Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][P:9]([O:19][CH2:20][CH2:21][N:22]1[C:31]2[C:26](=[CH:27][C:28]([C:32]3[CH:33]=[N:34][C:35]([NH:47][C:48](=[O:52])[NH:49][CH2:50][CH3:51])=[CH:36][C:37]=3[C:38]3[S:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[N:42]=3)=[CH:29][N:30]=2)[C:25](=[O:53])[C:24]([C:54]([OH:56])=[O:55])=[CH:23]1)([O:11]CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1.C[Si](Br)(C)C.O>ClCCl.CO>[CH2:50]([NH:49][C:48]([NH:47][C:35]1[N:34]=[CH:33][C:32]([C:28]2[CH:27]=[C:26]3[C:31](=[N:30][CH:29]=2)[N:22]([CH2:21][CH2:20][O:19][P:9]([OH:11])([OH:10])=[O:8])[CH:23]=[C:24]([C:54]([OH:56])=[O:55])[C:25]3=[O:53])=[C:37]([C:38]2[S:39][CH:40]=[C:41]([C:43]([F:45])([F:46])[F:44])[N:42]=2)[CH:36]=1)=[O:52])[CH3:51]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)O)cn3CCOP(=O)(OCc2ccccc2)OCc2ccccc2)cn1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)O)cn3CCOP(=O)(O)O)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
1-(2-{[bis(benzyloxy)phosphoryl]oxy}ethyl)-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (Example 13, 220 mg, 0.27 mmol) was dissolved in dry dichloromethane (30 mL), the reaction mixture was cooled to 0° C. Trimethylsilyl bromide (83.31 mg, 0.54 mmol) was added and the mixture was stirred for 2 h at room temperature. A solid formed on the walls of round bottom flask. The solvent was decanted and the solid was washed with ethyl acetate (20 mL) to give crude compound. The crude compound was dissolved in methanol (20 mL) and water (50 mL) was added to precipitate a solid compound which was filtered and dried to give crude compound. The crude compound was purified preparative HPLC to afford 45 mg (25.9%) of 6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1-[2-(phosphonooxy)ethyl]-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:17]=[CH:16][C:6]([CH:7]=[N:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH2:14][CH3:15])=[CH:5][CH:4]=1.CN(C)C1C=CC(C(=O)C[Br:27])=CC=1>>[Br-:27].[CH3:18][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[N:8][N+:9]2[CH:13]=[CH:12][NH:11][C:10]=2[CH2:14][CH3:15])=[CH:16][CH:17]=1
Reactant: CN(C)c1ccc(C(=O)CBr)cc1
Reactant: CCc1nccn1N=Cc1ccc(N(C)C)cc1
Product: CCc1[nH]cc[n+]1N=Cc1ccc(N(C)C)cc1
Product: [Br-]
Reaction time: 0.5 h

Procedure:
A solution of 2.42 g of 1-[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazole is treated with 2.42 g of p-dimethylaminophenacyl bromide. After stirring at 40° for 30 minutes, the product is crystallized out by the addition of ether and recrystallized from methylene chloride/ether. There is obtained 3-[p-dimethylamino)phenacyl]-1-[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazolium bromide of melting point 247°.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:27][S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])[CH:28]=[CH:29][CH:30]=1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: COc1cccc(N)c1
Product: CCC(=O)[O-]
Product: COc1cccc(NS(=O)(=O)c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)c1
Yield: 28.5 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 62 μL (0.55 mmol) of 3-methoxyaniline. After purification by chromatography on silica (eluent dichloromethane/methanol 95/5) then trituration in diethyl ether, 29 mg (14%) of 8-(3-methoxy-phenylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]1[C@H:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C@H:16]2[C@@H:15]([O:23]S(C(F)(F)F)(=O)=O)[CH2:14][N:13]1[S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:33])=[O:32])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]([O-])(=[O:44])[CH3:43].[Cs+].C1OCCOCCOCCOCCOCCOC1.C(OCC)(=O)C>C(#N)C>[CH2:1]([O:8][NH:9][C:10]([C@H:12]1[C@H:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C@@H:16]2[C@H:15]([O:23][C:42](=[O:44])[CH3:43])[CH2:14][N:13]1[S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:32])=[O:33])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc(S(=O)(=O)N2C[C@H](OS(=O)(=O)C(F)(F)F)[C@@H]3OC(C)(C)O[C@@H]3[C@@H]2C(=O)NOCc2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2C[C@@H](OC(C)=O)[C@H]3OC(C)(C)O[C@@H]3[C@@H]2C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.1 %

Procedure:
The above compound (2-1) (670 mg) was dissolved in acetonitrile (30 mL) and cesium acetate (0.5 g) and 18-Crown-6 (1.4 g) were added, and then the mixture was stirred at room temperature for 16 hours, To the reaction solution was added ethyl acetate (100 mL) and, after washing in turn with dilute hydrochloric acid, an aqueous saturated sodium hydrogencarbonate solution and saturated saline, the solution was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3→1:1) to obtain the titled compound (161 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[BH4-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2scnc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine was slurried in dry methanol/tetrahydrofuran (1:10). The solution was cooled to 0° C. under nitrogen and sodium borohydride (1.1 eq) was added in four portions. The solution was stirred at 0° C. for 30 min. An additional 0.1 eq sodium borohydride was added if necessary. The solvent was removed under vacuum and the resulting residue was purified by silica gel chromatography isocratic 1:1 methylene chloride: ethylacetate. The resulting white solid of 4-(5-chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].CO.O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1Cl
Temperature: 50 °C
Yield: 81 %

Procedure:
Methyl 3-chloro-4′-nitrobiphenyl-4-carboxylate (0.50 g, 1.4 mmol) was suspended in THF (6 mL), MeOH (6 mL) and water (3 mL), and NaOH (0.27 g, 6.9 mmol) was added. The reaction mixture was heated at 50° C. for 3 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure and acidified with 2N HCl. The resulting solid was collected by filtration and dried in a 40° C. vacuum oven, yielding 0.315 g (83%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.81-8.10 (m, 5H), 8.21-8.38 (m, 2H).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH:6]1([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][N+:17]([CH2:20][CH2:21][CH2:22][C:23](=[O:31])[C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[CH:16][CH:15]=3)[N:10]=2)[CH2:8][CH2:7]1.CO.[BH4-].[Na+]>O>[CH:6]1([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[OH:31])[CH2:16][CH:15]=3)[N:10]=2)[CH2:7][CH2:8]1
Reactant: O=C(CCC[n+]1ccc(-c2noc(C3CC3)n2)cc1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: OC(CCCN1CC=C(c2noc(C3CC3)n2)CC1)c1ccc(F)cc1

Procedure:
To a 1.8 g. portion of 4-(5-cyclopropyl-1,2,4-oxadiazol- 3-yl)-1-[3-(p-fluorobenzoyl)-propyl]pyridinium perchlorate, prepared as described in Example 3, in 80 ml. of methanol is added, portionwise with stirring, 1.8 g. of sodium borohydride. The mixture is stirred for 2 hours and then poured into 300 ml. of cold water, causing a white solid to separate. This solid is collected and recrystallized from acetonitrile, m.p. 89°-92° C.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:8][C:9]1[C:10](Br)=[C:11]2[O:16][CH2:15][CH:14]([CH3:17])[N:13]3[CH:18]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:20](=[O:23])[C:21]([CH:22]=1)=[C:12]23.Cl>O1CCCC1>[F:8][C:9]1[C:10]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]2[O:16][CH2:15][CH:14]([CH3:17])[N:13]3[CH:18]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:20](=[O:23])[C:21]([CH:22]=1)=[C:12]23
Reactant: CCOC(=O)c1cn2c3c(c(Br)c(F)cc3c1=O)OCC2C
Reactant: [Li]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(c(-c4ccccc4)c(F)cc3c1=O)OCC2C
Temperature: -78 °C
Yield: 46 %

Procedure:
A solution of phenyl lithium (2.7M) in etherbenzene [(3:7), 1.5 ml, 4 mmol] was added to dry tetrahydrofuran (10 ml) and the resulting solution was cooled to -78° C. with stirring under a nitrogen atmosphere. A solution of freshly fused zinc chloride (0.54 g, 4 mmol) in dry tetrahydrofuran (10 ml) was added dropwise over 5 minutes. The clear, colorless solution was warmed to -30° C. over 20 minutes. Ethyl 9-fluoro-10-bromo-3-methyl-7-oxo-2,3-dihydro-(7H)-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylate (1.0 g, 2.7 mmol) was added in one portion; then dichlorobis(triphenylphosphine) nickel (0.13 g, 0.2 mmol) was added in one portion. The reaction mixture was gradually warmed to ambient temperature and stirred for 24 hours. The dark brown mixture was poured onto a 1N hydrochloric acid solution (100 ml) and the aqueous mix was stirred for 15 minutes. Three extractions with chloroform (50 ml), drying the combined organic layers over magnesium sulfate, treatment with decolorizing charcoal and filtration through diatomaceous earth gave a yellow solution. Removal of solvent in vacuo afforded a bright yellow solid. Trituration with ether, filtration and drying in vacuo gave a pale yellow solid (0.67 g, 46% yield): m.p. 270°-272° C. NMR (CDCl3, 250 MHz): 8.42 (s, 1H), 7.85 (d, 1H, J=10 Hz), 7.55-7.40 (m, 5H), 4.42 (q, 2H, J=7 Hz), 4.50-4.35 (m, 3H), 1.62 (d, 3H, J=8 Hz), 1.45 (t, 3H, J=7 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[S:19](=[O:33])(=[O:32])[NH:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[S:19](=[O:33])(=[O:32])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)n(C(=O)OC(C)(C)C)c2ccc(F)cc12
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: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2C(F)(F)F)n(C(=O)OC(C)(C)C)c2ccc(F)cc12
Yield: 53.9 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 2-(4-bromo-2-trifluoromethyl-phenylsulfamoyl)-5-fluoro-3-methyl-indole-1-carboxylic acid tert-butyl ester (0.108 g), 4-pyridineboronic acid (0.036 g) in 1,2-dimethoxyethane (5.0 ml), ethanol (0.4 ml) and 2 M aqueous sodium carbonate solution (0.8 ml) with tetrakis(triphenylphosphine)palladium (0.023 g) to obtain the desired compound (0.058 g) as a brownish foam. MS (ISN): 548.3 (M−H)−
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[C:4]([CH3:13])[CH:3]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].C1OCCOCCOCCOCCOCCOC1.[N:44](OCCC(C)C)=O>C(Cl)(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[N:9]([C:10](=[O:12])[CH3:11])[N:44]=[CH:13]2
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1cc(F)c(Br)cc1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)n1ncc2cc(Br)c(F)cc21
Temperature: 25 °C

Procedure:
A solution of N-(4-bromo-5-fluoro-2-methylphenyl)acetamide (22B, 10.00 g, 40.64 mmol) in chloroform (100 mL) was treated with acetic anhydride (11.5 mL, 122.0 mmol), potassium acetate (8.00 g, 81.5 mmol), and 18-Crown-6 (540.00 mg, 2.0430 mmol) and then with isoamyl nitrite (12.3 mL, 871 mmol) and heated at 65° C. for 12 h. The reaction mixture was cooled to room temperature and treated with EtOAc (500 mL), washed with water, dried (MgSO4), filtered, and then concentrated in vacuo. A pale yellow solid of 1-(5-bromo-6-fluoro-1H-indazol-1-yl)ethanone (22C) precipitated out. The initial filtrate was concentrated and the residue was purified by chromatography (SiO2, EtOAc/Hexanes) to yield more of product 22C.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][C:8]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)([OH:12])[CH:9]([CH3:11])[CH3:10])(C)(C)C.[OH-].[Li+]>CO.O>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][C:8]([OH:12])([CH:9]([CH3:10])[CH3:11])[CH2:7][C:6]([OH:29])=[O:5])=[CH:16][CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)C(O)(CCc1ccc(OCc2ccccc2)cc1)CC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C(O)(CCc1ccc(OCc2ccccc2)cc1)CC(=O)O

Procedure:
The title compound was prepared by dissolving 3-[2-(4-benzyloxy-phenyl)ethyl]-3-hydroxy-4-methyl-pentanoic acid tert-butyl ester (28 g, 70.3 mmol) from Example QQQQ in MeOH (150 mL). Lithium hydroxide (5.9 g, 140.6 mmol) in water (50 mL) was added and the reaction heated to reflux for 5 hours, cooled and pumped to dryness under vacuum. The product was partitioned between water and Et2O. The aqueous layer was decanted, acidified with 1N HCL, and the precipitate was filtered and dried under vacuum to give the title compound (mp 97°-98° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])([CH3:4])([CH3:3])[CH3:2].[CH:24](O)([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][N:10]([CH:24]([CH3:26])[CH3:25])[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])(=[O:12])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)O
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)N(CCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 150.5 %

Procedure:
The compound (2.22 g, 6.43 mmol) obtained in step A, isopropanol (0.65 ml, 8.46 mmol), and triphenylphosphine (1.85 g, 7.05 mmol) were dissolved in tetrahydrofuran (50 ml) and the mixture was stirred under ice-cooling. Thereto was slowly added 40% diisopropyl azodicarboxylate-toluene solution (5 ml), and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated under reduced pressure and diluted with diethyl ether, and the precipitated colorless solid was filtered off. The mother liquor was concentrated under reduced pressure and the obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give tert-butyl[2-{isopropyl[(2-nitrophenyl)sulfonyl]amino}ethyl]carbamate (3.75 g) as a colorless crude oil. This was dissolved in dichloromethane (10 ml), 4N hydrochloric acid-dioxane solution 10 ml) was added at room temperature and the mixture was stirred for 1 hr. The reaction mixture was diluted with diethyl ether, and the mixture was extracted with water. The aqueous layer was alkalified with aqueous sodium hydroxide solution, extracted with dichloromethane, dried over sodium sulfate, the insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (1.39 g, yield 75%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](S(C)(=O)=O)[N:14]=2)=[CH:4][CH:3]=1.[CH3:23][NH2:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:24][CH3:23])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nccc(-c2cc[nH]c2-c2ccc(F)cc2)n1
Reactant: CN
Product: CNc1nccc(-c2cc[nH]c2-c2ccc(F)cc2)n1

Procedure:
In a similar manner to that described in Example 42(iii) above, 2-(4-fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-1H-pyrrole [prepared as described in step 1(ii) above] was reacted with methylamine to afford the title compound (quantitative yield) as a pale brown amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[N+:21]([O-])=O)[CH:5]=[CH:6][CH:7]=1.O.[Cl-].[NH4+]>C(O)C.ClCCl.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[N:11]=[CH:10][C:9]=2[NH2:21])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)COCCn1ncc([N+](=O)[O-])c1-c1cccc(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)COCCn1ncc(N)c1-c1cccc(Br)c1
Temperature: 75 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
To a solution of 5-(3-bromophenyl)-4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazole (800 mg, 2.4 mmol) in 25 mL ethanol was added 50 mL of water, ammonium chloride (636 mg, 12 mmol), and iron powder (806 mg, 14 mmol). The reaction mixture was stirred at 75° C. for 6 hours. After cooling to room temperature, the reaction was diluted with dichloromethane and filtered through a celite pad, rinsing with more dichloromethane. The filtrate was added to 150 mL of saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated to yield 530 mg (71%) of 5-(3-bromophenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-amine, which was carried forward without purification. LCMS (ESI) m+H=368.0.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][CH:8]([CH2:18][OH:19])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][CH:4]=1)#[N:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([CH:18]=[O:19])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:20][CH:21]=1)#[N:2]
Reactant: CCOC(=O)CCCCC(CO)Cc1ccc(C#N)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)CCCCC(C=O)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4.6 g (15.90 mmol) of ethyl 6-(4-cyanobenzyl)-7-hydroxyheptanoate in 250 ml of dichloromethane is mixed with 4.11 g (19.08 mmol) of pyridinium chlorochromate (PCC) and stirred at room temperature for 12 hours. After conversion is complete, 10 g of silica gel are added, and the solvent is cautiously concentrated to dryness in vacuo. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1:1). 4.09 g (14.23 mmol, 89% of theory) of a colorless solid are obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:20][CH2:19][C:13]2([O:17][C:16](=[O:18])[NH:15][CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:24]=1[CH2:25]Br.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]2([O:17][C:16](=[O:18])[N:15]([CH2:25][C:24]3[CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[CH:29]=[CH:30][C:23]=3[O:22][CH3:21])[CH2:14]2)[CH2:19][CH2:20]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)O2
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1CN1CC2(CCN(C(=O)OC(C)(C)C)CC2)OC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
Sodium hydride (82 mg, 60% dispersion in mineral oil, weight percent) was suspended under a nitrogen atmosphere in DMF (5 mL). Compound A3 (0.5 g, 1.95 mmol) was added thereto and the reaction mixture was stirred for 10 min at RT. 2-Methoxy-5-nitrobenzyl bromide (485 mg, 1.97 mmol) was added thereto. The reaction mixture was stirred for 18 h at RT, combined with water and extracted with EtOAc. The combined organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. The residue was dissolved in a mixture of ether and heptane. After removal of the ether, the desired product 3-(2-methoxy-5-nitrobenzyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (A87) (670 mg, 81% of theoretical) was obtained as a white solid by filtration.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)[Cl:32]>[Cu]I>[ClH:32].[ClH:32].[C:23]1([C:29]#[C:30][C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[CH3:15])[CH:5]=[N:6][CH:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C#Cc1ccccc1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Reactant: ClCCl
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CN1CCC[C@H]1COc1cncc(C#Cc2ccccc2)c1
Product: Cl

Procedure:
To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (272 mg, 1 mmol) in 6 mL of methylene chloride was added triethylamine (0.5 mL), Pd(II) (19 mg), CuI (a catalytic amount) and 0.22 mL of phenylacetylene (2 mmol). The reaction mixture was heated at reflux for 40 hours. The solvent was removed under reduced pressure, and the free base was purified by chromatography, during with 2 to 6% methanol in methylene chloride. MS (CI/NH3) m/z 293 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ2.07 (m, 2H), 2.25 (m, 2H), 2.81 (m, 1H), 2.88 (s, 3H), 3.47 (m, 1H), 3.67 (m, 1H), 4.23 (m, 1H), 4.64 (m, 1H), 7.38 (m, 4H), 7.54 (m, 2H), 8.28 (m, 1H), 8.42 (m, 1H). The salt was prepared by treatment with HCl in ether, as described above to give 90 mg of the title compound. mp 190°-192° C. MS (CI/NH3) m/z 293 (M+H)+. 1H NMR (D2O, 300 MHz) δ8.39 (d, J=1.5, 1H), 8.30 (d, J=2.6, 1H), 7.65 (m, 3H), 7.48 (m, 3H), 4.54 (dd, J=3.3, 11.0, 1H), 4.38 (dd, J=5.9, 11.4, 1H), 3.94 (br, 1H), 3.26 (br, 1H), 3.05 (s, 3H), 2.41 (m, 1H), 21.4 (m, 1H), 2.09 (m, 2H). Anal. Calcd for C19H20N2O·2.2 HCl: C, 61.25; H, 6.01; N, 7.52. Found: C, 61.14; H, 5.84; N, 7.52. [α]25D =-10.00° (c 0.22, MeOH).