16])[C:3]1[CH:4]=[CH:5][C:6]([N:9]=[N:10][C:11]2[S:12][CH:13]=[CH:14][N+:15]=2[CH2:18][CH2:17][CH2:23][S:20]([O-:22])(=[O:21])=[O:19])=[CH:7][CH:8]=1
Reactant: O=S1(=O)CCCO1
Reactant: CN(C)c1ccc(N=Nc2nccs2)cc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CN(C)c1ccc(N=Nc2scc[n+]2CCCS(=O)(=O)[O-])cc1
Temperature: 100 °C
Yield: 99.7 %

Procedure:
0.5 g (1.5 mmol) of N,N-dimethyl-4-[1,3-thiazol-2-yldiazenyl]aniline are dissolved in 1-methyl-2-pyrrolidinone (NMP), and 0.9 g (7.5 mmol) of 1,3-propane sultone is added. The reaction mixture is heated at, 100° C. for 4 hours. After cooling, 20 ml of tetrahydrofuran are added to the reaction mixture and the precipitated product is filtered off, washed with acetone and dried. The resulting dye is recrystallized from methanol/ethyl acetate. 0.53 g (45% of theory) of 3-(2-{[4-(dimethylamino)phenyl]diazenyl}-1,3-thiazol-3-ium-3-yl)-1-propanesulfonate is obtained as a dark blue powder.
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:10]([NH:12][C@H:13]([C:23]([NH:25][C@H:26]([C:28](O)=[O:29])[CH3:27])=[O:24])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:41][C@H:42]([C:47]([CH2:49][Cl:50])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45].Cl.N(C(OCC1C=CC=CC=1)=O)[C@H](C(NCC(N[C@H](C(N[C@H](C(CCl)=O)CC(C)C)=O)CC(C)C)=O)=O)CC1C=CC=CC=1>>[NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[C@H:2]([C:10]([NH:12][C@H:13]([C:23]([NH:25][C@H:26]([C:28]([NH:41][C@H:42]([C:47]([CH2:49][Cl:50])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:29])[CH3:27])=[O:24])[CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[C@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)CCl
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl
Agent: Cl
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl

Procedure:
Z-Phe-Ser(Bzl)-Ala-LeuCH2Cl was prepared by coupling Z-Phe-Ser(Bzl)-Ala-OH (1.37 g, 2.5 mmoles) to H-LeuCH2Cl.HCl by a mixed anhydride coupling procedure substantially analogous to that used for the preparation of Z-Phe-Gly-Leu-LeuCH2Cl in Procedure E. Product was obtained as a crystalline solid, 0.98 g (mp 167°-168°).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][NH:7][C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C=O.[CH:54](O)=O.O>CC(C)=O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][N:7]([CH3:54])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: O=CO
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN[C@H](C)[C@@H](O)[C@]1(C)O
Agent: C=O
Solvent: O
Solvent: CC(C)=O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN(C)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 58 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
In a 0.25 L three-necked round bottom flask equipped with a mechanical stirrer, a condenser and thermometer, 25 g of desmethyl-azithromycin was dissolved in 102 mL of acetone. Formaldehyde (5.3 mL) and formic acid (2.6 mL) were added and the clear solution was heated to reflux (˜58° C.). The mixture was maintained under reflux for 3 hours then cooled to less than 40° C. and 102 mL of water was added. The acetone was separated from the reaction mixture by distillation under low vacuum (˜300 mbar). The distillation was stopped when the temperature of the liquid phase reaches ˜40° C./300 mbar. Activated carbon SXI (1.25 g) was added and the suspension was mixed for 1 hour. Then the activated carbon was separated from the solution by filtration on a Büchner filter containing Hyflow. The filter cake was washed with 102 mL of water. The pH was adjusted with an NaOH solution of 47% to 10-10.5 (˜3.14 g). A massive precipitation of Azithromycin was observed. After stirring the suspension for 1 hour, the crude azithromycin was separated by filtration, washed twice with 25 mL of water and dried at 40° C. in a vacuum oven for>24 hours. After drying, 19.7 g of crude azithromycin was obtained (yield 77% based on weight). No impurities that were derivatives of azithromycin were detected.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[OH-].[K+].Cl.[CH2:17]([OH:19])[CH3:18]>O>[CH2:17]([O:19][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6])[CH3:18]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc(C(=O)O)ccc1[N+](=O)[O-]
Yield: 99 %

Procedure:
3-fluoro-4-nitrobenzoic acid (Apollo Scientific; 15 g, 81 mmol) and potassium hydroxide (10.5 g, 186.3 mmol) were stirred together in ethanol (150 mL) at ambient temperature. The reaction mixture was slowly heating to reflux over 10 minutes. The reaction refluxed vigorously and a solid precipitate formed. The reaction was cooled, diluted with water (100 mL) and acidified with 2N HCl to give a precipitate which was filtered, washed with water and air dried to yield the title compound as a pale brown solid (16.88 g, 99%)
Reaction SMILES: [Na].[C:2]([NH:4][C:5](=[N:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)S)#[N:3].[CH3:23][C:24]1[NH:25][C:26]([CH3:46])=[C:27]([C:42]([O:44][CH3:45])=[O:43])[CH:28]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH3:41])[CH:35]=2)[C:29]=1[C:30]([O:32][CH3:33])=[O:31].O>C1COCC1.Cl[Hg]Cl>[C:2]([N:4]=[C:5]([N:40]([CH3:41])[C:36]1[CH:35]=[C:34]([CH:28]2[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:24]([CH3:23])[NH:25][C:26]([CH3:46])=[C:27]2[C:42]([O:44][CH3:45])=[O:43])[CH:39]=[CH:38][CH:37]=1)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)#[N:3]
Reactant: CNc1cccc(C2C(C(=O)OC)=C(C)NC(C)=C2C(=O)OC)c1
Reactant: N#CNC(S)=NCCCN1CCC(c2ccccc2)CC1
Agent: Cl[Hg]Cl
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(N(C)C(=NC#N)NCCCN2CCC(c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.5 %

Procedure:
To a solution of N-cyano-N'-[3-(4-phenyl-1-piperidinyl)propyl]isothiourea sodium salt (IX) (115 mg, 0.35 mmol) and the aniline intermediate (XIV) from Example 12 (115 mg, 0.35 mmol) in THF (7 mL) at 0° C. was added HgCl2 (95 mg, 0.35 mmol). The reaction mixture was then refluxed for 3 h. After cooling to room temperature, H2O (1 mL) was added, and the mixture was stirred for 30 min. A gray precipitate was collected by filtration, and rinsed with CH2Cl2, the organic extract was dried (Na2SO4), and the solvent was removed in vacuo. The residue was subjected twice to flash chromatography (silica gel, MeOH:CH2Cl2, 4:96) to afford the compound as a white solid (15 mg, 4.5%). mp 85-90° C.; MS (ESI) m/z 599 (MH+); 1H NMR (CDCl3) δ 7.30 (m, 8 h), 6.98 (d, 1H, J=7.8 Hz), 6.91 (s, 1H), 5.29 (br s, 1H), 5.09 (s, 1 H), 3.67 (s, 6H), 3.63 (m, 2H), 3.47 (m, 2H), 3.37 (s, 3H), 3.00 (m, 2H), 2.73 (m, 4H), 2.45 (s, 6H), 2.38 (m, 1H), 2.26 (m, 2H), 2.03 (m, 2H); 13C NMR (CDCl3) δ 168.2, 150.4, 146.8, 130.6, 129.0, 128.0, 127.4, 127.0, 124.9, 124.1, 117.3, 102.3, 54.1, 51.4, 51.3, 40.8, 40.3, 39.9, 38.9, 30.4, 25.4, 19.3. HRMS (FAB) Calcd. for C34H43N6O4 (MH+): m/z 599.3346. Found: 599.3362.
Reaction SMILES: CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.[CH:19]1([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:35][CH:34]([OH:36])[CH2:33]3)=[O:31])[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1.[F:37][CH:38]([F:47])[O:39][C:40]1[CH:45]=[CH:44][C:43](I)=[CH:42][CH:41]=1>>[CH:19]1([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:33][CH:34]([O:36][C:43]4[CH:44]=[CH:45][C:40]([O:39][CH:38]([F:47])[F:37])=[CH:41][CH:42]=4)[CH2:35]3)=[O:31])[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1
Reactant: FC(F)Oc1ccc(I)cc1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(Oc2ccc(OC(F)F)cc2)C1

Procedure:
In a similar fashion (Route 21, GP J) except for replacing phenanthroline with 3,4,7,8-tetramethylphenanthroline, 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (50 mg, 0.19 mmol) and 1-(difluoromethoxy)-4-iodobenzene (81 mg, 0.3 mmol) gave the title compound as colourless oil after purification by preparative HPLC (47 mg, 57%).