Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][C@H:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:19][CH:20]=O)[CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].Cl.[NH:31]1[CH2:34][CH:33]([OH:35])[CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][C@H:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:19][CH2:20][N:31]2[CH2:34][CH:33]([OH:35])[CH2:32]2)[CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: OC1CNC1
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C[C@@H](CCN1CC(O)C1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Reaction time: 0.67 h
Yield: 80.1 %

Procedure:
3-Cyano-N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methyl-1-naphthamide (see WO 00/02859; 1.0 g, 2.3 mmol) was dissolved in CH2Cl2 (10 mL) and to the resultant solution were added azetidin-3-ol hydrochloride (0.24 g, 2.2 mmol) and triethylamine (0.30 mL, 2.2 mmol). After stirring for 40 min, sodium triacetoxyborohydride (0.65 g, 3.1 mmol) was added and the solution was stirred at room temperature for 3 h. The solvent was removed by evaporation and the residue was partitioned between saturated aqueous NaHCO3 solution and ethyl acetate. The solvent was removed by evaporation and the residue was dissolved in hydrochloric acid (1M). The solution was washed with CH2Cl2, alkalised with aqueous NaOH (2M) and then extracted with CH2Cl2. The solvent was removed by evaporation and there was obtained 0.85 g (80%) of 3-cyano-N-[(2S)-2-(3,4-dichlorophenyl)-4-(3-hydroxyazetidin-1-yl)butyl]-N-methyl-1-naphthamide as a white solid. 1H NMR (400 MHz, DMSO-d6): 0.8-4.4 (cm, 16H), 6.4-8.2 (cm, 8H), 8.6 (d, 1H); LCMS: m/z 482 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][NH2:10].[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20](O)=[O:21])=[CH:19][N:14]2[CH:13]=1>>[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20]([NH:10][CH2:9][C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:21])=[CH:19][N:14]2[CH:13]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: NCc1c(F)cccc1Cl
Product: O=C(NCc1c(F)cccc1Cl)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (2-chloro-6-fluorophenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccccc1F
Reaction time: 1 h

Procedure:
0.063 mL of triethylamine and 0.040 mL of 2-fluorobenzoyl chloride were added to 3.0 mL of Methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-phenylbenzoate at room temperature sequentially and stirred at the same temperature for 1 hour. 0.51 g of aminomethylated polystyrene was added to the reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(2-fluorobenzamido)-4-phenylbenzoate.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl>C(O)C.[Pd]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(N(C)C)cc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)N1CCC(Cc2ccc(N(C)C)cc2)CC1
Reaction time: 48 h
Yield: 74.9 %

Procedure:
In 100 mi of ethanol was dissolved 5.49 g of the 1-acetyl-4-(4-dimethylaminobenzoyl)piperidine (Compound No. 4) prepared in Example 4, followed by addition of concentrated hydrochloric acid (2 ml). Using 10% palladium-on-carbon as the catalyst, catalytic reduction was carried out at atmospheric temperature and pressure for 48 hours. After completion of the reaction, the solvent was distilled off and the residual oil was dissolved in ethyl acetate (100 ml). The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residual oil was subjected to silica gel column chromatography (eluent: methanol:dichloromethane=1:19, v/v) to give 3.9 g of the title compound as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](=[O:22])[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[OH-].[Li+].O>C(O)C>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:22])[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Temperature: 50 °C
Yield: 104.2 %

Procedure:
A mixture of 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid methyl ester (380 mg, 1.21 mmol, Eq: 1.00) and lithium hydroxide (3.8 ml, 3.8 mmol, Eq: 3.14) in ethanol (7.6 ml) was heated to 50° C. for 72 h in a sealed tube. Then water was added and the mixture was extracted with diethylether (3×). The pH of the aqueous layer was then adjusted to 1 by addition of 1N HCl and the mixture was extracted with ethyl acetate (3×). The combined ethyl acetate extracts were washed with brine, dried with Na2SO4 and evaporated to yield the title compound (378 mg) as off-white solid. MS (ESI): 300.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[C:3]=1[CH3:20].[CH3:21][C:22]1([CH3:37])[C:26]2=[N:27][CH:28]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:30]=[C:25]2[NH:24][CH2:23]1>C1(C)C=CC=CC=1>[CH3:21][C:22]1([CH3:37])[C:26]2=[N:27][CH:28]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:30]=[C:25]2[N:24]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[C:3]=2[CH3:20])[CH2:23]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1Br
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 1-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)pyrrolidin-2-one (55.0 mg, 0.160 mmol) and 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine in toluene to give 1-(4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-quinolinyl)-2-pyrrolidinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.67 (1H, d, J=2.3 Hz), 7.54 (1H, ddd, J=9.2, 2.4, 1.3 Hz), 7.05 (1H, ddd, J=12.3, 8.6, 2.5 Hz), 6.14 (1H, d, J=2.2 Hz), 4.26-4.41 (1H, m), 4.07-4.12 (1H, m), 4.04 (1H, d, J=9.2 Hz), 3.69-3.83 (5H, m), 3.12-3.18 (4H, m), 2.63-2.71 (2H, m), 2.27-2.40 (2H, m), 2.18 (3H, s), 1.70 (3H, s), 1.67 (3H, s). Mass Spectrum (ESI) m/e=494.2 (M+1).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:17])[CH:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH:18](=O)[CH2:19][CH2:20][CH3:21]>CO>[ClH:1].[CH2:19]([C@H:18]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH2:7][C@@H:5]([C:4]([O:3][CH3:2])=[O:17])[NH:6]1)[CH2:20][CH3:21]
Reactant: CCCC=O
Reactant: COC(=O)C(N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CO
Product: CCC[C@@H]1N[C@H](C(=O)OC)Cc2c1[nH]c1ccccc21
Yield: 38.5 %

Procedure:
A mixture of DL-tryptophan methyl ester hydrochloride (33 g), n-butyraldehyde (21.0 g) and methanol (450 ml) is refluxed for 48 hours. After the reaction, the reaction mixture is concentrated to about 1/3 in volume and allowed to stand. The precipitated crystals are collected by filtration and recrystallized from methanol to give methyl (1RS, 3RS)-cis-1-n-propyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate hydrochloride (15.4 g, 38.4%) as colorless prisms, m.p. 205°-207° C.
Reaction SMILES: [CH2:1]([C@H:4]1[O:6][C@@H:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH3:3].C(=O)([O-])O.[Na+].[C:17](#[N:19])[CH3:18]>>[CH3:18][C:17]1[O:6][C@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C@H:4]([CH2:1][CH2:2][CH3:3])[N:19]=1
Reactant: CC#N
Reactant: CCC[C@H]1O[C@@H]1C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC[C@@H]1N=C(C)O[C@@H]1C(=O)OCC
Temperature: 5 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
Acetonitrile (5 ml) was added to ethyl (2S,3R)-3-propyl-2-oxiranecarboxylate (0.8 g, 5 mmol). The mixture was cooled to 5° C., and boron trifluoride diethyl ether complex (0.4 g, 5.5 mmol) was gradually added dropwise thereto. The mixture was stirred at room temperature for 6 hours, and then saturated aqueous solution of sodium hydrogencarbonate (15 ml) was added thereto. The mixture was concentrated, and was extracted with ethyl acetate (20 ml). The organic layer was washed twice with water (10 ml), and the solvent was evaporated away under reduced pressure. The concentrated matter was purified by silica gel column chromatography to obtain the title compound as a colorless oil (0.69 g, yield: 65%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:46])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][O:38]C3CCCCO3)[CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:46])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][OH:38])[CH:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-(dimethyl-amino)-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M284) (0.46 g, 0.70 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[F:13][C:14]1[C:15](/[CH:20]=[N:21]/[S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])=[N:16][CH:17]=[CH:18][CH:19]=1.CCOC(C)=O>C1COCC1>[F:13][C:14]1[C:15]([C@H:20]([C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)[NH:21][S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ncccc1F
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F
Reaction time: 4 h

Procedure:
To a stirred suspension of magnesium (170 g, 2365 mmol) in THF (1.35 L), was added 4-bromobenzotrifluoride (532 g, 2365 mmol). Stirring was continued for 4 h (cautious: slightly exothermic, cooled with a water bath if needed). The solution was cannulated to a stirred solution of (S,E)-N-((3-fluoro-pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (270 g, 1182 mmol) in THF (1.3 L) at −78° C. dropwise. Stirring was continued for 1 h. The progress of reaction was monitored by TLC (50% EtOAc in petroleum ether). After completion of the reaction, the reaction mixture was quenched with saturated aqueous NH4Cl (2.5 L), and the solution extracted with Et2O (5×500 mL). The organic layers were combined, dried over Na2SO4, concentrated, and purified by column chromatography using silica (100-200 mesh) with 25-30% EtOAc in petroleum ether as eluent to give (S)—N—((S)-(3-fluoropyridin-2-yl)(4(trifluoro-methyl)phenyl)methyl)-2-methylpropane-2-sulfinamide as a brown oil. 1H-NMR (400 MHz, CDCl3): δ ppm 8.45 (d, J=3.6 Hz, 1H), 7.73-7.78 (m, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.63 (m, 2H), 7.43-7.48 (m, 1H), 6.23 (d, J=6.8 Hz, 1H), 5.99 (d, J=6.8 Hz, 1H), 1.36 (s, 9H). MS (ESI pos. ion) m/z: 375.1 (M−O and t-Bu).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][CH2:7][CH:8]([CH2:42][OH:43])[CH2:9][CH2:10][N:11]1[C:19](NC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:18][C:17]2[C:12]1=[N:13][C:14](OC)=[N:15][CH:16]=2.C(=O)(O)[O-].[Na+].[N:49]1C=CC=CC=1>O>[NH2:49][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][OH:6])[CH2:42][OH:43])=[CH:16][N:15]=1
Reactant: COc1ncc2nc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n(CCC(CO)CO)c2n1
Reactant: c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ncc2ncn(CCC(CO)CO)c2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled solution of phosphorus oxychloride (93 μl, 1.0 mmol) in pyridine (2 ml) was added dropwise over 45 minutes a solution of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)-2-monomethoxytritylaminopurine (0.46 g, 0.9 mmol) in pyridine (4 ml). The solution was stirred for a further 20 minutes at room temperature and was then added dropwise to a solution of sodium bicarbonate (0.34 g, 4.0 mmol) in water (6 ml). The solvent was removed and the residue was taken up in 80% acetic acid (9 mm) and the solution was stirred at 70° for 25 minutes. The solvent was removed and the residue was taken up in water and brought to PH 6 by addition of ammonia. The solution was extracted twice with chloroform and the solvent was removed. The residue was purified by preparative high pressure liquid chromatography on a C18 reverse-phase μ-Bondapack column eluting with 4% methanol in ammonium acetate buffer (pH 4.5, 50 mM) to afford 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl) purine 4':4"-phosphate as a white powder (225 mg, 75%); λmax (H2O) 220, 242, and 303 nm; νmax (KBr) 2900-3200 (br), 1705, 1615, and 1580cm-1 ; &H [(CD3)SO] 1.63 (1H, m, 3'-H), 1.74 (2H, q, J 7.OHz, 2'-H), 3.80 (2H, q, J 9.2Hz, 2×Hax), 3.98 (2H, ddd, J 14.3, 10.9, and 3.5Hz, 2×Heq), 4.08 (2H, t, J 7.1 Hz, 1'-H), 6.51 (2H, s, D2O exchangeable, 2-NH2), 8.10 (1H, s, 8-H), and 8.56 (1H, s, 6-H); (Found: C, 36.41; H, 5.18; N, 22.38%. C10H14N5O4P . 0.3 NH3. 1.5H2O requires C, 36.25; H, 5.45; N, 22.40%).
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15]O)=[NH:5].N[N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[N:20]=[C:19]1[NH2:31]>C(O)(C)C>[ClH:1].[ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15][N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[N:20]=[C:19]1[NH2:31])=[NH:5]
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Reactant: COc1cccc(-c2cn(N)c(N)n2)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cccc(-c2cn(N=C3CCc4c(C(=N)NO)cccc43)c(N)n2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
6.0 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) are added, with stirring, to a mixture of 4.1 g (0.02 mol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 4.08 g (0.02 mol) of 1,2-diamino-4-(3-methoxyphenyl)-imidazole and 100 ml of isopropanol, and the reaction mixture is stirred at 80° C. for 18 hours. The reaction mixture is filtered while hot and the filtration product is washed with isopropanol and dried. In that manner there is obtained the title compound, m.p. 257°-259° C., 1H-NMR (DMSO/D2O): δ=8.24 (d, 1H); 7.91 (s, 1H); 7.75 (d, 1H); 7.61 (t, 1H); 7.38 (t, 1H); 7.25 (m, 2H); 6.95 (m, 1H); 3.76 (s, 3H), 3.27 (s, 4H).
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.FC(F)(F)S(O)(=O)=O.[SH:51][C@@H:52]1[CH2:56][N:55]([C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=2)=[O:58])[C@H:54]([CH:70]2[CH2:74][CH2:73][N:72]([CH3:75])[CH2:71]2)[CH2:53]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:51][C@@H:52]3[CH2:56][N:55]([C:57]([O:59][CH2:60][C:61]4[CH:62]=[CH:63][C:64]([N+:67]([O-:69])=[O:68])=[CH:65][CH:66]=4)=[O:58])[C@H:54]([CH:70]4[CH2:74][CH2:73][N:72]([CH3:75])[CH2:71]4)[CH2:53]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: CN1CCC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Agent: O=S(=O)(O)C(F)(F)F
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CCN(C)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 74.5 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (680 mg, 1.14 mmol) and (2S,4S)-4-mercapto-2-(N-methylpyrrolidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethane sulfonate (650 mg, 1.26 mmol, compound of Reference Examples 6-9) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-(N-methylpyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (603 mg, yield: 74.3%).
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][CH2:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:7]([C:17]([O:19]C)=[O:18])[CH2:6]1.[Li+].[OH-].Cl>C1COCC1.CO>[C:13]([O:12][C:10]([N:8]1[CH2:9][C@@H:5]([CH2:4][O:3][CH:2]([F:1])[F:21])[CH2:6][C@H:7]1[C:17]([OH:19])=[O:18])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)[C@@H]1C[C@H](COC(F)F)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](COC(F)F)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-((difluoromethoxy)methyl)pyrrolidine-1,2-dicarboxylate (2.41 g, 7.79 mmol) in a mixture of THF (39 mL) and MeOH (15.6 mL) was added LiOH (2.5 M aqueous, 15.6 mL, 38.9 mmol). The resulting solution was stirred at room temperature for 1 h. Upon completion by TLC the reaction mixture was acidified with aqueous HCl (1N). The desired product was extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4 and concentrated to provide (2S,4S)-1-(tert-butoxycarbonyl)-4-((difluoromethoxy)methyl)pyrrolidine-2-carboxylic acid (2.4 g, 99%). MS (ESI) m/z 294.96 [M−H]−. 1H-NMR: 400 MHz, (acetone-d6) δ (mixture of rotamers): 6.50 (t, 1H), 4.36-4.17 (m, 1H), 3.93 (d, 2H), 3.77-3.67 (m, 1H), 3.63-3.59 (m, 1H), 3.26-3.12 (m, 1H), 2.72-2.41 (m, 2H), 1.89-1.73 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: Cl[C:2]([F:19])([F:18])[CH2:3][O:4][C:5]([F:17])([F:16])[C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].[OH-].[K+]>CS(C)=O>[F:18][C:2]([F:19])=[CH:3][O:4][C:5]([F:16])([F:17])[C:6]([F:14])([F:15])[C:7]([F:12])([F:13])[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(Cl)COC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: FC(F)=COC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 81.9 %

Procedure:
A mixture of perfluorobutyl 2-chloro-2,2-difluoroethyl ether (42.2 g), KOH (50.0 g) and DMSO (0.5 ml) was heated to distill the product bp <68° C. The product was redistilled to give 30.8 g of perfluorobutyl 2,2-difluorovinyl ether, bp 65° C., yield 82%. 19 F NMR (CDCl3) −81.5 (t, J=10 Hz, 3 F), −86.8 (s, 2 F), −91.0 (ddt, J=52, 13, 3 Hz, 1 F), −108.7 (dd, J=52.4 Hz, 1 F), −126.6 (m, 2 F), −127.1 (m, 2 F) ppm. 1 H NMR (CDCl3) 6.14 (dd, J=13, 4 Hz) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:15]2[C:14](=[O:17])[N:11]3[N:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:10]3=[N:16]2)=[CH:29][CH:28]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 90 °C
Yield: 27.7 %

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (300 mg, 0.84 mmol), prepared as described in Example 1, 4-(trifluoromethyl)benzyl bromide (200 mg, 0.84 mmol) and K2CO3 (290 mg, 2.1 mmol) in DMF (10 ml), was heated at 90° C. for 2 hours. After this time, the reaction mixture was cooled to RT and diluted with ethyl acetate. The resultant solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative HPLC to give the title compound, 2-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (120 mg, 28%) as a yellow solid. MS M+H=515; 1H NMR (CDCl3) δ 8.19 (1H), 7.60 (2H), 7.50 (2H), 7.34 (4H), 7.28 (2H), 7.10 (2H), 5.27 (2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[Cl:29][CH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>O1CCCC1>[Cl:29][CH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([NH:9][C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:13]=[CH:12][N:11]=3)[CH:3]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CCl)cc1
Reaction time: 0.5 h
Yield: 114.4 %

Procedure:
N-(3-amino-4-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (11 g, 39.8 mmol) was dissolved in tetrahydrofuran (100 ml), triethylamine (8.3 ml, 59.5 mmol) was added thereto, and the mixture was stirred for 30 minutes. 4-Chloromethyl benzoyl chloride (2.03 g, 10.78 mmol) was added, and the resulting mixture was reacted under reflux for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated and crystallized from methylene chloride to give N-(5-(4-chloromethylbenzoylamino)-4-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (5.3 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][N:13]=1)[C:7]([O:9]C)=O)([O-:3])=[O:2].[CH2:14]([NH2:16])[CH3:15]>>[CH2:14]([NH:16][C:7](=[O:9])[C:6]1[CH:11]=[CH:12][N:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:15]
Reactant: COC(=O)c1ccnc([N+](=O)[O-])c1
Reactant: CCN
Product: CCNC(=O)c1ccnc([N+](=O)[O-])c1

Procedure:
A mixture of 500 mg. of methyl 2-nitroisonicotinate and 2 ml. of 70% ethylamine was stirred at room temperature for 5 hours. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, dried and then the solvent was distilled off. The crystalline residue was recrystallized from ethyl acetate - n-hexane to give 328 mg. of the desired product.