Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH:19]=[O:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].[CH3:21][Mg]Cl>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:1]([C:3]1([CH2:18][CH:19]([OH:20])[CH3:21])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC=O)OCC3
Reactant: C[Mg]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(C)O)OCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of compound 8 (275 mg, 1.01 mmol) in dry THF (4 mL) was added dropwise over five minutes to a stirred solution of 1M MeMgCl in THF (1.52 mL, 1.52 mmol, 1.5 eq) at 0° C. under argon and allowed to warm slowly to room temperature. After stirring for two hours, another equivalent of 3M MeMgCl in THF (337 μL, 1.01 mmol, 1.0 eq) was added, and the mixture was stirred for an additional hour. The mixture was then diluted with saturated NaHCO3 and extracted three times with EtOAc. The combined organic phases were dried with Na2SO4, concentrated, and purified by column chromatography using 20:80:EtOAc:Hexane to give a yellow solid (280 mg, 96%): mp 103–104° C. 1HNMR (CDCl3, δ TMS) shows a 2:1 mixture of diastereomers. MS−: m/z 322 (MCl−), 286 ([M−H]−). Anal. (C18H25NO2): C, H, N. The product was carried on to the next step as a mixture of diastereomers.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[CH:7]=[C:8]2[C:13]=1[NH:12][CH2:11][CH2:10][NH:9]2)([O-:3])=[O:2].[CH:18](=O)[CH3:19]>>[CH2:18]([N:9]1[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[CH:7]=2)[NH:12][CH2:11][CH2:10]1)[CH3:19]
Reactant: CC=O
Reactant: COC(=O)c1cc2c(c([N+](=O)[O-])c1)NCCN2
Product: CCN1CCNc2c1cc(C(=O)OC)cc2[N+](=O)[O-]

Procedure:
Methyl 4-ethyl-8-nitro-1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (D210) was prepared from methyl 8-nitro-1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (D209) in an analogous manner to the process described for Ester 35 (B35) using acetaldehyde instead of propionaldehyde. [M+H]+=266.3, RT=3.07 min.
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[NH2:2].[Cl:21][CH2:22][C:23](=O)[CH3:24]>>[Cl:21][CH2:22][C:23](=[N:2][NH:1][C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[CH3:24]
Reactant: NNC1=Nc2ccccc2C(c2ccccc2Cl)=NC1
Reactant: CC(=O)CCl
Product: CC(CCl)=NNC1=Nc2ccccc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be reacted with chloropropanone to give 2-[(2-chloro-1-methylethylidene)hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4]>[OH-].[Na+]>[O:1]=[C:2]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[CH:13][CH:14]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(=O)Cc1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1ccc(CC(=O)C(=O)O)cc1

Procedure:
Hydrolyze ethyl 2-oxo-3-p-cyanophenylpropionate, prepared in Example 72, by stirring in 5% sodium hydroxide at room temperature overnight, washing the reaction mixture with ether, acidifying the aqueous layer to pH 2 with conc. HCl, extracting the product into a mixture of ether and ethyl acetate, and removing the solvent to obtain 2-oxo-3-p-cyanophenylpropionic acid. Reductively couple the acid with the ethyl ester of L-homophenylalanine in the presence of sodium cyanoborohydride in the manner described in Example 13 and purify as described in that Example to obtain the mixture of diastereoisomers of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-D,L-p-cyanophenylalanine. Condense this with benzyl L-prolinate hydrochloride in dimethylformamide by the use of the diphenylphosphoryl azide reagent in the manner described in Example 13 to obtain the mixture of diastereoisomers of N-(1-(S)-carbethoxy-3-phenylpropyl)-D,L-p-cyanophenylalanyl-L-proline benzyl ester. Hydrogenate this intermediate in ethanol containing hydrogen chloride over palladium on carbon catalyst as described in Example 72 and work up as outlined there to obtain the desired product as a mixture of diastereoisomers.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=3)[O:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.B1([C:27]2[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[O:11][N:10]=[C:9]([C:4]3[CH:3]=[C:2]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:7]=[C:6]([F:8])[CH:5]=3)[N:13]=2)=[N:15][CH:16]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Fc1ccc(-c2nc(-c3cc(F)cc(Br)c3)no2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Fc1ccc(-c2nc(-c3cc(F)cc(-c4cccnc4)c3)no2)nc1
Yield: 17.6 %

Procedure:
A mixture of 3-(3-bromo-5-fluorophenyl)-5-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole (80 mg, 0.236 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (80 mg, 0.49 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 40 mg, 0.0346 mmol), in a solution of ethylene glycol dimethyl ether (1.5 mL) and 2M sodium carbonate (1.5 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 50% ethyl acetate in hexane, afforded 14 mg (17.7%) 5-(5-fluoro-pyrid-2-yl)-3-[3-fluoro-5-(3-pyridyl)-phenyl]-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 8.95 (s, 1H), 8.76 (d, 1H), 8.66 (d, 1H), 8.37 (dd, 2H), 8.25 (s, 1H), 7.95 (d, 2H), 7.43 (m, 2H).
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][C:10]([CH3:14])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:2]=[CH2:3].[OH-].[K+].Br[C:25](P(=O)(OCC)OCC)([F:27])[F:26]>C(#N)C.O>[CH2:1]([C:4]1[C:12]([O:13][CH:25]([F:27])[F:26])=[CH:11][C:10]([CH3:14])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: C=CCc1c(OC(F)F)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-allyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate (3.6 g, 12.53 mmol) was dissolved in acetonitrile (62.6 mL) and water (62.6 mL), then KOH (14.06 g, 251 mmol) was added and the solution was stirred until all the KOH went into solution. The resulting solution was then cooled to −78° C. (solution froze) and diethyl bromodifluoromethylphosphonate (4.45 mL, 25.06 mmol) was added. The reaction was removed from the dry ice bath and allowed to warm to room temperature. After 1 hour, EtOAc and water were added, and the resulting layers were separated. The aqueous layer was further extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69 (d, J=3.79 Hz, 1H) 7.08 (t, J=74.7 Hz, 1H) 6.96 (s, 1H) 6.76 (d, J=3.79 Hz, 1H) 5.89 (dd, J=16.93, 10.36 Hz, 1H) 4.91-5.05 (m, 2H) 3.57 (d, J=6.32 Hz, 2H) 1.59 (s, 9H). MS (ESI+) m/z 338.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[H-].[Na+].Cl[CH2:19][C:20](=O)[CH3:21]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[C:11]2[C:20]([CH3:21])=[CH:19][O:15][C:10]=2[CH2:9]1
Reactant: O=C1CC(=O)CC(c2ccccc2Br)C1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1ccccc1Br)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(2-bromophenyl)cyclohexane-1,3-dione (mp174-175° C.; 1.07 g) in DMF (15 ml) was added 60% sodium hydride (0.18 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added chloroacetone (0.36 ml), and the mixture was stirred at 150° C. overnight (13 hours). The reaction solution was cooled and concentrated under reduced pressure. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(2-bromophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.28 g).
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:28][C:29]3[S:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:38][CH2:39][CH3:40])(C)(C)C.C(O)(C(F)(F)F)=O>>[S:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[CH2:28][N:17]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)(=[O:19])=[O:20])[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:41])=[O:5])[C:9]([CH2:38][CH2:39][CH3:40])=[N:10][C:11]=2[CH:16]=1
Reactant: CCCc1nc2cc(N(Cc3nc4ccccc4s3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3nc4ccccc4s3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[Benzothiazol-2-ylmethyl-(4-fluoro-benzenesulfonyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ8.08 (m, 1H), 7.86 (m, 1H), 7.79 (m, 2H), 7.45 (m, 4H), 7.25 (m, 2H), 6.91 (d, 1H), 5.33 (s, 2H), 4.39 (s, 2H), 2.65 (t, 2H), 1.72 (m, 2H), 0.92 (t, 3H). MS calculated for C26H23FN4O4S2+H: 539, observed: 539.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][CH:10]=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH2:20]([Mg]Br)[CH:21]=[CH2:22]>C(OCC)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][CH:10]([OH:11])[CH2:22][CH:21]=[CH2:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CC=O)c1cccc(Br)c1
Reactant: C=CC[Mg]Br
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCC(O)CC(O[Si](C)(C)C(C)(C)C)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a 0° C. solution of 3-(3-bromophenyl)-3-(tert-butyldimethylsilyloxy)propanal (17.9 g, 52.1 mmol) in dry diethyl ether (150 mL) is added 1 M allylmagnesium bromide solution in ether (52.1 mL, 52.1 mmol). The resulting mixture is warmed to room temperature over 1 hour. The mixture is diluted with dichloromethane and is quenched by addition of saturated aqueous solution of ammonium chloride. The mixture is extracted three times with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a racemic diastereomeric mixture (18.8 g, 84%). 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.38-7.34 (m, 1H), 7.24-7.21 (m, 1H), 7.19-7.15 (m, 1H), 5.84-5.76 (m, 1H), 5.09-5.04 (m, 1H), 5.00 (t, J=5.3 Hz, 1H), 4.86-4.80 (m, 1H), 3.83-3.75 (m, 2H), 2.23-2.15 (m, 2H), 1.80-1.69 (m, 2H), 0.89 (d, 9H, J=6.6 Hz), 0.06-0.04 (m, 3H), −0.17 (d, J=40.4 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[NH:8][C@H:7]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:6]3[C:5]=2[CH:4]=1)[CH3:2].[H-].[Na+].[CH2:27](I)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:7]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:17][C@@H:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: ICCc1ccccc1
Reactant: CCc1cc(C)c2c(c1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(C)c2c(c1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N(CCc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To a solution of (3aR,9bS)-tert-butyl 8-ethyl-6-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting peak from Example 74, Part B, (30 mg, 0.09 mmol) in 1 mL of DMF at ambient temperature was added sodium hydride (4 mg of 60% in mineral oil, 0.10 mmol) and phenethyliodide (33 mg, 0.14 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 h. Starting material remained so the reaction was heated at 60° C. for 4 h. The reaction was quenched with water and extracted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (elution with 3:1 hexane ethyl acetate) to afford 16 mg (41%) of the title compound as an oil. LRMS (ESI): 435.4 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][N:8]1[C:7]2=[O:21])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:28][N:29]([CH3:32])C=O>>[N:29]1[CH:32]=[CH:1][CH:2]=[C:4]([CH2:13][CH2:12][CH2:11][O:19][C:18]([C:16]2[CH:15]=[CH:14][C:9]3[N:8]([CH:17]=2)[C:7](=[O:21])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=2)[N:10]=3)=[O:20])[CH:28]=1
Reactant: CC(C)c1ccc2nc3ccc(C(=O)O)cn3c(=O)c2c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)c1ccc2nc3ccc(C(=O)OCCCc4cccnc4)cn3c(=O)c2c1
Temperature: 70 °C
Yield: 38 %

Procedure:
A mixture of 5.0 g of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, 5.2 g of 3-(3-pyridine)propylbromide hydrobromide, and 5.2 g of potassium carbonate in 200 ml of dimethylformamide was heated to a bath temperature of 70° C. for 45 minutes. The reaction mixture was partitioned between water (100 ml) and dichloromethane (100 ml) and the aqueous layer was extracted with 3×100 ml of dichloromethane. The combined extracts were washed with 100 ml portions of 10% sodium hydroxide and water, were dried over potassium carbonate and evaporated to 6.3 g of an oil which was purified by preparative liquid chromatography over silica gel eluting with 3:1 ethyl acetate-hexane. The major fraction contained 4.6 g of a orange oil which was crystallized from ethyl acetate-hexane to give 2.7 g (38%) of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid 3-(3-pyridyl)propyl ester, mp 108°-109° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>CC(C)=O>[F:14][C:8]1[CH:7]=[CH:6][C:5]([S:2]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)(=[O:4])=[O:3])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1CCN(S(=O)(=O)c2ccc(F)c(C(=O)O)c2)CC1
Reaction time: 3 h
Yield: 24.2 %

Procedure:
A solution of 5-chlorosulphonyl-2-fluorobenzoic acid (47.72 g, 0.2 mol) in acetone (250 ml) was added to a mixture of N-methylpiperazine (22.04 g, 0.22 mol) and triethylamine (24.29 g, 0.24 mol) and the reaction was stirred at ambient for three hours. The mixture was filtered, the resulting solid was recrystallised from water to afford the title compound (14.63 g, 24.2%) as a white solid. δ (DMSO): 2.30 (3H, s), 2.58 (4H, m), 2.95 (4H, m), 7.52 (1H, m), 7.90 (1H, m), 8.10 m/z (Found: 303 [M+H]+, 100%, C12H16FN2O4S requires 303).
Reaction SMILES: [K].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:18][C:17](=[O:19])[C:16]2[C:11](=[C:12]([C:20]([OH:22])=[O:21])[CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH2:23](Br)[CH:24]=[CH2:25].CN(C)C=O>O>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:18][C:17](=[O:19])[C:16]2[C:11](=[C:12]([C:20]([O:22][CH2:25][CH:24]=[CH2:23])=[O:21])[CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: C=CCBr
Reactant: O=C(O)c1cccc2c1N=C(c1ccccc1Cl)CC2=O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1cccc2c1N=C(c1ccccc1Cl)CC2=O
Reaction time: 6 h

Procedure:
To 7 grams of the potassium salt of 2-(2-chlorophenyl)-4-quinolone-8-carboxylic acid were added 2 ml of allyl bromide and 200 ml of dimethyl formamide, the mixture was stirred at 70° to 80° C. for 6 hours, and poured into water. The mixture was extracted with chloroform, the solvent was removed from the extract, and the residue was recrystallized from acetone to give 5.6 grams of the title compound, pale yellow needles, melting point 121° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[C@@H:19]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Sc2ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc2)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Sc2ccc(S(=O)(=O)N(CCN3CCOCC3)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of N-[[4-[(4-methylphenyl)thio]-phenyl]sulfonyl]-D-valine, 1,1-dimethylethyl ester, from Example 2a (2.4 g ,5.5 mmole) in DMF (50 ml) was added potassium carbonate (2.28 g, 16.5 mmole) and 4-(2-chloroethyl)morpholine hydrochloride (3.07 g, 16.5 mmole). After vigorously stirring at 60° C. for 18 hours, the reaction was worked up by adding water and extracting with ethyl acetate. The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo to give an oil which was purified on silica gel eluting with 50/50 ethyl acetate/hexane to give N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-N-[2-(4-morpholinyl)-ethyl]-D-valine, 1,1-dimethylethyl ester (3.62 g, 100%): anal. calc'd for C28H40N2S2O5 : C, 61.28; H, 7.35; N, 5.10. Found: C, 61.12; H. 7.69; N, 4.91. HRMS MH+ calc'd for C28H40N2S2O5 : 548.2379, found: 548.2386.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH:6]1[O:8][CH2:7]1)(=O)=O.[NH2:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:18]=1[OH:26].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[NH2:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:18]=1[O:26][CH2:5][CH:6]1[O:8][CH2:7]1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Nc1c(OCC2CO2)cccc1[N+](=O)[O-]

Procedure:
21.7 g (0.095 mol) of glycidyl tosylate, 10 g (0.0475 mol) of 2-amino-3-nitrophenol and 6.5 g of crushed K2CO3 are mixed in acetone and the mixture is heated at reflux for 18 hours. The mixture is filtered and the solvent is evaporated under reduced pressure. The crude reaction product is purified by flash chromatography, elution being carried out with a 9/1 hexane/ethyl acetate mixture. The title compound is obtained. M.p.: 7°-78° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]2[N:9]([CH2:12][CH2:13][N:14]=[N+:15]=[N-:16])[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[N:14]([CH2:13][CH2:12][N:9]1[C:8]2[CH:17]=[CH:18][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[CH:10]1)=[N+:15]=[N-:16]
Reactant: COC(=O)c1ccc2c(c1)ncn2CCN=[N+]=[N-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=NCCn1cnc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
To a solution of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid methyl ester (5.0 g, 0.0204 mol) in THF/water 1:1 (100 mL) was added with stirring LiOH (0.73 g, 0.0306 mol) and the mixture was stirred for 5 h at ambient temperature. The solvent was evaporated and to the residue was added ice water (100 mL). The pH of the reaction mixture was adjusted to 5 with 1N HCl and the mixture extracted with EtOAc (5×100 mL). The combined organic phases were washed with saturated brine solution (100 mL), dried (Na2SO4) and the solvent evaporated affording 4.2 g (89%) of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid as an ash coloured solid. MS-ESI m/z 232 (M+1); 1H NMR (300 MHz, DMSO-d6) δ 3.8 (t, 2H), 4.5 (t, 2H), 7.8 (d, 1H), 7.9 (d, 1H), 8.25 (s, 1H), 8.4 (s, 1H).
Reaction SMILES: B.C1C[O:5]CC1.[CH3:7][O:8][CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][O:10]1>C1COCC1>[CH3:7][O:8][CH:9]1[O:10][CH2:11][CH:12]([OH:5])[CH2:13][CH2:14]1
Reactant: C1CCOC1
Reactant: COC1CCC=CO1
Agent: B
Product: COC1CCC(O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 217.7 %

Procedure:
Borane-THF 1M (14.6 ml, 14.6 mmol) was added slowly to an ice cooled solution of 3,4-dihydro-2-methoxy-2H-pyran (55.0 g, 44 mmol) in THF (15 ml). The ice bath was removed and the reaction was stirred at room temperature for 1 h, cooled to 0° C. and 3 N sodium hydroxide (14.6 ml) was added followed with 30% hydrogen peroxide (9 ml). This was allowed to stir for 4 hs warming to room temperature. The reaction was extracted with ethyl acetate (2×50 ml). The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 6-methoxytetrahydro-2H-pyran-3-ol (4.2 g, 72%) as an oil.
Reaction SMILES: [Cl-].[CH3:2][C:3]1([CH3:10])[O:7][C@@H:6]([CH2:8][NH3+:9])[CH2:5][CH2:4]1.[Br:11][C:12]1[CH:17]=[CH:16][N:15]2[C:18]([C:21]([NH:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=3[F:33])[C:27](O)=[O:28])=[O:22])=[CH:19][N:20]=[C:14]2[CH:13]=1>>[Br:11][C:12]1[CH:17]=[CH:16][N:15]2[C:18]([C:21]([NH:23][C:24]3[CH:25]=[C:26]([C:27](=[O:28])[NH:9][CH2:8][C@@H:6]4[CH2:5][CH2:4][C:3]([CH3:10])([CH3:2])[O:7]4)[CH:30]=[CH:31][C:32]=3[F:33])=[O:22])=[CH:19][N:20]=[C:14]2[CH:13]=1
Reactant: O=C(O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Reactant: CC1(C)CC[C@H](C[NH3+])O1
Agent: [Cl-]
Product: CC1(C)CC[C@@H](CNC(=O)c2ccc(F)c(NC(=O)c3cnc4cc(Br)ccn34)c2)O1

Procedure:
The title compound was prepared from (R)-(5,5-dimethyltetrahydrofuran-2-yl)methanaminium chloride (Intermediate 9B) and 3-(7-Bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluoro benzoic acid (prepared by hydrolysis of methyl 3-(7-bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluorobenzoate (Intermediate 1A) using NaOH) analogously to Example 7.4 step 1;