Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.C(NC(C)C)(C)C.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH2:24]([NH:31][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[N:9][CH:10]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: CN1CCN(c2ccc(C(=O)O)cn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: O
Product: CN1CCN(c2ccc(C(=O)NCc3ccccc3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 6-(4-methyl-piperazin-1-yl)-nicotinic acid (200 mg) in DMF (2 ml) was treated under an argon atmosphere with diisopropylamine (0.50 ml), benzylamine (0.12 ml) and BOP (600 mg). The reaction mixture was stirred at r.t. overnight, then diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give N-benzyl-6-(4-methyl-piperazin-1-yl)-nicotinamide (120 mg) as off-white solid. MS (ISP): 311.3 ([M+H]+)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH2:18])[C@H:13]([OH:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(O)(C)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[C@H:13]([OH:19])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: Clc1ccncc1
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)N1CC[C@H](CNc2ccncc2)[C@H](O)C1
Temperature: 25 °C

Procedure:
A mixture of the cis 4-aminomethyl-3-hydroxy-piperidine-1-carboxylic acid benzyl ester (245 mg) from Step 4 above, 4-chloropyridine (105 mg) and isopropanol (0.4 mL) was heated to 120° C. in a sealed vial for 24 h, cooled to room temperature and the solvents evaporated. The resulting crude mixture was purified by flash column chromatography (DCM to 80/20/2 DCM MeOH NH4OH) to give impure cis 3-hydroxy-4-(pyridin-4-ylaminomethyl)-piperidine-1-carboxylic acid benzyl ester. This was purified by preparative reverse phase HPLC (95% H2O 5% MeCN to 100% MeCN both containing 0.1% TFA). Evaporation gave an oil which was partitioned between DCM and aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and solvent evaporated to give a white solid. M.S (M+1): 342.
Reaction SMILES: BrC1C(C(C)(C)C)=CC(C(C)(C)C)=CC=1C(C)(C)C.C([Li:24])CCC.[C:25]1([N:31]2[CH2:36][CH2:35][O:34][CH2:33][C:32]2=[O:37])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C:38](=[O:40])=[O:39]>C1COCC1>[O:37]=[C:32]1[CH:33]([C:38]([O-:40])=[O:39])[O:34][CH2:35][CH2:36][N:31]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1.[Li+:24]
Reactant: [Li]CCCC
Reactant: O=C1COCCN1c1ccccc1
Reactant: O=C=O
Agent: CC(C)(C)c1cc(C(C)(C)C)c(Br)c(C(C)(C)C)c1
Solvent: C1CCOC1
Product: O=C([O-])C1OCCN(c2ccccc2)C1=O
Product: [Li+]
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
A dry 100 mL Schlenk-type flask was fitted with a nitrogen/vacuum line and charged with 2-bromo-1,3,5-tri-tert-butylbenzene (0.521 g, 1.601 mmol), 20 mL dry THF, and a stirbar. The solution was cooled to −78° C. and treated with 2.5M butyllithium (0.582 ml, 1.456 mmol). The reaction was stirred for 15 min and treated with 4-phenylmorpholin-3-one (0.258 g, 1.456 mmol) dissolved in 2 mL dry THF dropwise over 5 min. The reaction was stirred for 2 h at −78° C. The side arm compartment of the Schlenk-type flask was charged with ˜1 g dry ice. The system was sealed, and the dry ice was allowed to sublime into the solution. After 30 min, a nitrogen needle was fitted to the flask, and a solid was noted in the solution. The cooling bath was removed, which caused the solids to bubble (presumably dry ice). The solution was allowed to warm to RT overnight. The solution was diluted with 40 mL water and extracted with dichloromethane (2×10 mL). The water was concentrated in vacuo and dried at 60° C. and 0.15 mmHg to afford lithium 3-oxo-4-phenylmorpholine-2-carboxylate (0.200 g, 60.5% yield). 1H NMR (400 MHz, D2O) 3.72 (t, J=5.23 Hz, 2H), 3.99 (dt, J=12.10, 5.29 Hz, 1H), 4.08 (dt, J=12.15, 5.22 Hz, 1H), 4.61 (s, 1H), 7.24-7.28 (m, 2H), 7.32 (tt, 1H), 7.38-7.44 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH2:17][CH2:18][CH2:19]Cl)[C:9]=3[CH:8]=2)=[N:4][N:3]=1.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:24][C:23]=2[O:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH2:17][CH2:18][CH2:19][N:33]4[CH2:32][CH2:31][CH:30]([C:25]5[CH:26]=[CH:27][C:28]6[O:29][CH2:21][O:22][C:23]=6[CH:24]=5)[CH2:35][CH2:34]4)[C:9]=3[CH:8]=2)=[N:4][N:3]=1
Reactant: Cc1nnc(-c2cc3c(OCCCCl)cccc3o2)o1
Reactant: c1cc2c(cc1C1CCNCC1)OCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nnc(-c2cc3c(OCCCN4CCC(c5ccc6c(c5)OCO6)CC4)cccc3o2)o1
Temperature: 80 °C
Yield: 62.9 %

Procedure:
5-Methyl-2-(4-(3-chloropropyloxy)benzo(b)furan-2-yl)-1,3,4-oxadiazole (1.0 g), 4-(3,4-methylenedioxyphenyl)piperidine (0.7 g), potassium carbonate (1.5 g) and potassium iodide (1.0 g) were dissolved in a mixed solvent (50 ml) of DMF-toluene (2:1) and the solution was stirred with refluxing under heating at 80° C. for 4 hr. The reaction mixture was poured into water, extracted with ethyl acetate and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.99 g) as white crystals, melting point 125–127° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH2:16]O)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH2:16][Cl:22])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCCCCc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4-(4-phenylbutoxy)benzyl alcohol (556 mg, 2.17 mmol) in chloroform (10 ml) was added with thionyl chloride (0.288 ml) and left under stirring at room temperature for 24 h, then evaporated to dryness under reduced pressure to obtain 595 mg of the title compound (quantitative yield).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)[CH3:11]>>[CH2:10]([O:12][C:13]1[CH:18]=[C:17]([C:7]2[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:11]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cc1F
Product: CCOc1cccc(-c2ccc(N)c(F)c2)c1
Yield: 44.2 %

Procedure:
The title compound (1.34 g) was prepared from 2-fluoro-4-bromo aniline (2.5 g, 13.1 mmol) and 3-ethoxyphenylboronic acid (2.8 g, 17.0 T mmol) as a pale-yellow liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.38-7.20 (m, 3H), 7.10 (d, J 7.9, 1H), 7.07-7.05 (m, 1H), 6.83-6.76 (m, 2H), 5.24 (s, 2H), 4.06 (q, J 7, 2H), 1.32 (t, J 7, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:27]=[O:28].O>O1CCCC1>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:27]=[O:28])[C:12]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Into a round bottom flask was added (2,4-difluoro-phenyl)-carbamic acid benzyl ester (21, 3.83 g, 14.5 mmol) in 148 mL of tetrahydrofuran. The solution was chilled to −78° C. and n-butyllithium (19.1 mL, 1.60 M in hexane, 30.0 mmol) was added over 30 minutes, followed by the addition of N,N-dimethylformamide (1.12 mL, 14.5 mol). The reaction mixture was allowed to warm to ambient temperature and was stirred overnight, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was crystallized from ether to provide the desired compound (22, 3.0 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C23C=CC=CC2C(NC3=O)=O)=[CH:4][CH:3]=1.O.[NH2:27]N.CCO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:27])=[CH:6][CH:7]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C1NC(=O)C2(CCCCCCNc3ccc(Cl)cc3)C=CC=CC12
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: NCCCCCCNc1ccc(Cl)cc1
Product: Nc1ccc(Cl)cc1

Procedure:
2-[6-(4-Chloro-phenylamino)-hexyl]-phthalimide (3.41 g crude from above, 8.4 mmol) and hydrazine hydrate (2.5 ml, 41.5 mmol) were dissolved in THF (25 mL) and EtOH (25 mL) and stirred under reflux for 21 h. The solvent was removed under reduced pressure, the residue was suspended in THF (50 mL) and the precipitate was filtered off, washed with THF (2×5 mL) and the filtrate was concentrated under reduced pressure to give the title compound together with some 4-Chloroaniline (≈3:2).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:18]=1[CH3:34].Cl.O1CCOCC1>CN1C(=O)CCC1>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:19]1[C:18]([CH3:34])=[C:17]([NH:1][C:2]2[CH:9]=[C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Cl
Reactant: N#Cc1ccc(N2CCOCC2)cc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(N2CCOCC2)ccc1C#N

Procedure:
Prepared according to Procedure K, Method 2 using 2-amino-4-morpholinobenzonitrile (82 mg, 405 μmol), 4-chloro-2-(2-fluorophenyl)-3-methylquinoline (110 mg, 405 μmol) and 4N hydrochloric acid solution in dioxane (0.010 mL, 40 μmol) in NMP (0.50 mL) to afford product as a tan solid upon purification by chromatography on silica gel, eluting with EtOAc gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 8.11 (1H, d, J=8.6 Hz), 7.90 (1H, d, J=8.6 Hz), 7.61-7.74 (1H, m), 7.45-7.61 (2H, m), 7.32-7.45 (2H, m), 7.26 (1H, t, J=7.4 Hz), 7.08 (1H, t, J=9.2 Hz), 6.55 (1H, br. s.), 6.31 (1H, dd, J=8.8, 2.5 Hz), 5.76 (1H, br. s.), 3.54-3.73 (4H, m), 2.88-3.11 (4H, m), 2.04-2.23 (3H, m). Mass Spectrum (ESI) m/e=439.1 (M+1).
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[S:8][CH:9]=[C:10](Br)[CH:11]=1.[CH3:13][C:14]1[S:15][CH:16]=[C:17]([CH:19]=[O:20])[CH:18]=1.[NH4+].[Cl-]>CCOCC>[CH3:6][C:7]1[S:8][CH:9]=[C:10]([CH:19]([C:17]2[CH:18]=[C:14]([CH3:13])[S:15][CH:16]=2)[OH:20])[CH:11]=1
Reactant: Cc1cc(C=O)cs1
Reactant: Cc1cc(Br)cs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cc(C(O)c2csc(C)c2)cs1
Temperature: 25 °C

Procedure:
113 mL of 1.6 M n-BuLi solution (0.18 mol) was added to a solution of 31.3 g of 2-methyl-4-bromo-thiophene (0.177 mol) in 150 mL of ether at −70° C. under stirring. The resulting solution was kept under stirring at −60 to −70° C. for 30 min and then was added of 22.3 g of 2-methyl-4-formyl-thiophene (0.177 mol) in 100 mL of ether. The mixture was allowed to warm to room temperature, then neutralized with 10% aqueous solution of NH4Cl and washed with water. The organic phase was separated and evaporated. The crude bis(2-methyl-4-thienyl)methanol (or 2,2′-dimethyl-4,4′-dithienyl carbinol) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[S:6][CH2:5][NH:4][C@H:3]1[C:7](N)=[O:8].[OH-].[Na+].CC1(C)SCNC1C(N)=[O:20]>C(O)C(C)C>[CH3:1][C:2]1([CH3:10])[S:6][CH2:5][NH:4][C@H:3]1[C:7]([OH:20])=[O:8]
Reactant: CC1(C)SCN[C@H]1C(N)=O
Reactant: CC1(C)SCNC1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)CO
Product: CC1(C)SCN[C@H]1C(=O)O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Optically active (4S)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid amide (5.0 g, 31.3 mmol), sodium hydroxide (0.25 g, 11.2 mmol) and i-butyl alcohol (50 ml) were placed in a 200-ml three-necked flask attached with a stirrer, thermometer and reflux condenser and stirred at 110° C. for 2 hours. After completion of the reaction, the reaction mixture was analyzed by liquid chromatography. As a result, it was found that the residual ratio of the 5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid amide was 82.3%, and the racemization ratio of the optically active (4S)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid amide was 97.5%.
Reaction SMILES: [CH3:1]Cl.[Cl:3][C:4]1[C:12]([Cl:13])=[C:11]2[C:7]([CH2:8][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]2=[O:14])=[CH:6][C:5]=1[O:21][CH3:22].[Br-].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:3][C:4]1[C:12]([Cl:13])=[C:11]2[C:7]([CH2:8][C:9]([CH3:1])([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:10]2=[O:14])=[CH:6][C:5]=1[O:21][CH3:22]
Reactant: CCl
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A 35 ml glass pressure bottle, fitted with an efficient magnetic stirrer was charged with 25 ml of toluene. Methyl chloride (1.01 g, 20 mmole) were dissolved in the toluene and to this solution there were added 0.61 g (2 mmole) of 6,7-dichloro-5-methoxy-2-phenyl-1-indanone, 0.21 g (0.4 mole) of N-p-(trifluoromethylbenzyl) cinchoninium bromide and 5 ml of 50% aqueous sodium hydroxide. The reaction mixture was sealed with a screw cap and vigorously stirred for 18 hours at room temperature (22°-25° C.). The reaction mixture was then diluted with 25 ml of toluene and 15 ml of water. The aqueous layer was separated and the toluene layer was washed twice with 25 ml of 4N hydrochloric acid. An aliquot of the toluene solution was concentrated in vacuo to dryness on a rotary evaporator. An LC assay indicated a 98% yield while an NMR assay using the chiral shift reagent [tris-[3-heptafluoropropylhydroxymethylene)-d-camphorato]europium (III)] showed a (+):(-) isomer ratio of 95.3:4.7.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:24]([C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:28])[F:29])=[CH:23][CH:22]=3)(=[O:26])=[O:25])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 4-trifluoromethyl benzenesulfonyl chloride (322 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12f as a solid (333 mg, 86.9%). HPLC: 99.42% (Rt=11.936 min).
Reaction SMILES: C[OH:2].Cl.Cl.Cl.[CH2:6]([NH:12][C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[NH:17])=[NH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:26][C:27]([CH3:29])=[O:28]>>[C:27]([OH:2])(=[O:28])[CH3:29].[CH3:26][C:27]1([CH3:29])[N:14]=[C:13]([NH:12][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N:17]1
Reactant: CO
Reactant: CC(C)=O
Reactant: CCCCCCCNC(=N)NC(=N)NCCCCCC
Agent: Cl
Product: CC(=O)O
Product: CCCCCCCNC1=NC(C)(C)N=C(NCCCCCC)N1

Procedure:
100 ml of methanol, 80 ml of acetone and 0.7 ml of concentrated hydrochloric acid were added to 10.0 g (28.1 mmol) of N1-hexyl-N5-heptyl-biguanide dihydrochloride. The mixture was refluxed for 23 hours, and the solvent was distilled off under reduced pressure. To the residue were added 100 ml of ethanol, 60 ml of water and 11.3 ml of 5N sodium hydroxide, and the mixture was refluxed for 1 hour, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed successively with 10% aqueous sodium acetate and water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from methyl ethyl ketone to obtain 8.4 g of colorless crystals having a melting point of 70 to 75° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[N:19]=[CH:20][S:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]([C:32](OC(C)(C)C)=O)[NH:24]C(OC(C)(C)C)=O.[C:39]([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:32]([CH3:39])=[N:23][N:24]=3)[C:11]=2[CH:10]=[C:9]1[C:18]1[N:19]=[CH:20][S:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: Clc1ccc2c(cc(-c3cscn3)n2Cc2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1nnc2ccc3c(cc(-c4cscn4)n3Cc3ccccc3)n12
Temperature: 108 °C

Procedure:
1-Benzyl-5-chloro-2-(1,3-thiazol-4-yl)-1H-pyrrolo[3,2-b]pyridine (32 mg, 0.098 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (27 mg, 0.12 mmol) and Cs2CO3 (32 mg, 0.098 mmol) were combined in toluene (3.0 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (7.7 mg, 0.0098 mmol) was added. The mixture was degassed by a stream of nitrogen through the solution for 10 minutes. The reaction was heated to 108° C. overnight. Additional di-tert-butyl hydrazine-1,2-dicarboxylate (23 mg, 0.098 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (7.7 mg, 0.0098 mmol) were added. The reaction was heated to 110° C. over a second night. The mixture was partitioned between EtOAc and water, extracted three times, and the combined extracts were dried over sodium sulfate, filtered and concentrated. The intermediate di-tert-butyl 1-[1-benzyl-2-(1,3-thiazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) and the eluent was evaporated. The product was dissolved in AcOH (0.60 mL) and was heated in the microwave to a temperature of 156° C. for 5 minutes. The AcOH was removed in vacuo and the sample was reconstituted and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (1.0 mg, 2.9%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[C:10](=O)([O:21]C1C=CC([N+]([O-])=O)=CC=1)[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4])=[O:21])=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 60 °C
Reaction time: 20 h
Yield: 28 %

Procedure:
A 300 ml round-bottomed flask equipped with a Dimroth condenser was charged with 13.13 g (100 mmol) of L-isoleucine and 1000 ml of tetrahydrofuran. After the addition of 30.4 g (100 mmol) of bis(4-nitrophenyl) carbonate, the mixture was stirred at 60° C. for 20 hours. After evaporating the solvent, the residue was purified by column chromatography to obtain 8.3 g of N-(4-nitrophenoxycarbonyl)-L-isoleucine.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:33]=[N:32][C:18]3[N:19]([CH2:29][CH2:30][CH3:31])[CH2:20][CH2:21][CH2:22][C:23]([C:25]([O:27]C)=[O:26])=[CH:24][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:33]=[N:32][C:18]3[N:19]([CH2:29][CH2:30][CH3:31])[CH2:20][CH2:21][CH2:22][C:23]([C:25]([OH:27])=[O:26])=[CH:24][C:17]=3[CH:16]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)OC)CCCN3CCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)O)CCCN3CCC)cc1
Temperature: 90 °C
Yield: 89.7 %

Procedure:
To a solution of methyl 3-[4-(2-butoxyethoxy)phenyl]-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate (850 mg) in THF (30 ml) and methanol (30 ml) was added a 1 N aqueous sodium hydroxide solution (7.5 ml), and the mixture was heated at 90° C. for 3 hours. After cooling to 0° C., water was added thereto, and the mixture was neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was washed with hexane to give 3-[4-(2-butoxyethoxy)phenyl]-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylic acid (739 mg) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22]O.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:17]([CH3:22])=[N:18][N:19]=[C:20]1[CH2:21][N:29]1[C:25](=[O:35])[C:26]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:27]2[C:28]1=[O:30]
Reactant: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, a mixture of 2',5-dichloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone, phthalimide and triphenylphosphine in tetrahydrofuran was treated with diethyl azodicarboxylate to give 2',5-dichloro-2-[3-(phthalimidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone of melting point 262°-265°C.