Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:35])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([F:35])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:36])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:26])=[O:27])=[CH:33][CH:32]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccc(Cl)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
Lithium hydroxide monohydrate (0.013 g, 0.30 mmol) was added to a stirred solution of {4-[4-(4-chloro-benzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.037 g, 0.076 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(4-chloro-benzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.035 g, 98%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s., 1 H) 8.14 (d, J=7.82 Hz, 2 H) 8.09 (d, J=8.80 Hz, 2 H) 7.97-8.04 (m, 1 H) 7.90 (s, 1 H) 7.77 (d, J=7.82 Hz, 2 H) 7.53 (d, J=7.83 Hz, 2 H) 7.38 (td, J=8.30, 2.40 Hz, 1 H) 6.63 (d, J=10.76 Hz, 1H) 3.83 (s, 2 H) 2.02 (s, 3 H). MS calcd. for C25H18ClFO4S [(M−H)−] 467, obsd. 467.3.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C@@H:10]([NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[CH3:32][Li]>C1COCC1.C(OCC)C>[OH:3][C:1]([C:4]1[CH:9]=[C:8]([C@@H:10]([NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)([CH3:32])[CH3:2]
Reactant: [Li]C
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C(C)=O)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a chilled (−78°) solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-acetyl-pyridin-4-yl)-propyl]-amide (32 mg, 0.08 mmol) in anhydrous THF (2 mL) was added a solution of 1.6 N methyl lithium (0.29 mL, 0.46 mmol) in diethyl ether. The reaction mixture was slowly warmed to room temperature. After 18 hours, the mixture was cooled to −78° C., quenched with saturated aqueous ammonium chloride and extracted with EtOAc (4×60 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by reversed-phase HPLC (Sunfire PrepC18 OBD 5 μM 30×150 mm column) using a gradient of 15-65% acetonitrile in water with 0.1% TFA. Fractions from the chromatography were concentrated, made basic by saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The solid was triturated with EtOAc-hexanes to afford the title.
Reaction SMILES: FC(F)(F)[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)[S:6][CH:7]=1.C(NC1C=CC([C@@H](C)C(OC)=O)=CC=1)(=S)N.ClCC=O>>[S:6]1[CH:7]=[CH:3][N:4]=[C:5]1[NH:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1
Reactant: C[C@@H](C(=O)O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Agent: COC(=O)[C@H](C)c1ccc(NC(N)=S)cc1
Agent: O=CCCl
Product: C[C@@H](C(=O)O)c1ccc(Nc2nccs2)cc1
Yield: 55 %

Procedure:
The acid was obtained following the same procedure described for (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid and starting from methyl (2R)-2-[4-(carbamothioylamino)phenyl]propanoate (2.0 g, 8.40 mmol) and chloroacetaldehyde (50 wt. % in H2O, 0.54 ml, 8.40 mmol). The following acid hydrolysis afforded the pure (2R)-2-{4-[(1,3-thiazol-2-yl)amino]phenyl}propanoic acid (1.47 g, 5.62 mmol) as pale yellow oil (55%). 1H-NMR (CDCl3): δ 8.30 (bs, 1H, NH), 8.10 (d, 1H, J=2.5 Hz), 7.50 (d, 1H, J=2.5 Hz) 7.40 (d, 2H, J=7 Hz), 7.20 (d, 2H, J=7 Hz), 3.75 (q, 1H, J=7 Hz), 1.50 (d, 3H, J=7 Hz),
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O.[BH4-].[Na+]>CO.C(O)(=O)C>[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH2:34][NH:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Reactant: O=Cc1ncc[nH]1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NCc3ncc[nH]3)s2)cc1C#N
Temperature: 55 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
Prepared using General Procedure 11. To (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (25 mg, 0.06 mmol) and 1H-imidazole-2-carbaldehyde (6.4 mg, 0.06 mmol) in anhydrous MeOH (1 mL) was added acetic acid (1 drop). The solution was stirred at 55° C. for 3 h before cooling to room temperature and the addition of NaBH4 (4.6 mg, 0.12 mmol). The mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (0.5 mL) and partitioned between EA (5 mL) and water (5 mL). The organic layers washed with water and brine, and the product purified by preparative HPLC to afford 22 mg (81%) of (S)-5-(5-(1-(((1H-imidazol-2-yl)methyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 28 as half-white solid. LCMS-ESI (m/z) calculated for C25H24N6OS: 456.2; found 457.2 [M+H]+, tR=2.38 min.
Reaction SMILES: C(N(CC)CC)C.[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9].[CH2:16]([CH:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17]>C(#N)C>[C:8]([C:10](=[C:19]([OH:20])[CH:18]([CH2:22][CH3:23])[CH2:16][CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9]
Reactant: CCOC(=O)CC#N
Reactant: CCC(CC)C(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=C(O)C(CC)CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
With ice-cooling, 227 g (2.15 mol) of triethylamine were poured into a solution of 170 g (1.5 mol) of ethyl cyanoacetate in acetonitrile, and 101 g (0.75 mol) of 2-ethylbutyryl chloride were added dropwise at from 10 to 25° C. After 2 h of stirring at 25° C., the mixture was concentrated and the residue was dissolved in MTBE (methyl tert-butyl ether). By washing with 5% strength NaOH, the enolate was transferred into the aqueous phase, from which it was released by acidification to pH 3. The acidic aqueous solution was extracted and the extract was dried and concentrated. Customary purification gave 100 g (63% of theory) of the title compound as an oil (b.p. 78 to 80° C./1.5 mbar).
Reaction SMILES: [C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])([O:3][CH3:4])=[O:2].C1([Se]Cl)C=CC=CC=1.O.OO>C(OCC)(=O)C.O1CCCC1>[C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[C:7](=[O:12])[CH:8]=[CH:9][CH2:10][CH2:11]1)([O:3][CH3:4])=[O:2]
Reactant: CCC1(CC(=O)OC)CCCCC1=O
Agent: Cl[Se]c1ccccc1
Agent: OO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCC1(CC(=O)OC)CCC=CC1=O
Reaction time: 4 h
Yield: 55.3 %

Procedure:
The ketone, 2-carbomethoxymethyl-2-ethylcyclohexanone (IX) (141 mmol, 28 g) was stirred in 1.25 l of ethyl acetate (dried over 3A molecular sieves) and treated with 169 mmol (32.5 g) of PhSeCl. The reaction was stirred under nitrogen for 4 hours then treated with 250 ml of water. The mixture was shaken vigorously in a separatory funnel and the organic phase was returned to the reaction flask. Tetrahydrofuran (550 ml) was then added followed by 35 ml of 30% H2O2 (aq.) added dropwise. The reaction mixture was stirred for one hour then washed with 500 ml of water and 500 ml of saturated Na2CO3 (aq.). The product was then dried over MgSO4 and concentrated in vacuo. Flash chromatography afforded 15.3 g (78.0 mmol, 55%) of the product as a pale yellow oil. Rf =0.9 in 15% ethyl acetate/petroleum ether on TLC.
Reaction SMILES: CC([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[C:29]([CH3:30])=[N:28][N:27]([CH2:31][CH:32]([OH:44])[C:33]5[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=5)[C:26]4=[O:45])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[C:29]([CH3:30])=[N:28][N:27]([CH2:31][CH:32]([OH:44])[C:33]5[CH:38]=[CH:37][C:36]([O:39][C:40]([F:41])([F:43])[F:42])=[CH:35][CH:34]=5)[C:26]4=[O:45])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[CH:11][CH:12]=1
Reactant: Cc1nn(CC(O)c2ccc(OC(F)(F)F)cc2)c(=O)n1-c1ccc(N2CCN(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(CC(O)c2ccc(OC(F)(F)F)cc2)c(=O)n1-c1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1
Yield: 46 %

Procedure:
A mixture of (±)-4-[4-[4-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-hydroxy-2-[4-(trifluoromethoxy)phenyl]ethyl]-5-methyl-3H-1,2,4-triazol-3-one (0.0043 mol) was dissolved in dichloromethane (100 ml) upon stirring. A solution of tetrabutylammonium fluoride in tetrahydrofuran (0.0045 mol) was added and the mixture was stirred at room temperature for 15 minutes. Water was added and the mixture was stirred for 30 minutes. The precipitate was filtered off, dried and crystallized from n-butanol, yielding 1.1 g (58.2%) of (±)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-[2-hydroxy-2-[4-(trifluoromethoxy)-phenyl]ethyl]-5-methyl-3H-1,2,4-triazol-3-one; mp. 230.6° C. (comp. 36).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([OH:18])[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[Cl:21][C:22]1[C:27]([C@@H:28](O)[CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=1[O:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([O:18][C@@H:28]([C:27]4[C:22]([Cl:21])=[C:23]([O:31][CH:32]5[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]5)[CH:24]=[CH:25][CH:26]=4)[CH3:29])[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(Br)ccc32)cc1O
Reactant: C[C@H](O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Product: COC(=O)c1sc(-n2cnc3cc(Br)ccc32)cc1O[C@H](C)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Yield: 98.1 %

Procedure:
The title compound was prepared from methyl 5-(5-bromo-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxylate (0.64 g, 1.8 mmol) and 1,1-dimethylethyl 4-({2-chloro-3-[(1S)-1-hydroxyethyl]phenyl}oxy)-1-piperidinecarboxylate (0.78 g, 2.2 mmol) using a procedure analogous to Intermediate 2, Step C to give 1.22 g of the desired product. MS (ESI): 692.4 [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](O)=[O:9])[CH:2]=1.N#[N+][O-].Cl.[CH3:16][N:17](C)[OH:18].[CH2:20](Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:20][O:18][N:17]([CH3:16])[C:8](=[O:9])[CH2:7][C:3]1[CH:4]=[CH:5][CH:6]=[C:1]([CH3:11])[CH:2]=1
Reactant: CN(C)O
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: ClCCCl
Agent: Cl
Agent: N#[N+][O-]
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)Cc1cccc(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.6 %

Procedure:
To a solution of m-tolyl acetic acid (2.0 g, 0.013 mol) in DMF (20 mL) were added N2O-dimethyl hydroxylamine hydrochloride (1.6 g, 0.016 mol), EDC (3.06 g, 0.016 mol), HOAt (2.17 g, 0.016 mol), and DIPEA (11.6 mL, 0.067 mol). The resulting solution was stirred at RT for 18 h then was diluted with EtOAc (200 mL) and washed with HCl 1M (100 mL), water (100 mL), sat. sol. NaHCO3 (100 mL), and brine (100 mL). The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title intermediate (2.2 g, 88%) as colorless oil used in the next step without further purification.
Reaction SMILES: [OH-].[Mn+2:2].[OH-].[NH2:4][C@H:5]([C:11]([OH:13])=[O:12])[CH2:6][CH2:7][C:8]([OH:10])=[O:9].CCCCCC>O>[NH2:4][C@H:5]([C:11]([O-:13])=[O:12])[CH2:6][CH2:7][C:8]([O-:10])=[O:9].[Mn+2:2]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: [Mn+2]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Product: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Reaction time: 3 h

Procedure:
The recovered manganese hydroxide was than placed into a beaker provided with a reflux condenser and Dean Stark water trap. 15.5 grams (0.105 Mole) glutamic acid was added. 100 ml hexane was thereafter added and stirred and boiled at atmospheric pressure for 3 hours. During the course of the reaction about 3.6-3.8 ml water was removed from the reaction media and acquired in the Dean Stark apparatus. The reaction mixture was then cooled and filtered yielding 21 grams of manganese glutamate. The product, manganese glutamate, was hygroscopic and requires handling in conditions to avoid absorption of moisture from the air by methods known for those skilled in the art.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].[H-].[Na+].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][CH:13]=1>CN(C=O)C>[O:7]=[C:2]1[CH2:3][CH2:4][C:5](=[O:6])[N:1]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(CBr)cc1
Reactant: O=C1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1Cc1ccc(B(O)O)cc1
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a solution (10 mL) of pyrrolidine-2,5-dione (500 mg) in DMF was added sodium hydride (60% dispersion in mineral oil, 252 mg) at 0° C., and the mixture was stirred for 1 hr. (4-(Bromomethyl)phenyl)boronic acid (903 mg) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and crystallized from ethyl acetate and diisopropyl ether to give the title compound (520 mg).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1>C(O)CCC.O>[CH2:11]([O:12][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1)[CH2:16][CH2:15][CH3:14]
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: O
Product: CCCCOc1nc(N)c2ncn(C3CCCCO3)c2n1

Procedure:
The product from step (i) (40 g) was dissolved in 19% (w/w)-sodium butoxide in butanol (250 ml). The reaction mixture was stirred under reflux for 6 h. The resultant suspension was cooled to rt, diluted with water and extracted with diethyl ether. The combined organic phase was washed with water, dried and concentrated in vacuo. The subtitle compound was crystallized from diethyl ether/isohexane (1/1, 300 ml) and obtained by filtration. Yield 19 g.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=3[O:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:14]1[C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:21][CH:22]=3)[O:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2oc(-c3ccc(OCCN4CCCC4)cc3)c(-c3ccccc3)c12
Product: Clc1ncnc2oc(-c3ccc(OCCN4CCCC4)cc3)c(-c3ccccc3)c12

Procedure:
Compound 26 (60 mg, 0.149 mmol) was refluxed in phosphorous oxychloride (2 mL) for 1 h. The reaction mixture was concentrated and diluted with ice-cold water, brought to pH ˜8 with slow addition of saturated NaHCO3 and extracted with dichloromethane. The organic layer was dried over Na2SO4 and concentrated to afford 27, which was used in Step 3 without purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(O)(C(F)(F)F)=O.[CH:35]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45](=[O:50])[CH2:46][C:47](=O)[CH3:48])=[CH:41][CH:40]=1)([CH3:37])[CH3:36]>>[CH:35]([O:38][C:39]1[CH:40]=[CH:41][C:42]([C:45](=[O:50])/[CH:46]=[C:47](\[NH:1][C@@H:2]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:9][CH:8]=2)[C:3]([OH:5])=[O:4])/[CH3:48])=[CH:43][CH:44]=1)([CH3:37])[CH3:36]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC(=O)CC(=O)c1ccc(OC(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C/C(=O)c1ccc(OC(C)C)cc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 435 mg (0.91 mmol) of Intermediate 45 (as the TFA salt) and 200 mg (0.91 mmol) of Intermediate 29 to yield 125 mg of Example 27 as a beige glassy solid: TLC (DCM/MeOH (4:1): Rf=0.50; 1H NMR (DMSO-d6, 400 MHz) δ11.29 (d, 1H, J=8.8), 7.88 (m, 2H), 7.70 (d, 2H, 8.8), 7.48 (m, 3H), 7.09 (d, 2H, J=8.0), 6.85 (d, 2H, J=8.8), 6.78 (d, 2H, J=8.0), 5.46 (s, 1H), 4.62 (septuplet, 1H, J=6.4), 4.12 (t, 2H, J=6.4), 4.0 (m, 1H), 3.14 (m, 2H), 2.87 (t, 2H; J=6.4), 2.70 (dd, 1H, J=13.2, 9.6), 2.31 (s, 3H), 1.61 (s, 3H), 1.21 (d, 6H, J=6.4); low resolution MS (ES+)m/e 569 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:27])=[C:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=3[O:21][CH2:22][C:23]([F:26])([F:25])[F:24])C=O)[CH:11]=2)[C:6]([CH3:29])([CH3:28])[CH2:5][C:4]1=[O:30])[CH3:2].[CH2:31]([CH:33](P(O)(O)=O)/[C:34](/CC)=[C:35](\CC)/[C:36]([O-:38])=[O:37])C>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:27])=[C:10]([C:13]3[CH:14]=[C:15]([CH:31]=[CH:33][CH:34]=[CH:35][C:36]([OH:38])=[O:37])[CH:18]=[CH:19][C:20]=3[O:21][CH2:22][C:23]([F:26])([F:24])[F:25])[CH:11]=2)[C:6]([CH3:29])([CH3:28])[CH2:5][C:4]1=[O:30])[CH3:2]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OCC(F)(F)F)cc21
Reactant: CC/C(C(=O)[O-])=C(/CC)C(CC)P(=O)(O)O
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=CC=CC(=O)O)ccc3OCC(F)(F)F)cc21

Procedure:
Compound 23 was prepared from Compound 1D using procedures similar to those described for Example 20B and 20C, except using triethyl-4-phosphonocrotonate in step 20B. MS (electrospray): mass calculated for C27H28F3NO4, 487.20; m/z found 488.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([N+:13]([O-:15])=[O:14])=[C:4](Cl)[N:3]=1.[CH:17]1([C:20]2[NH:24][N:23]=[C:22]([NH2:25])[CH:21]=2)[CH2:19][CH2:18]1.O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([NH:25][C:22]2[CH:21]=[C:20]([CH:17]3[CH2:19][CH2:18]3)[NH:24][N:23]=2)[N:3]=1
Reactant: CCOC(=O)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(Cl)nc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a THF (20 ml) solution of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (1.0 g, 3.80 mmol) was slowly added the 5-cyclopropyl-1H-pyrazol-3-amine (0.48 g, 3.85 mmol) in THF (5 ml) at 0° C. The reaction was stirred at 0° C. for 10 minutes, treated with water (50 ml), and then extracted with DCM (3×50 ml), dried, filtered, and concentrated to give the title compound (1.2 g). MS: Calcd.: 352; Found: [M+H]+ 353.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].CS[C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20].[C:24](#[N:26])C>>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:17]([NH:26][CH3:24])=[CH:18][N+:19]([O-:21])=[O:20])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CC#N
Reactant: N=C(N)Nc1nc(CCCCN)cs1
Product: CNC(=C[N+](=O)[O-])NCCCCc1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 2-guanidino-4-(4-aminobutyl)thiazole (0.43 g.) and 1,1-di(methylthio)-2-nitroethylene (0.33 g.) in acetonitrile (15 ml.) was heated under reflux for 1 hour. The mixture evaporated to dryness and 33% w/v ethanolic methylamine (200 ml.) added. The mixture was stirred for 5 days at room temperature, then filtered and the filtrate evaporated to dryness. The residue was crystallized from ethanol to give 1-[4-(2-guanidinothiazol-4-yl)butylamino]-1-methylamino-2-nitroethylene, m.p. 225° C. (decomposed).
Reaction SMILES: C(OCC)(=O)C.Cl(O)(=O)(=O)=O.Cl([O-])(=O)(=O)=O.[CH3:17][CH:18]1[CH2:27][C:26]2[CH:25]=[C:24]3[O:28][CH2:29][O:30][C:23]3=[CH:22][C:21]=2[CH:20]([C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)[OH+:19]1.[NH:40]([C:42]1[N:47]=[CH:46][CH:45]=[CH:44][N:43]=1)[NH2:41]>C(O)(C)C>[N+:37]([C:34]1[CH:35]=[CH:36][C:31]([C:20](=[N:41][NH:40][C:42]2[N:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[C:21]2[C:26]([CH2:27][CH:18]([OH:19])[CH3:17])=[CH:25][C:24]3[O:28][CH2:29][O:30][C:23]=3[CH:22]=2)=[CH:32][CH:33]=1)([O-:39])=[O:38]
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)[OH+]1)OCO3
Reactant: NNc1ncccn1
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(O)Cc1cc2c(cc1C(=NNc1ncccn1)c1ccc([N+](=O)[O-])cc1)OCO2
Yield: 64 %

Procedure:
A stirred mixture of 3.29 g (9.99 mmol) of (±)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochroman-5-ol, 40 ml of ethyl acetate and 1.0 ml (1.15 mmol) perchloric acid was refluxed for 1 h. After cooling the precipitated (±)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isochromen-6-ylium perchlorate was filtered off, and it was stirred at reflux temperature with 1.6 g (14.55 mmol) of 2-hydrazinopyrimdine in 50 ml of isopropanol for 2 h, then concentrated. The residue was dissolved in dichloromethane and washed several times with water. After drying and evaporation the crude product was purified by column chromatography using silica gel (MN Kieselgel 60) as adsorbent and a mixture of toluene-ethyl acetate (0.1:4) as eluent to yield 2.71 g (64%) of the title compound; Mp.: 125-127° C.