Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[N:24]([CH2:27][CH3:28])=[C:25]=[O:26]>ClCCl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([C:25](=[O:26])[NH:24][CH2:27][CH3:28])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: CCN=C=O
Reactant: COC(=O)Cc1cc(OC2CCNCC2)c2cc(F)ccc2c1
Solvent: ClCCl
Product: CCNC(=O)N1CCC(Oc2cc(CC(=O)OC)cc3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
A mixture of [6-fluoro-4-(piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (the intermediate for example 4-1, 1st step, 20 mg, 0.063 mmol) and isocyanato-ethane (0.05 mL) and dichloromethane was stirred at room temperature for 4 hours. The resulting mixture was concentrated in vacuo. The residue was purified by flash column (gradient elution with 0-30% ethyl acetate in petroleum ether) to afford [4-(1-ethylcarbamoyl-piperidin-4-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid methyl ester (21.0 mg, 85%) as a viscous oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:22])=[C:14]([C:19]([NH2:21])=[O:20])[C:15]([F:18])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:23]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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.O>[F:22][C:13]1[C:12]([O:11][CH2:10][C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)=[CH:23][C:6]=3[N:7]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:14]=1[C:19]([NH2:21])=[O:20]
Reactant: OB(O)c1ccncc1
Reactant: NC(=O)c1c(F)ccc(OCc2nc3cc(Br)ccc3s2)c1F
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: C1COCCO1
Solvent: O
Product: NC(=O)c1c(F)ccc(OCc2nc3cc(-c4ccncc4)ccc3s2)c1F
Temperature: 25 °C
Yield: 28 %

Procedure:
A mixture of 3-[(5-bromo-1,3-benzothiazol-2-yl)methoxy]-2,6-difluorobenzenecarboxamide (168 mg, 0.42 mmol, 1 equiv.), 4-pyridine boronic acid (98 mg, 0.63 mmol, 1.5 equiv.) and 2M aqueous Na2CO3 solution (0.42 ml, 0.82 mmol, 2 equiv.) were suspended in dioxane (3.5 ml) and the mixture was degassed and flushed with N2. Tetrakis(triphenylphosphine)palladium(0) catalyst (37 mg, 0.031 mmol, 0.075 equiv.) was added and the reaction mixture was heated under reflux for 12 h. After cooling at r.t., the mixture was diluted with H2O and the precipitant solid was filtered and rinsed with H2O, IMS, IMS/Et2O and Et2O. Re-crystallised from CH3CN, to give the desired product as an off-white solid, 47 mg (28% yield), mp 255-258° C. HPLC-MS: m/z 398 [M+H]+, Rt=3.28 min.
Reaction SMILES: [CH3:1][N:2]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=O)[C@H:3]1[C@H:7]2[CH2:8][CH2:9][C@@H:4]1[C@H:5]([O:10][C:11](=[O:24])[C:12]([OH:23])([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:6]2.[NH2:35][CH2:36][C@@H:37]([C:46]1[CH:55]=[CH:54][C:53]([OH:56])=[C:52]2[C:47]=1[CH:48]=[CH:49][C:50](=[O:57])[NH:51]2)[O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[C:42]([Si:39]([CH3:41])([CH3:40])[O:38][C@H:37]([C:46]1[CH:55]=[CH:54][C:53]([OH:56])=[C:52]2[C:47]=1[CH:48]=[CH:49][C:50](=[O:57])[NH:51]2)[CH2:36][NH:35][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:2]([CH3:1])[C@H:3]1[C@H:7]2[CH2:8][CH2:9][C@@H:4]1[C@H:5]([O:10][C:11](=[O:24])[C:12]([OH:23])([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:6]2)([CH3:45])([CH3:44])[CH3:43]
Reactant: CN(CCCCCCCCC=O)[C@H]1[C@H]2CC[C@@H]1[C@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(CCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12)[C@H]1[C@H]2CC[C@@H]1[C@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-[methyl-(9-oxo-nonyl)amino]bicyclo[2.2.1]hept-2-yl ester (max 0.73 mmol), 5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-8-hydroxy-1H-quinolin-2-one (245 mg, 0.73 mmol), sodium triacetoxyborohydride (186 mg, 0.88 mmol), and acetic acid (2 drops) in dry 1,2-dichloroethane was stirred at ambient temperature overnight. The reaction mixture was partitioned between DCM and satd NaHCO3 (aq). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to afford a dark green/brown gum that solidified on standing, which was purified by preparative HPLC (system 2, 35% B+1% B/min). The fractions containing pure product were concentrated, neutralised with satd NaHCO3 (aq), and extracted with DCM. After concentration in vacuo a green/brown oil was obtained.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][C:13](=[O:26])[C:14]=2[C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18]([OH:20])=O)[N:10]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[CH:45]1([NH2:48])[CH2:47][CH2:46]1>C(Cl)Cl>[CH:45]1([NH:48][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([C:14]3[C:13](=[O:26])[CH:12]=[CH:11][N:9]4[C:8]=3[CH:7]=[CH:6][C:5]([O:4][C:3]3[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:2]=3[F:1])=[N:10]4)[CH:16]=2)[CH2:47][CH2:46]1
Reactant: COc1ccc(C(=O)O)cc1-c1c(=O)ccn2nc(Oc3ccc(F)cc3F)ccc12
Reactant: NC1CC1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NC2CC2)cc1-c1c(=O)ccn2nc(Oc3ccc(F)cc3F)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Intermediate 1 in CH2Cl2 was added triethyl amine and ethylchloroformate at 0° C. The mixture was warmed to ambient temperature and stirred for 10 min. The reaction was complete by LCMS analysis and concentrated in vacuo to yield crude residue. To the crude residue was added CH2Cl2 and cyclopropyl amine, followed by stirring for ½ hr. LCMS indicated the reaction was complete. The reaction was diluted with CH2Cl2, washed with 0.5 N NaOH, H2O, brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc/CH2Cl2/MeOH).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([C:11](=[O:13])[CH3:12])=[CH:6][N:5]=1.Br>C(O)(=O)C>[Br:1][CH2:12][C:11]([C:7]1[CH:8]=[C:9]([Cl:10])[C:4]([NH2:3])=[N:5][CH:6]=1)=[O:13]
Reactant: BrBr
Reactant: CC(=O)c1cnc(N)c(Cl)c1
Agent: Br
Solvent: CC(=O)O
Product: Nc1ncc(C(=O)CBr)cc1Cl
Reaction time: 2 h
Yield: 74.2 %

Procedure:
16 g (0.1 mol) of bromine are added dropwise to a solution of 17.05 g (0.1 mol) of 2-amino-3-chloro-5-acetylpyridine in a mixture of 19.3 g of hydrogen bromide (47% strength aqueous solution; 0.11 mol) and 500 ml of glacial acetic acid. The mixture is subsequently stirred for two hours, brought to pH 8 and extracted with ethyl acetate. Drying and evaporation gives 18.5 g (74%) of the title compound, melting point 134° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:9](Br)Br)=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.CC[OH:14]>O.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[C:3]([CH:9]=[O:14])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: Brc1ccc(Br)c(C(Br)Br)n1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: O=Cc1nc(Br)ccc1Br
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of silver nitrate (8.5 g, 50 mmol) in water (26 mL) was added dropwise to a solution of compound 84 (8.17 g, 20 mmol) in refluxing EtOH (100 mL). The mixture was stirred at 80° C. for 5 hours. After the mixture was cooled to room temperature, it was diluted with water (100 mL), extracted with EtOAc (3×), dried over Na2SO4, filtered and concentrated under reduced pressure. The product was obtained after silica gel chromatography eluting with 0-40% EtOAc in hexane (2.85 g, 51% over two steps).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([O:25][C:26]3[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=3[F:36])(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.CC1(C)C(C)(C)OB([C:45]2[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH:46]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[F:36][C:27]1[C:28]([F:35])=[C:29]([F:34])[C:30]([F:33])=[C:31]([F:32])[C:26]=1[O:25][S:22]([C:19]1[CH:20]=[CH:21][C:13]2[N:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[C:45]3[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH:46]=3)[CH2:17][CH2:16][O:15][C:14]=2[CH:18]=1)(=[O:23])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Oc4c(F)c(F)c(F)c(F)c4F)ccc32)CC1
Temperature: 100 °C
Yield: 79.8 %

Procedure:
A vial was charged with perfluorophenyl 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (EXAMPLE 46, STEP 1) (134.9 mg, 0.223 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (104 mg, 0.335 mmol), Pd(AmPhos)2Cl2 (7.90 mg, 0.011 mmol), potassium phosphate (142 mg, 0.670 mmol), dioxane (1116 μL), and water (372 μL). The vial as sealed and heated in a microwave reactor for 1 h at 100° C. The mixture was extracted with EtOAc (3×). The combined organic extracts were concentrated, and the residue was purified by chomatography on silica gel (12 g, 0 to 40% EtOAc/Heptane) to give tert-butyl 4-(2-(7-((perfluorophenoxy)sulfonyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (125.5 mg, 0.178 mmol) as a clear oil. m/z (ESI) 729.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:15][OH:16].Cl.CC([O-])=O.[Na+]>C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:15][OH:16])=[CH:4][C:3]=1[CH2:10][C:11]([F:14])([F:13])[F:12]
Reactant: O=Cc1ccc(Br)c(CC(F)(F)F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(Br)c(CC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 4-bromo-3-(2,2,2-trifluoroethyl)benzaldehyde (700 mg, 2.62 mmol, 1.00 equiv) in ethanol:H2O (20:5 mL), NH2OH. hydrogen chloride (235 mg, 3.41 mmol, 1.30 equiv), NaOAc (279 mg, 3.40 mmol, 1.30 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 700 mg (crude) of N-[[4-bromo-3-(2,2,2-trifluoroethyl)phenyl]methylidene]hydroxylamine as yellow oil.
Reaction SMILES: [OH-].[K+].[CH2:3]([OH:9])[CH2:4][O:5][CH2:6]CO.[CH2:10]1[O:18][C:17]2[C:12](=[CH:13][C:14]([N+:22]([O-:24])=[O:23])=[C:15]([N+:19]([O-:21])=[O:20])[CH:16]=2)[O:11]1>C(O)(=O)C>[N+:19]([C:15]1[C:14]([N+:22]([O-:24])=[O:23])=[CH:13][C:12]([OH:11])=[C:17]([O:18][CH2:10][CH2:6][O:5][CH2:4][CH2:3][OH:9])[CH:16]=1)([O-:21])=[O:20]
Reactant: OCCOCCO
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(O)c(OCCOCCO)cc1[N+](=O)[O-]

Procedure:
0.4 mol (26.4g) of 85% pure potassium hydroxide pellets is added at 70° C. to 200 ml of diethylene glycol. 0.2 mol (42 4g) of 4,5-methylenedioxy-1,2-dinitrobenzene is added to this solution. The heating is maintained for 31/2 hours After dilution with ice-cold water and neutralization with 22 ml of acetic acid, the expected product precipitates. After being dried, it is recrystallized from 96° strength alcohol. It melts at 135° C. Analysis of the product gives the following results:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:10]O.[OH-].[K+].CI>O>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1C
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: COc1ccc(C)c(C)c1
Yield: 81 %

Procedure:
To 3,4-dimethylphenol(19.3 g, 0.16 mol), methanol(150 ml) and KOH(9.65 g, 0.25 mol) were added and then refluxed for 2 hrs. Methyl iodide(36.5 g, 0.25 mol) was added thereto, refluxed for 3 hours and then followed by addition of water(150 ml). The resulting mixture was extracted with ethylacetate and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:14]([CH3:17])(O)[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Na+].C([O-])(O)=O.[Na+].N1C=CC=CC=1.[FH:46]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]2[CH2:12][CH:11]([C@@H:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:14]([F:46])([CH3:17])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: F
Reactant: CC(C)(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 42 °C
Reaction time: 9 h

Procedure:
To a solution of 175 mg (0.368 mmol) of 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol in 3 mL of CH2Cl2, 1 mL of hydrogen fluoride-pyridine was added and the reaction was stirred for 9 h at 42° C. Then the reaction mixture was poured to 7 mL of 5N NaOH, 7 mL of ag NaHCO3 and 30 mL of CH2Cl2. Adjusted pH to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with 10% methyl tert-butyl ether-hexane to afford the title compound as a white solid. 1H NMR(CDCl3) δ 1.25 (t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H), 4.20 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.33 (m, 8H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]2[CH:41]=[C:42]([Sn](CCCC)(CCCC)CCCC)[S:43][C:39]=2[C:38](C)=[N:37]1>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:42]3[S:43][C:39]4[CH:38]=[N:37][N:36]([CH3:35])[C:40]=4[CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(s1)c(C)nn2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1ncc2sc(-c3nc(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)cc21
Temperature: 90 °C

Procedure:
In a 30 mL sealed cap glass vessel, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (119 mg, 0.238 mmol), 1,3-dimethyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (210 mg, 0.476 mmol) and tetrakis(triphenylphosphine)palladium(0) (137 mg, 0.119 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. The mixture was concentrated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and the reaction mixture was stirred for 1 hour. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparatory HPLC eluting with a gradient of 15-50% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (65 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79 (d, J=10.86 Hz, 1H), 2.04-2.26 (m, 1H), 3.55-3.68 (m, 2H), 3.80 (d, J=11.62 Hz, 1H), 3.89 (br s, 1H), 3.99 (s, 3H), 4.02-4.06 (m, 1H), 4.33 (td, J=8.27, 4.67 Hz, 1H), 4.45 (s, 2H), 7.40 (d, J=5.05 Hz, 1H), 7.74 (d, J=0.76 Hz, 1H), 7.96 (d, J=4.55 Hz, 2H), 8.65 (s, 1H), 9.28 (d, J=0.76 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C18H19FN6O2S, 403. found, 403.
Reaction SMILES: [N+](C1C=CC(CC([O:11][CH2:12][CH:13]2[N:18](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:17][CH2:16][N:15]([C:32]([C@@H:34]3[CH2:38][C@H:37]([S:39][C:40]4[C@H:41]([CH3:64])[C@@H:42]5[C@@H:59]([C@H:60]([OH:62])[CH3:61])[C:58](=[O:63])[N:43]5[C:44]=4[C:45]([O:47]CC4C=CC([N+]([O-])=O)=CC=4)=[O:46])[CH2:36][N:35]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:33])[CH2:14]2)=O)=CC=1)([O-])=O.[ClH:80]>O1CCCC1.O>[ClH:80].[OH:11][CH2:12][CH:13]1[NH:18][CH2:17][CH2:16][N:15]([C:32]([C@@H:34]2[CH2:38][C@H:37]([S:39][C:40]3[C@H:41]([CH3:64])[C@@H:42]4[C@@H:59]([C@H:60]([OH:62])[CH3:61])[C:58](=[O:63])[N:43]4[C:44]=3[C:45]([OH:47])=[O:46])[CH2:36][NH:35]2)=[O:33])[CH2:14]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C(COC(=O)Cc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCNC(CO)C4)C3)[C@H](C)[C@H]12

Procedure:
140 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[3-(4-nitrobenzylcarbonyloxymethyl)-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 2 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.13 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 140 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 7(b), to give 20 mg of the title compound, as a powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1.[CH3:21][P:22]([C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28]([NH2:33])=[CH:27][CH:26]=1)([CH3:24])=[O:23].Cl>COCCO.C(O)C>[CH3:24][P:22]([C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28]([NH:33][C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:5]=[CH:6][N:7]=2)=[CH:27][CH:26]=1)([CH3:21])=[O:23]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncn1
Reactant: COc1nc(P(C)(C)=O)ccc1N
Agent: Cl
Solvent: COCCO
Solvent: CCO
Product: COc1nc(P(C)(C)=O)ccc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)ncn1

Procedure:
To a solution of 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0.250 mmol) in 1 mL of 2-methoxyethanol is added 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (50.0 mg, 0.250 mmol) and 0.15 mL of 2.5 M HCl in ethanol. The mixture is heated in a sealed tube at 90° C. until formation of the desired compound. The mixture is basified with 1N NaOH solution, and extracted with ethyl acetate. The organic layers can be combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue can be purified by silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[S:36][C:35]([S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:33]=1.O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][NH:15][S:37]([C:35]2[S:36][C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[CH:33][CH:34]=2)(=[O:38])=[O:39])[CH2:10][CH2:11]1
Reactant: NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)(NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1ccc(-c2ccccn2)s1
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
The product of Example 2, Step (b) (0.2 g) was dissolved in acetone (4 ml). Potassium carbonate [0.130 g dissolved in H2O (1 ml)] was then added, followed by 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.171 g) and the reaction left to stir for 10 mins. Water was then added and the product extracted with ethyl acetate. The combined organic extracts dried, filtered and concentrated. Purification by reverse phase HPLC {with a gradient eluent system [30% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)]} gave the title compound as a solid (0.135 g).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=S.F[C:12](F)(F)C(F)=C(F)F.C=C=O>>[F:1][C:2]([F:10])([F:9])[C:3](=[CH2:12])[C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C(=S)C(F)(F)F
Reactant: FC(F)=C(F)C(F)(F)F
Agent: C=C=O
Product: C=C(C(F)(F)F)C(F)(F)F
Temperature: 150 °C

Procedure:
Hexafluorothioacetone is a known compound (b.p. 6° C.) and is a relatively reactive and unstable monomer. It is convenient to handle this compound in the form of its dimer 2,2,4,4-tetrakis (trifluoromethyl)-1,3-dithietane which is a stable liquid (b.p. 110° C.). Hexafluorothioacetone may be conveniently generated from its dimer by thermal cracking which may be readily accomplished by passng the dimer through a hot tube at about 590°-600° C. The dimer, in turn, is rapidly formed from hexafluorothioacetone at about room temperature and the dimerization is catalyzed by bases. Alternatively, hexafluorothioacetone may be prepared by reacting sulfur and hexafluoropropene over a carbon bed at about 400° C. and the hexafluorothioacetone produced can be used immediately after it has been prepared. The effluent gases from such reaction containing hexafluorothioacetone, unreacted hexafluoropropene and by-products should be passed through traps maintained at 150° C. to remove unreacted sulfur. The presence of sulfur lowers the yield of hexafluoroisobutylene from the reaction of ketene with hexafluorothioacetone. These gases are then contacted with ketene to form hexafluoroisobutylene. The total effluent should then be passed through caustic traps to remove residual amounts of ketene and hexathioacetone. This procedure eliminates the need to isolate and purify the hexafluorothioacetone dimer.