Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[N:5].BrCC1C=CC=C(C#N)C=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2([C:28]3=[CH:29][C:30]4[O:34][CH2:33][O:32][C:31]=4[CH:35]=[C:27]3[O:26][CH2:25]2)[C:17]1=[O:36].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[O:36]=[C:17]1[C:18]2([C:28]3=[CH:29][C:30]4[O:34][CH2:33][O:32][C:31]=4[CH:35]=[C:27]3[O:26][CH2:25]2)[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]1[CH2:2][CH2:3][C:4]#[N:5]
Reactant: N#CCCBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: N#Cc1cccc(CBr)c1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: N#CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 44 and making non-critical variations using 3-bromopropionitrile to replace α-bromo-m-tolunitrile, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propanenitrile was obtained (86%) as a colorless solid: mp 200-202° C.; 1H NMR (300 MHz, DMSO-d6) δ7.32 (ddd, J=7.6, 7.4, 1.2 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.15 (d, J=6.7 Hz, 1H), 7.04 (ddd, J=7.4, 7.4, 1.0 Hz, 1H), 6.66 (s, 1H), 6.24 (s, 1H), 5.89 (d, J=2.2 Hz, 2H), 4.69 (ABq, J=9.3 Hz, 2H), 4.10-3.88 (m, 2H), 2.95 (t, J=6.5 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.1, 155.8, 148.8, 142.2, 141.9, 132.3, 129.3, 124.1, 123.7, 120.1, 119.1, 109.8 103.6, 101.9, 93.7, 80.3, 57.9, 35.9, 16.2; MS (ES+) m/z 335.1 (M+1).
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]3[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=3[CH3:13])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1oc(C(=O)O)cc1COc1ccc(I)cc1
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2ccc(F)cc2)cc1

Procedure:
Compound (118) was prepared from compound (26) and (4-fluoro-phenyl)-boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt=1.79 mins, m/z (ES−)=325 (M−H for C19H15FO4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]1[NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH2:51][CH:50]([C:54](O)=[O:55])[CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42].C(Cl)CCl>C(Cl)Cl.O>[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH2:51][CH:50]([C:54]([N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:15]4[NH:16][C:17]5[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=5[N:19]=4)[CH:4]=3)[CH2:9][CH2:10]2)=[O:55])[CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: Clc1ccc(N2CCCNCC2)cc1-c1nc2ccccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCCN(c3ccc(Cl)c(-c4nc5ccccc5[nH]4)c3)CC2)C1
Temperature: 20 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
2-(2-Chloro-5-[1,4]diazepan-1-yl-phenyl)-1H-benzoimidazole (0.25 g, 0.76 mmol), HOBt (0.12 g, 0.86 mmol), NMM (0.5 mL, 3.9 mmol), piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (0.17 g, 0.76 mmol), and EDC (0.22 g, 1.16 mmol) were dissolved in DCM (8.0 mL) and stirred at 20° C. for 16 h. Water (6.0 mL) was added. Organic layer was separated, concentrated under reduced pressure and crude was purified by flash chromatography (eluent: 100% of AcOEt) to afford 0.25 g of the title compound. (100%).
Reaction SMILES: [CH:1]1[C:6](C(F)(F)F)=[CH:5][C:4](Cl)=[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+]([O-])=O)=[C:15](C([O-])=O)[CH:14]=2)[CH:2]=1.[Na+].COC(C1C=C(OC2C=CC(Cl)=CC=2Cl)C=CC=1[N+]([O-])=O)=O.CCOC1C=C(OC2C=CC(C(F)(F)F)=CC=2Cl)C=CC=1[N+]([O-])=O.CCOC(C(OC(C1C=C(OC2C=CC(C(F)(F)F)=CC=2Cl)C=CC=1[N+]([O-])=O)=O)C)=O.CS(NC(C1C=C(OC2C=CC(C(F)(F)F)=CC=2Cl)C=CC=1[N+]([O-])=O)=O)(=O)=O.COC1C=C(OC2C=CC(Cl)=CC=2Cl)C=CC=1[N+]([O-])=O.C1C=CC(OC2C=CC([N+]([O-])=O)=C(N)C=2Cl)=CC=1>>[C:13]1([O:12][C:3]2[CH:2]=[CH:1][CH:6]=[CH:5][CH:4]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C([O-])c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: CCOC(=O)C(C)OC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: CCOc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: COC(=O)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Product: c1ccc(Oc2ccccc2)cc1

Procedure:
Acifluorfen-sodium, bifenox, oxyfluorfen, lactofen, fomesafen, chlomethoxynil, and aclonifen.
Reaction SMILES: [C:1](=[O:4])([O-])[NH2:2].N[C@H:6]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:7][N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=2[F:23])=[C:11]([CH3:24])[N:10](CC2C(C(F)(F)F)=CC=CC=2F)[C:9]1=[O:37].C([O-])([O-])=O.[K+].[K+].C(=O)=O>O.CN(C=O)C>[F:23][C:16]1[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[C:13](=[O:14])[N:8]([CH2:7][C@H:6]([NH:2][C:1](=[O:4])[C:12]([CH3:15])([CH3:13])[CH3:11])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:9](=[O:37])[NH:10][C:11]=1[CH3:24]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Reactant: NC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(C)[nH]c(=O)n(C[C@H](NC(=O)C(C)(C)C)c3ccccc3)c2=O)c1F
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 70 %

Procedure:
DMF (anhydrous, 70 mL) was added to carbamate residue 3a (7.5 g, 19.7 mmol) and the mixture was cooled to 0° C. t-BOC-(1R)-amino-2-amino-1-phenylethane acetate salt (6.41 g, 21.6 mmol) was added followed by K2CO3 (4.08 g, 29.6 mmol). The mixture was stirred for ˜3 hours (all carbamate 3a (tR=11.5 minute in HPLC method 1) was converted to urea intermediate (tR=10.5 minute in HPLC method 1)). The temperature was raised to 60° C. to control the CO2 release. The mixture was heated for 2-3 hours then 210 mL of water was slowly added over 30-60 minutes maintaining the temperature at 60° C. The slurry was stirred for 30-60 minutes at 50-60° C. and was cooled down to 25° C. over 30-60 minutes. The slurry was filtered and the cake was washed with 210 mL water to remove the residual base. The cake was dried at 10 mm/50° C. to give 6.5 g (70% yield) of off-white fine needle crystal 3b. Alternately, the cake may be washed with acetonitrile/water 2:1 before drying.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[CH2:11][S:10][N:9]=[C:8]([N:13](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:7]3=[N:28][N:29]([CH2:31][C:32]4[C:37]([CH3:38])=[C:36]([O:39][CH3:40])[C:35]([CH3:41])=[CH:34][N:33]=4)[N:30]=[C:5]([C:6]=23)[CH:4]=1.Br[CH2:43][CH2:44][O:45][CH2:46][CH2:47]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:40][O:39][C:36]1[C:35]([CH3:41])=[CH:34][N:33]=[C:32]([CH2:31][N:29]2[N:30]=[C:5]3[CH:4]=[C:3]([CH2:2][N:1]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[C:12]4[CH2:11][S:10][N:9]=[C:8]([NH2:13])[C:7]([C:6]=43)=[N:28]2)[C:37]=1[CH3:38]
Reactant: COc1c(C)cnc(Cn2nc3cc(CN)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1c(C)cnc(Cn2nc3cc(CN4CCOCC4)c4c-3c(n2)C(N)=NSC4)c1C
Temperature: 55 °C
Reaction time: 24 h

Procedure:
A mixture composed of di-tert-butyl {8-(aminomethyl)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 112 (20 mg), 90% bis(2-bromoethyl)ether (10 μl), potassium carbonate (9.5 mg) and acetonitrile (0.3 ml) was heated with stirring at 55° C. for 24 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. Dichloromethane (2 ml) and trifluoroacetic acid (0.5 ml) were added to the resulting residue, and the mixture was stirred at room temperature for four hours. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution was placed into the resulting residue, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel chromatography (chloroform-methanol). The resulting oil was dissolved in dioxane, followed by lyophilization to obtain the title compound (5.6 mg) as an amorphous.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[S:9][CH2:10][CH2:11][S:12][CH:13]=1)[C:5]([OH:7])=O.[NH2:14][CH:15]1[C:36](=[O:37])[N:17]2[C:18]([C:33]([OH:35])=[O:34])=[C:19]([CH2:22][S:23][C:24]3[N:28]([CH2:29][C:30]([OH:32])=[O:31])[N:27]=[N:26][N:25]=3)[CH2:20][S:21][C@H:16]12.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.CC(C)=O>[CH3:1][O:2][N:3]=[C:4]([C:8]1[S:9][CH2:10][CH2:11][S:12][CH:13]=1)[C:5]([NH:14][CH:15]1[C:36](=[O:37])[N:17]2[C:18]([C:33]([OH:35])=[O:34])=[C:19]([CH2:22][S:23][C:24]3[N:28]([CH2:29][C:30]([OH:32])=[O:31])[N:27]=[N:26][N:25]=3)[CH2:20][S:21][C@H:16]12)=[O:7]
Reactant: CON=C(C(=O)O)C1=CSCCS1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)C1=CSCCS1
Reaction time: 0.17 h
Yield: 78 %

Procedure:
Ethyl acetate (15 ml.) and 2-methoxyimino-2-(2,3-dihydro-1,4-dithiin-5-yl)acetic acid (syn isomer) (2.0 g.) were added to the solution at -10° C. to give a solution. On the other hand, a suspension of 7-amino-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.83 g.) in water (40 ml.) was changed to a solution by adding sodium bicarbonate (1.45 g.), and then acetone (40 ml.) was added thereto. After the solution was adjusted to pH7.3, the ethyl acetate solution obtained above was added dropwise thereto over 10 minutes with stirring at -5° to -7° C., during which the pH of the mixture was kept at 6.8 to 7.3 with an aqueous solution of sodium bicarbonate. The mixture was stirred for 1.5 hours at the same temperature. The resultant solution was adjusted to pH7.8 and washed with ethyl acetate (40 ml.). The solution was adjusted to pH6 and washed with ethyl acetate (40 ml.). And the solution was adjusted to pH2 and extracted with ethyl acetate (100 ml.). The extract was washed with a saturated aqueous solution of sodium chloride (60 ml.) and dried over magnesium sulfate. The extract was concentrated in vacuo, and the residue was washed with diethyl ether and collected by filtration to give pale yellow crystals of 7-[2-methoxyimino-2-(2,3-dihydro-1,4-dithiin-5-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (3.4 g.).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:29])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)[O:15][N:14]=2)=[CH:8][C:7]=1[CH3:28].[C:30](O)(=[O:33])[CH2:31][OH:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[OH:33][CH2:30][C:31]([NH:1][CH2:2][CH:3]([OH:29])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[CH:20][CH:19]=3)[O:15][N:14]=2)=[CH:8][C:7]=1[CH3:28])=[O:32]
Reactant: Cc1cc(-c2noc(-c3ccc(OC(C)C)cc3)n2)cc(C)c1OCC(O)CN
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2noc(-c3ccc(OC(C)C)cc3)n2)cc(C)c1OCC(O)CNC(=O)CO
Yield: 20.1 %

Procedure:
A solution of 1-amino-3-{4-[5-(4-isopropoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (277 mg, 0.698 mmol), glycolic acid (80 mg, 1.05 mmol), DIPEA (362 mg, 2.80 mmol) and TBTU (382 mg, 1.19 mmol) in DMF (10 mL) is stirred at rt for 16 h before it is diluted with EA, washed with water, and concentrated. The crude product is purified by chromatography on prep. TLC plates with DCM containing 10% of methanol to give 2-hydroxy-N-(2-hydroxy-3-{4-[5-(4-isopropoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propyl)-acetamide (64 mg) as a pale yellow solid, LC-MS: tR=0.94 min, [M+1]+=456.18, 1H NMR (D6-DMSO): δ 1.30 (d, J=5.9 Hz, 6H), 2.31 (s, 6H), 3.16-3.25 (m, 2H), 3.63-3.79 (m, 2H), 3.81 (d, J=5.6 Hz, 2H), 3.86-3.97 (m, 1H), 4.72-4.83 (m, 1H), 5.28 (d, J=5.3 Hz, 1H), 5.54 (t, J=5.9 Hz, 1H), 7.14 (d, J=9.1 Hz, 2H), 7.68 (t, J=5.6 Hz, 1H), 7.73 (s, 2H), 8.08 (d, J=9.1 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:32]([N:34](CC)[CH2:35]C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CNC>C(Cl)Cl>[CH3:31][O:30][C:28](=[O:29])[CH2:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10](=[O:12])[N:34]([CH3:35])[CH3:32])=[CH:19][CH:18]=2)=[CH:21][CH:22]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)CCc1ccc(-c2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCc1ccc(-c2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
The hydrogenated compound 44 (4.3 g, 10.0 mmol) was dissolved in CH2Cl2 (50 mL) and stirred at room temperature under an atmosphere of argon. Triethylamine (1.68 mL, 12.0 mmol) and BOP reagent (4.9 g, 11.0 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 25.0 mL, 50.0 mmol) was added and the resulting solution was stirred at room temperature for about 2-3 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (100 mL). The organic layer was extracted with 0.5 N NaOH (1×10 mL), water (2×50 mL) and brine (1×50 mL). Drying and concentration of the organic layer gave the desired amide 45 (4.4 g, 96%). 1H NMR (400 MHz, DMSO-d6): 7.56 (overlapped d, J=8.4 Hz, 2H), 7.55 (overlapped d, J=8.4 Hz, 2H), 7.32 (d, J=8.8 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.4 Hz, 1H), 4.58 (m, 1H), 3.60 (s, 3H), 2.94 (s, 3H), 2.89 (t, J=7.6 Hz, 2H), 2.79-2.83 (m, 5H), 2.67 (t, J=7.6 Hz, 2H), 1.31 (s, 9H).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[C:6]([O:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([N:32](CC)[CH2:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:7]=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16].[C:42]([C:44](=CC1C=CC(O)=CC=1)C(O)=O)#N>>[ClH:1].[ClH:1].[CH3:3][C:4]1[CH:5]=[C:6]([O:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:32][CH2:33][C:34]2[C:35]([CH2:42][CH3:44])=[CH:36][N:37]=[CH:38][CH:39]=2)(=[O:30])=[O:31])(=[O:21])=[O:22])[CH:7]=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16]
Reactant: CCN(Cc1ccncc1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Reactant: N#CC(=Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Product: CCc1cnccc1CNS(=O)(=O)c1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Yield: 84 %

Procedure:
{3-[5-Methyl-3-(2-(N-ethyl-N-(4-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy) phenoxy]propoxy}guanidine dihydrochloride: The title compound was prepared in 84% yield from N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-ethyl-N-(4-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy) phenoxy]propoxy}guanidine, as prepared in the preceding step, in a manner analogous to step i of Example 20. 1H-NMR (300 MHz, DMSO-d6) δ 8.54 (d, J=4.5 Hz, 2H), 8.23 (d, J=7.9 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H), 8.01 (t, J=7.7 Hz, 1H), 7.89 (t, J=7.7 Hz, 1H), 7.42 (br s, 4H), 7.34 (d, J=5.8 Hz, 2H), 6.74 (s, 1H), 6.54 (s, 1H), 6.50 (s, 1H), 4.67 (s, 2H), 3.97 (t, J=6.3 Hz, 2H), 3.87 (t, J=6.3 Hz, 2H), 3.36 (t, J=7.1 Hz, 2H), 2.21 (s, 3H), 2.00 (pentet, J=6.1 Hz, 2H), 0.92 (t, J=7.1 Hz, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C25H31N5O7S2: 578.2 (M+H), 600.2 (M+Na), 616.1 (M+K). Found: 578.1, 599.9, 616.0.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[C:4]([F:10])[C:3]=1[Cl:11].[NH3:12]>C(#N)C>[NH2:12][C:6]1[C:7]([F:8])=[C:2]([Br:1])[C:3]([Cl:11])=[C:4]([F:10])[N:5]=1
Reactant: Fc1nc(F)c(Cl)c(Br)c1F
Reactant: N
Solvent: CC#N
Product: Nc1nc(F)c(Cl)c(Br)c1F
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To 20 ml of acetonitrile were added 4.9 g of 4-bromo-3-chloro-2,5,6-trifluoropyridine and 4 ml of 25% aqueous solution of ammonia, and the mixture was stirred at 55° C. for 2 hours. The solvent and the like were distilled off under reduced pressure. 50 ml of chloroform was added to the residue, and the solution was washed with 50 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dispersed in the mixed solution of diisopropylether and n-hexane and collected by filtration to obtain 3.8 g of the title compound as pale yellow needle crystals. 5
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(C)=O>[N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Product: O=Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A mixture of 2-nitro-4-trifluoromethylbenzoyl chloride (8.0 g) and triphenylphosphine (16.5 g) in dry acetone (75 ml) was treated with bis-(triphenylphosphine)tetrahydroboratocopper(I) (19.8 g). The resulting suspension was stirred for 1 hour, filtered and washed with diethyl ether. The filtrate was evaporated to dryness and the resulting residue was subjected to chromatography, eluting with a mixture of diethyl ether and n-hexane (1:5 v/v), to give 2-nitro-4-trifluoromethylbenzaldehyde (5.91 g) in the form of an off-white solid, m.p. 63° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([OH:8])=[N:6][CH:7]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[N:6]([CH3:10])[CH:7]=1
Reactant: Cc1cc(Br)cnc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(Br)cn(C)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 5-bromo-2-hydroxy-3-methyl pyridine A1 (1.000 g; 5.053 mmol) and potassium carbonate (1.397 g; 10.105 mmol) in DMF (5.000 ml) is carefully added iodomethane (0.346 ml; 5.558 mmol). The reaction mixture is stirred overnight (16 h) at room temperature. The reaction mixture is then quenched with 10% ammonia solution (10 ml) and 30 ml water is added. It is extracted with 3×50 ml EtOAc. The combined organic layer is dried with Na2SO4, filtered and concentrated under reduced pressure to afford the product.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:12][C:11]([OH:23])=[C:10]([O:24]C)[C:9]=3[C:8]2=[O:26])=[CH:4][CH:3]=1.Br.C(O)(=O)CC>C(Cl)Cl.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:19])=[O:20])=[N:12][C:11]([OH:23])=[C:10]([OH:24])[C:9]=3[C:8]2=[O:26])=[CH:27][CH:28]=1
Reactant: COc1c(O)nc(N(C)S(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Agent: Br
Solvent: ClCCl
Solvent: CCC(=O)O
Solvent: CC(=O)O
Product: CN(c1nc(O)c(O)c2c1CCN(Cc1ccc(F)cc1)C2=O)S(C)(=O)=O
Reaction time: 1.5 h

Procedure:
To a solution of N-[6-(4-fluorobenzyl)-3-hydroxy-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide (0.0207 g, 0.506 mmol) in CH2Cl2 (6 mL) was added 30% by weight HBr in propionic acid (0.196 g HBr, 2.42 mmol). Alternatively, 30% HBr in acetic acid can be used. After 1.5 hours, the product mixture was evaporated and the residue partitioned between CHCl3 and 10% KHSO4. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum. The residual material was purified using reverse phase HPLC eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compound.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)(C)=O.[CH2:13]([O:15][C:16](=[O:31])[CH:17]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[CH3:14]>O>[CH:17]1([C:16]([O:15][CH2:13][CH3:14])=[O:31])[C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:8]1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 15 °C
Reaction time: 0.33 h
Yield: 54.1 %

Procedure:
Sodium hydride (60% in mineral oil) (2.06 g, 85.8 mmol) was added to dimethylsulfoxide (100 mL) at 15° C., and the mixture was stirred at 15° C. for 20 min. See FIG. 6. Trimethylsulfoxonium iodide (19.0 g, 85.8 mmol) was added, and the reaction mixture was stirred for 2 h, then 165b (7.72 g, 28.7 mmol) was added and the resulting mixture was stirred at 15° C. for 50 h. Water (100 mL) was added, and the mixture was extracted with EtOAc (200 mL×3). The combined organic extracts were washed with brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: EtOAc=2:1) to yield 6-tert-butyl 1-ethyl 6-azaspiro[2.5]octane-1,6-dicarboxylate 165c (4.4 g, 54%) as a colorless oil. 1H NMR (400 MHz, CD3CN): δ 4.06-4.04 (m, 2H), 3.40-3.18 (m, 4H), 1.92-1.90 (m, 1H), 1.59-1.50 (m, 3H), 1.39-1.30 (m, 10H), 1.19-1.16 (m, 3H), 1.03-1.01 (m, 1H), 0.91-0.93 (m, 1H).
Reaction SMILES: [C:1]([N:8]([CH3:16])[C@H:9]([CH2:14][OH:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])(O)=O.[Na+].[K+].[Br-].Cl[O-].[Na+]>ClCCl.O>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]([CH:14]=[O:15])[C@@H:10]([CH3:11])[CH2:12][CH3:13])[CH3:16])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC[C@H](C)[C@@H](CO)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](C=O)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 97.3 %

Procedure:
To a solution of 37.0 g Boc-N-methyl-isoleucinol (160 mmol) in 160 ml dichloromethane was added a solution of 5.4 g NaHCO3 (64 mmol) and 1.9 g KBr (16 mmol) in 160 ml deionized water. The reaction mixture was cooled to 0° C. and after the addition of 125 mg 2,2,6,6-tetramethyl-piperidin-1-oxyl (TEMPO, 0.8 mmol), 122.6 g 10.2% aqueous sodium hypochlorite (176 mmol Cl2) were added under stirring over 2.5 h at 0-5°. After additional stirring for 30 min the excess of NaOCl was destroyed by the addition of ca. 1 ml 38% aqueous sodium bisulfite and the reaction mixture was warmed up to 20°. The aqueous layer was extracted with 160 ml dichloromethane and the organic layers were washed with 10% brine and dried (Na2SO4). Removal of the solvent by rotary evaporation afforded 35.7 g (97.2%) crude product as a light orange oil.