Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:19](Cl)(=[O:22])[CH2:20][CH3:21].CCCCCC>C1COCC1>[O:22]=[C:19]([N:9]1[C@@H:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][O:11][C:10]1=[O:13])[CH2:20][CH3:21].[O:11]1[CH2:12][CH2:8][NH:9][C:10]1=[O:13]
Reactant: CCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Product: O=C1NCCO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 131.1 %

Procedure:
To (S)-4-(Phenylmethyl)-2-oxazolidinone (17.5 g, 0.1 mole) in THF (250 ml) at -70° C. under a blanket of nitrogen was added 2.5M n-BuLi (0.11 mole, 44 ml) dropwise in 10 minutes. After 5 minutes, the clear cloudy solution was treated rapidly with propionyl chloride (10 g, 0.105 mole). The colorless solution was then slowly warmed to room temperature in the course of 1 hour, quenched with saturated ammonium chloride (20 ml) and diluted with ether (100 ml). The organic extract washed with water (20 ml), aqueous NaHCO3 (20 ml), dried over anhydrous MgSO4 and evaporated to give a viscous solid mass. Trituration with hexane (100 ml) gave the oxazolidinone 3-(1-OxoPropyl)-(S) -4-(Phenylmethyl)-2-Oxazolidinone (21 g, 90%) as white plates MP.44°-46° C.IR:3030, 2980, 1780, 1705, 1455 cm-1.
Reaction SMILES: [NH2:1][CH:2]([CH3:28])[C:3]([NH:5][C:6]1[N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[N:8]=[C:9]([C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:10]=1)=[O:4].[F:29][C:30]1[CH:31]=[C:32]([CH:38]=[C:39]([F:41])[CH:40]=1)[C@H:33]([OH:37])[C:34](O)=[O:35].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C1COCC1>[C:24]([N:7]1[C:6]([NH:5][C:3](=[O:4])[CH:2]([NH:1][C:34](=[O:35])[CH:33]([C:32]2[CH:38]=[C:39]([F:41])[CH:40]=[C:30]([F:29])[CH:31]=2)[OH:37])[CH3:28])=[CH:10][C:9]([C:11]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[N:8]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(N)C(=O)Nc1cc(C2(c3ccccc3)CCN(C)CC2)nn1C(C)(C)C
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)Nc1cc(C2(c3ccccc3)CCN(C)CC2)nn1C(C)(C)C
Reaction time: 16 h

Procedure:
A solution of 0.14 g (0.4 mmol) of 2-amino-N-[2-tert-butyl-5-(1-methyl-4-phenylpiperidin-4-yl)-2H-pyrazol-3-yl]propionamide and 0.08 g (0.4 mmol) of (S)-3,5-difluoromandelic acid (Garofalo, et al. Bioorg. Med. Chem. Lett. 2002, 12, 3051) in 5.0 mL of THF was stirred at rt as 0.06 g (0.4 mmol) of HOBT and 0.08 mL (0.7 mmol) of NMM was added followed by 0.90 g (0.5 mmol) of EDC.HCl. After 16 h, the reaction was quenched with 1M HCl and extracted with EtOAc. The organic layer washed with sat. aq. NaHCO3, dried over MgSO4 and concentrated. Purification on silica gel using 4% Et3N-MeOH as eluant afforded N-[2-tert-butyl-5-(1-methyl-4-phenylpiperidin-4-yl)-2H-pyrazol-3-yl]-2-[2-(3,5-difluorophenyl)-2-hydroxyacetylamino]propionamide.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14]O)[C:8]=2[N:7]=[C:6]1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23].O=S(Cl)[Cl:31]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][Cl:31])[C:8]=2[N:7]=[C:6]1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23]
Reactant: OCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Fc1cccc(F)c1Cn1c(-c2c(F)cccc2F)nc2c(CCl)cccc21
Reaction time: 3 h
Yield: 91.4 %

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-hydroxylmethylbenzimidazole (Example 112) (0.54 g, 1.40 mmol) dissolved in CHCl3 (3.0 mL) was added SOCl2 (0.15 mL, 2.06 mmol, 150 M%). After 3 h at room temperature, the reaction was diluted with CHCl3, and washed with NaHCO3 (sat. soln) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography eluting with 1% MeOH/CH2Cl2. Recrystallization from diethylether:hexane (3:1) yielded white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-chloromethylbenzimidazole (0.52 g, 1.28 mmol, 92% yield). M.p. 143-144° C. 1H-NMR (300 MHz, CD2Cl2): δ7.55 (m, 1H, H4′), 7.48 (dd, J=7.7, 1.1 Hz, 1H, H7), 7.36 (dd, J=7.6 Hz, 1.1 Hz, 1H, H5), 7.30 (dd, J=7.7, 7.6 Hz, 1H, H6), 7.25 (m, 1H, H4″), 7.09 (m, 2H, H3′,5′), 6.82 )m, 2H, H3″,5″), 5.36 (s, 2H, CH2PhF2), 5.07 (s, 2H, CH2Cl).
Reaction SMILES: [N:1]1([CH2:10][C:11](OC)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1([CH2:10][CH2:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)Cn1ccc2cccnc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCn1ccc2cccnc21
Yield: 87.1 %

Procedure:
A procedure similar to that described in Preparation 2 was repeated, except that 7.50 g of methyl 7-azaindol-1-acetate (prepared as described in Preparation 17), 1.80 g of lithium aluminum hydride and 260 ml of anhydrous tetrahydrofuran were used, to give 5.57 g of the title compound, melting at 52.7°-53.3° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([OH:22])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])=[CH:9][CH:8]=2)=[N:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].CO>N1C=CC=CC=1>[C:24]([O:22][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([C:4]2[O:5][CH2:6][C:2]([CH3:23])([CH3:1])[N:3]=2)=[CH:12][CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])(=[O:26])[CH3:25]
Reactant: COc1ccccc1C(O)c1ccc(C2=NC(C)(C)CO2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccccc1C(OC(C)=O)c1ccc(C2=NC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[4-(4,4-Dimethyloxazolin-2-yl)phenyl]-1-(2-methoxyphenyl)methyl alcohol (100 mg) was dissolved in pyridine (0.4 ml), added with acetic anhydride (0.25 ml) with ice cooling and stirred at room temperature for 4 hours. After the reaction mixture was added with methanol (0.25 ml) with ice cooling and stirred at room temperature for 10 minutes, the solvent was evaporated under reduced pressure to obtain 1-[4-(4,4-dimethyloxazolin-2-yl)phenyl]-1-(2-methoxyphenyl)methyl acetate.
Reaction SMILES: [Cl-:1].[NH4+:2].C[Al](C)C.CCCCCC.[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][CH2:30][CH3:31])=[C:25]([CH:28]=1)[C:26]#[N:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.ClCCl>[ClH:1].[CH2:13]([O:20][C:21]1[CH:28]=[C:25]([C:24]([O:29][CH2:30][CH3:31])=[CH:23][CH:22]=1)[C:26]([NH2:2])=[NH:27])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [Cl-]
Reactant: CCOc1ccc(OCc2ccccc2)cc1C#N
Reactant: [NH4+]
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOc1ccc(OCc2ccccc2)cc1C(=N)N
Product: Cl
Temperature: 2.5 °C

Procedure:
46.46 g of ammonium chloride (868.5 mol) are suspended in 650 ml of toluene, and the mixture is cooled to 0-5° C. Trimethylaluminum is added dropwise as a 2M solution in hexane (445 ml, 888.3 mmol), and the mixture is then stirred at room temperature until the evolution of gas has ceased. 5-Benzyloxy-2-ethoxybenzonitrile (100 g, 394.8 mmol) (example 32A) is added, and the mixture is stirred at 80° C. overnight. The cooled reaction mixture is, with ice-cooling, added to a suspension of 200 g of silica gel and 2 l of dichloromethane, and the mixture is stirred for 30 min. The mixture is filtered off with suction and the filter cake is washed with methanol. The organic phases are combined and concentrated. The resulting residue is triturated using a mixture of dichloromethane/methanol 9:1, filtered and concentrated using a rotary evaporator. The residue is then triturated with ether, and the colorless solid is filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[ClH:17].[CH3:18]O>>[Cl:17][CH:12]([CH2:11][C:10]([C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)=[O:16])[C:13]([O:15][CH3:18])=[O:14]
Reactant: Cl
Reactant: Cc1c(Cl)cc(C(=O)C=CC(=O)O)cc1Cl
Reactant: CO
Product: COC(=O)C(Cl)CC(=O)c1cc(Cl)c(C)c(Cl)c1

Procedure:
5.18 g (0.02 mole) of 4-(3,5-dichloro-4-methylphenyl)-4-oxo-2-butenoic acid, prepared as described in Example 1(b), were suspended in 50 ml of methanol and the suspension was then saturated with dry hydrogen chloride gas by blowing the gas through the suspension whilst ice-cooling and stirring it. The resulting mixture was then stirred at room temperature for a further 2 hours, to give methyl 2-chloro-4-(3,5-dichloro-4-methylphenyl)-4-oxobutyrate. The resulting mixture was then heated under reflux for a further 2 hours to replace the chlorine substituent at the 2-position by a methoxy group. After completion of this reaction, methanol was distilled off and the residue was extracted with diethyl ether. The extract was washed with water and then dried over anhydrous sodium sulphate. The solvent was then distilled off, giving 5.93 g of a crude product, which was subjected to column chromatography through silica gel, eluted successively with benzene and then with a 20:1 by volume mixture of benzene and ethyl acetate, to give 4.46 g (yield 73.1%) of the desired methyl 4-(3,5-dichloro-4-methylphenyl)-2-methoxy-4-oxobutyrate, melting at 75°-78° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[H-].[Na+].[I-].[CH3:22][S+](C)(C)=O.C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[C:7]3([C:8](=[O:16])[O:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]3=[O:13])[CH2:22]2)=[CH:17][CH:18]=1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(Br)cc2)C(=O)O1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C2(CC2c2ccc(Br)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 43.3 %

Procedure:
To a cooled solution of 5-(4-bromobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.48 g) in DMF (20 mL) at 0-5° C. was added by dropwise addition a prepared solution of the dimethylsufoxonium-methylide from sodium hydride (60% in oil) (0.209 g), trimethylsulfoxonium iodide (1.152 g) in DMF (20 mL) at room temperature. Upon completion of addition the mixture was stirred at this temperature for a further 20 min. The mixture was then carefully poured onto a stirred mixture of ice/water and ethyl acetate. The crude product was extracted into ethyl acetate, washed well with saturated brine and dried over sodium sulfate. Filtration and evaporation gave the crude product. This sample was then recrystallised from a mixture of ethyl acetate:isohexane (3:1) to give the subtitle compound (0.670 g) as a colourless solid.
Reaction SMILES: O[C:2](C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][NH:35][CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:20][CH2:19]1)[C:12]#[N:13].C=O.CCN(C(C)C)C(C)C.[Na]>CO>[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][N:35]([CH3:2])[CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:22][CH2:23]1)[C:12]#[N:13]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CCNC2
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: [Na]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CCN(C)C2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
A solution of 3-fluoro-4-((1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (12.8 mg, 0.024 mmol) and formaldehyde (2.2 mg, 0.027 mmol) in MeOH (244 μL) at room temperature was treated with DIPEA (8.5 μL, 0.049 mmol) and sodium triacetoxyhydroborate (10.3 mg, 0.049 mmol). The reaction mixture was stirred for 45 min at room temperature. The crude reaction mixture was purified directly by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 30% to 55% ACN gradient to give the title compound (about 90% purity), as a TFA salt, as a pale yellow solid. (6.0 mg, 46%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.6 Hz, 6H), 1.98 (m, 2H), 2.19 (m, 2H), 3.08 (m, 7H), 3.38 (m, 3H), 3.76 (br s, 1H), 4.16 (m, 1H), 4.29 (m, 2H), 4.79 (m, 1H), 7.34 (m, 1H), 7.53 (m, 2H); ESI-MS m/z [M+H]+ 425.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][CH:26]=3)=O)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31].Cl.[O:35]([NH2:37])[CH3:36].CCN(CC)CC>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19](=[N:37][O:35][CH3:36])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[NH:27][CH:28]=[CH:29][C:22]=34)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:30]([F:33])([F:31])[F:32]
Reactant: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccnc2[nH]ccc12
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CON=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccnc2[nH]ccc12
Temperature: 25 °C

Procedure:
A solution of 4-chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (41 mg), methoxyl amine hydrochloride salt (67 mg) and Et3N (0.14 mL) in THF (1 mL) was heated to 80° C. for 12 h. The mixture was cooled to room temperature, diluted with EtOAc (5 mL), filtered and evaporated in vacuo. The residue was purified by flash chromatography (silica) to afford the title compound as a white powder. MS (M+H)+: 544.0.
Reaction SMILES: [C:1]([C:4]1[C:9]([CH3:10])=[C:8]([Cl:11])[C:7]([CH3:12])=[CH:6][N:5]=1)(O)=[O:2].B.C1COCC1.C1COCC1.O.[Cl-].[Na+]>CN(C)C=O>[Cl:11][C:8]1[C:7]([CH3:12])=[CH:6][N:5]=[C:4]([CH2:1][OH:2])[C:9]=1[CH3:10]
Reactant: Cc1cnc(C(=O)O)c(C)c1Cl
Agent: B
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cnc(CO)c(C)c1Cl
Reaction time: 1.5 h
Yield: 51 %

Procedure:
2-carboxy-4-chloro-3,5-lutidine (1 eq.) was suspended in dry dimethylformamide and BH3.THF solution (1M in tetrahydrofuran, 3.5 eq.) was added. The mixture was heated to 60ℑ C. and stirred under a nitrogen atmosphere until completion (1.5 hours). The mixture was cooled in an ice bath and THF/H2O (1:1) mixture (10 volumes) was added slowly. The aqueous layer was saturated with sodium chloride and the tetrahydrofuran layer was separated. The aqueous layer was extracted with ether. The combined organic extracts were dried over sodium sulfate, filtered and the solvent was evaporated under vacuum. The 4-Chloro-2-hydroxymethyl-3,5-Lutidine product was obtained in 51% yield.
Reaction SMILES: N#N.[NH2:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([F:10])[CH:9]=1.[Br:11]N1C(=O)CCC1=O>CN(C=O)C>[NH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([Br:11])=[N:6][CH:5]=1
Reactant: Nc1cncc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: N#N
Solvent: CN(C)C=O
Product: Nc1cnc(Br)c(F)c1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 3-amino-5-fluoropyridine (900 mg, 8.03 mmol) in dry DMF (13 mL) was treated at 0° C. with N-bromo-succinimide (1.43 g, 8.03 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then partitioned between Et2O and water. The layers were separated and the org. layer successively washed with water, sat. aq. NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA 9:1 to 1:1) and the title compound obtained as an orange solid. LC-MS-conditions 07: tR=0.52 min; [M+H]+=191.30.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1C.COC(=O)C1C=CC(CBr)=CC=1.[CH2:21]([O:23][C:24]([C:26]1[O:27][C:28]([CH2:31]Cl)=[CH:29][CH:30]=1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1[O:27][C:28]([CH2:31][N:4]2[C:3]([CH2:2][OH:1])=[CH:7][N:6]=[CH:5]2)=[CH:29][CH:30]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: Cc1[nH]cnc1CO
Agent: COC(=O)c1ccc(CBr)cc1
Product: CCOC(=O)c1ccc(Cn2cncc2CO)o1

Procedure:
The following compounds were obtained using the same procedure as in Example A1 but replacing 4-hydroxymethylimidazole hydrochloride with 4-hydroxymethyl-5-methylimidazole and 4-bromomethylbenzoic acid methyl ester by 5-chloromethylfuran-2-carboxylic acid ethyl ester.
Reaction SMILES: C([N:4](C(C)C)CC)(C)C.Cl.Cl.N[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].I.[NH2:33][C:34]1[C:35]([C:42]([NH:44][C:45](=[NH:48])SC)=[O:43])=[N:36][C:37]([Cl:41])=[C:38]([NH2:40])[N:39]=1>C(O)C>[NH2:33][C:34]1[C:35]([C:42]([N:44]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:25])[N:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]2)[C:45]([NH2:48])=[NH:4])=[O:43])=[N:36][C:37]([Cl:41])=[C:38]([NH2:40])[N:39]=1
Reactant: NCCCCCCCCCCCC(=O)N1CCNCC1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: I
Solvent: CCO
Product: N=C(N)N(CCCCCCCCCCCC(=O)N1CCNCC1)C(=O)c1nc(Cl)c(N)nc1N
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
Diisopropylethylamine (1.67 mL, 9.59 mmol) was added to a suspension of 12-amino-1-piperazin-1-yl-dodecan-1-one dihydrochloride (11) (342 mg, 0.96 mmol) in absolute ethanol (10 mL). The resulting solution was stirred at 70° C. (oil bath) for 10 min and then 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (380 mg, 0.98 mmol) added in one portion. The reaction mixture was then stirred at this temperature for 3 hours and cooled to room temperature. The solvent was removed by rotary evaporation and the resulting residue was dissolved in small volume of methanol, and the solution passed through an ion exchange resin column (Dowex 550A OH type). The resin column was rinsed thoroughly with methanol and the methanol solution was concentrated in vacuo. The resulting residue was purified by Biotage silica gel column chromatography, eluting with 0% to 20% of 9:1 methanol/ammonium hydroxide in dichloromethane to give N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N-(12-oxo-12-piperazin-1-yl-dodecyl)guanidine as a yellow solid. About half of this material was further purified by preparative HPLC using acetonitrile/water/0.05% TFA. The TFA salt obtained was co-evaporated twice with aqueous 2N HCl and further dried under high vacuum to give the desired compound 12 (123 mg, 45%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 1.28 (m, 14H), 1.52 (m, 4H), 2.29 (t, 2H), 3.00 (m, 4H), 3.30 (m, 2H), 3.68 (m, 4H), 7.40 (br, 4H), 8.96 (m, 2H), 9.25 (m, 11H), 9.50 (br, 2H), 10.50 (s, 1H). m/z (ESI) 496 [C22H38ClN9O2+H]+. mp 148-150° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH:13]=O)=[CH:8][C:7]=1[CH3:15])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:18]([F:17])[CH:19]=2)=[CH:8][C:7]=1[CH3:15])[CH3:2]
Reactant: CCOC(=O)Nc1c(C)cc(C=O)cc1C
Reactant: Nc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Nc1c(C)cc(CNc2cccc(F)c2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To (4-formyl-2,6-dimethyl-phenyl)-carbamic acid ethyl ester (230 mg) and 3-fluoroaniline (122 mg) dissolved in dry ethanol (25 mL) was added 3 Å molecular sieves (0.5 g) and the reaction mixture was refluxed for 16 hours under argon. Upon cooling to 25° C., sodium cyanoborohydride (320 mg) and acetic acid (3 mL) were added and stirred for 1 hour. A second batch of sodium cyanoborohydride (320 mg) was added and the mixture stirred for 1 additional hour. Saturated aqueous sodium carbonate (5 mL) was added and the mixture stirred for 1 hour, water (50 mL) was added and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 95 mg (29% yield) of the title compound as a white solid. LC-MS-TOF (m/z) 317 (MH+); tR=3.37, (UV, ELSD) 99%, 96%. 1H NMR (500 MHz, CDCl3): 1.31 (b, 3H), 2.25 (s, 6H), 4.20 (m, 5H), 5.98 (b, 1H), 6.30 (dt, 1H), 6.39 (m, 2H), 7.06 (s, 2H), 7.08 (q, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([C@@H:28]3[CH2:32][CH2:31][CH2:30][C@H:29]3[C:33]([O:35]CCCC)=[O:34])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([C@@H:28]3[CH2:32][CH2:31][CH2:30][C@H:29]3[C:33]([OH:35])=[O:34])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CCCCOC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC)cc4s3)c(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2nc(Nc3ccc(-c4ccc(C(=O)[C@@H]5CCC[C@H]5C(=O)O)cc4)cc3F)sc2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of butyl (1R,2R)-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)-amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylate in methanol (8 mL) was added 1 N aqueous sodium hydroxide (6.15 mL), and the mixture was stirred at 50° C. overnight. The solvent was then removed by rotary evaporation. Water (5 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The aqueous layer was then treated with 1 N aqueous HCl to adjust the acidity to pH 2, and then extracted with ethyl acetate. The organic phase was evaporated under reduced pressure, and the residue was purified by flash chromatography (Biotage Flash 40S, 6:1 EtOAc/hexane) to afford (1R,2R)-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid (129 mg, 30%, 89% ee). LC-MS ret. time 3.56 min, m/z 491.3 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 1.58–1.84 (m, 4H), 1.96–2.01 (m, 1H), 2.14–2.17 (m, 1H). 3.22 (q, 1H), 3.77 (s, 3H), 4.02–4.10 (q, 1H), 6.94 (dd, 1H), 7.46 (d, 1H), 7.53 (d, 1H), 7.65–7.76 (m, 2H), 7.86 (d, 2H), 8.04 (d, 2H), 8.72 (t, 1H), 10.33 (br s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([N:23]=[N+]=[N-])[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.O.S>C(O)(=O)C>[NH2:23][CH:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][N:12]1[C:13](=[O:22])[C:14]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]2[C:16]1=[O:17]
Reactant: [N-]=[N+]=NC(COCc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: S
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: NC(COCc1ccccc1)CN1C(=O)c2ccccc2C1=O
Reaction time: 4 h
Yield: 20 %

Procedure:
Into a stirred solution of 2-benzyloxymethyl-2-azido-1-phthalimido-ethane (500 mg, 1.5 mmol) in 4:1 pyridine/water (25 ml) was bubbled hydrogen sulphide, and the reaction was monitored by TLC. After 4 hours, the gas flow was stopped, and the reaction flask sealed. The intense green reaction mixture was stirred for another 17 hours. TLC indicated full conversion of the starting material. Glacial acetic acid was added to pH 7, and the reaction mixture was evaporated to dryness in vacuo. After evaporation from ethanol (3×25 ml), the resulting brown solid was purified by chromatography. Yield=20%. The structure was confirmed by NMR and IR.