Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:20][C:21]1([CH3:30])[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23](=O)[CH2:22]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:8](=[C:23]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26][C:21]([CH3:30])([CH3:20])[CH2:22]2)[C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(C(=O)c2ccc(O)cc2)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(S(C)(=O)=O)cc2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.4 %

Procedure:
To a stirred suspension of zinc powder (0.36 g, 5.50 mmol) in THF (15 mL) was slowly added TiCl4 (0.30 mL, 2.75 mmol) via syringe at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 2 h. A solution of (4-hydroxyphenyl)[4-(methylsulfonyl)phenyl]methanone (93) (0.19 g, 0.69 mmol) and 3,3,5,5-tetramethyl cyclohexanone (0.33 g, 2.06 mmol) in THF (4 mL) was added to the mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 1.5 h. The reaction mixture was allowed to cool at room temperature. To the reaction mixture was slowly added 10% aqueous K2CO3 (15 mL). The reaction mixture was filtered through a pad of celite and the pad was washed with ethyl acetate (70 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with ethyl acetate (25 mL). The combined organic phase was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as yellow oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 25% EtOAc:hexanes to give white foam residue, which was triturated with hot hexanes (containing 1% MeOH) to afford 0.21 g (76%) of the title compound (94) as white solid, m.p. 149-150° C. 1H NMR (300 MHz, DMSO-d6): δ 0.90 (s, 6H), 0.91 (s, 6H), 1.28 (s, 2H), 1.88 (s, 2H), 1.95 (s, 2H), 3.20 (s, 3H), 6.70 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 7.84 (d, J=8.2 Hz, 2H), 9.34 (s, 1H). LCMS (ES): m/z 397 (M−H)−.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[OH:11])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH:10]([OH:11])[CH2:9][NH:8][CH3:1])=[CH:17][CH:16]=1
Reactant: CN(Cc1ccccc1)CC(O)c1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCC(O)c1ccc(F)cc1
Yield: 72.4 %

Procedure:
2-(Benzyl-methyl-amino)-1-(4-fluorophenyl)-ethanol (54.6 g) and 10% palladium-carbon (5.8 g) was stirred in ethyl acetate-methanol (3:1) (800 mL) at 50° C. under hydrogen atmosphere for three hours. The catalyst was removed by filtration, and the filtrate was concentrated. After solidifying with an ether-hexane solvent, and the title compound (25.8 g) was obtained as a colorless solid.
Reaction SMILES: [P:1]([O-:36])([O:32][CH2:33][CH2:34]Br)([O:3][CH2:4][CH:5]([O:26][C:27]1[CH:31]=[CH:30][O:29][N:28]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2].[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[P:1]([O-:36])([O:32][CH2:33][CH2:34][N+:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([O:3][CH2:4][CH:5]([O:26][C:27]1[CH:31]=[CH:30][O:29][N:28]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCBr)Oc1ccon1
Reactant: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCC[n+]1ccccc1)Oc1ccon1
Reaction time: 11 h

Procedure:
A solution of 0.663 g of crude (2RS)-3-octadecyloxy-2-(3-isoxazolyloxy)propyl 2-bromoethyl phosphate (prepared as described in the first part of Example 2) in 4.5 ml of pyridine was heated on an oil bath kept at 60° C. for 11 hours. After allowing the mixture to cool, excess pyridine was distilled off. The residue was dissolved in 10 ml of chloroform, and the solution was heated under reflux for 1 hour. The mixture was then cooled, and the solvent was evaporated off under reduced pressure. Methanol was then added to the residue, and the resulting insoluble material was filtered off. The filtrate was concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through 15 g of silica gel. 0.305 g of the title compound was obtained as a hygroscopic powder, melting at 49°-52° C., from the fractions eluted with a 2:1 by volume mixture of methylene chloride and methanol.
Reaction SMILES: [CH2:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:21])[C:16](OCC)=[O:17])[CH3:13].CC[O-].[Na+]>>[CH2:12]([O:14][C:15](=[O:21])[C:16](=[O:17])[CH2:10][C:9](=[O:11])[CH2:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:13]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)CCc1ccccc1
Temperature: 25 °C
Yield: 43.8 %

Procedure:
Benzylacetone (1.0 g, 6.75 mmol) and diethyloxalate (0.92 mL, 6.75 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 2.3 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 19. The crude material was purified with 1:1 Hexanes: CH2Cl2 to obtain 0.7348 g (43.9%) of 19. 1H (CD3OD, 400 MHz): δ 7.27-7.12 (5H, m), 4.26 (2H, q, J=7.2Hz), 2.89 (2H, t, J=7.3 Hz), 2.81 (2H, t, J=7.3 Hz), 1.30 (3H, t, J=7.1 Hz) ppm. Partial 13C (CD3OD, 100 MHz): δ 163.32, 141.74, 129.43, 129.29, 127.16, 126.95, 103.06, 63.34, 43.46, 31.34, 14.24 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 14.24; CH2 carbons: 63.34, 43.46, 31.34; CH carbons: 129.43, 129.29, 127.16, 103.06 ppm. HPLC: 10.279 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]#[N:1])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: N#CCCCCCCCCN
Solvent: c1ccncc1
Product: N#CCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 16.4 %

Procedure:
A solution of 9-aminononanenitrile (2.0 g) in pyridine (60 ml) was treated with 4-chlorobenzenesulphonyl chloride (2.74 g) in portions. The solution was stirred for 18 hours then the solvent was removed in vacuo. The residue was dissolved in dilute hydrochloric acid and extracted with chloroform. The chloroform extract was dried over magnesium sulphate, the solvent was removed and the residue was chromatographed on silica gel eluted with chloroform to give the title compound (0.7 g) as a low melting solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6].CI.[C:15]([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[Br:1][C:2]1[C:3]([O:12][CH3:15])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(Br)c(O)c(C=O)c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(Br)c(OC)c(C=O)c1
Reaction time: 4 h
Yield: 66.4 %

Procedure:
A solution of 50 (10 g, 43 mmol), Methyl Iodide (7.3 g, 52 mmol), and K2CO3 (12 g, 86 mmol) in acetone (200 ml) was heated to reflux. After 4 hr, the reaction was cooled, poured into water and extracted with ether. The ether layer was dried concentrated and the product was purified by silica gel column chromatography (10%EtOAc/Hex) to give 51 as a solid (7.0 g, 67%): Mp=62-64° C.; 1H NMR (CDCl3) δ 10.32 (s, 1 H), 7.38 (d, 1 H, J=2.8 Hz), 7.28 (d, 1 H, J=3.2 Hz), 3.93 (s, 3 H), 3.82 (s, 3 H); MS 245/247 (M+H)+
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O>C(#N)C.C(OCC)(=O)C>[O:18]1[CH2:19][CH2:20][N:15]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: O=Cc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: O=Cc1cnc(N2CCOCC2)s1
Reaction time: 23.5 h
Yield: 66.4 %

Procedure:
2-Chlorothiazole-5-carbaldehyde (200 mg, 1.36 mmol) was dissolved in acetonitrile (4 mL). To this, potassium carbonate (376 mg, 2.72 mmol) and morpholine (0.237 mL, 2.72 mmol) were added at room temperature and the mixture was stirred at the same temperature for 23.5 hours. After water was added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=15/1) to give 2-morpholinothiazole-5-carbaldehyde (179 mg, yield: 66%).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1
Reactant: COC(=O)CCc1ccc(Oc2cc(F)cc(Br)c2)cc1C
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1
Product: Cc1cc(Oc2cc(F)cc(Oc3ccc(Cl)cc3Oc3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-chloro-2-phenoxy-phenol as in Example 18 to afford 0.118 g (22%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C28H22O5ClF 492, found 493 and 495 (M+1 and M+3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]([C:24]2[C:25]([OH:35])=[N:26][C:27]([N:30]3[CH:34]=[CH:33][CH:32]=[N:31]3)=[N:28][CH:29]=2)=[O:23])[C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:20])(=[O:19])[O:16]CC)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:21][C:22]([C:24]2[C:25]([OH:35])=[N:26][C:27]([N:30]3[CH:34]=[CH:33][CH:32]=[N:31]3)=[N:28][CH:29]=2)=[O:23])[C:9]2[CH:10]=[CH:11][C:12]([P:15]([CH3:20])(=[O:16])[OH:19])=[CH:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CCOP(C)(=O)c1ccc(C(NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CP(=O)(O)c1ccc(C(NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2)cc1
Temperature: 80 °C

Procedure:
Ethyl 4-((4-fluorophenyl)(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)methyl)phenyl(methyl)phosphinate, 17-f, (2 g, 4.03 mmol) was dissolved in 20 ml of dioxane and treated with 10 ml of 3N NaOH. The mixture was heated at 80° C. for one hour. Then the mixture was concentrated under vacuum and the residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with conc. HCl to pH=1 and the expected product crashed out (1.7 g of crude). The product can be further purified via prep-HPLC give the title product, 17-1, (1.4 g, 75%). 1H NMR (300 MHz, CD3OD): δ 8.66 (s, 1H), 8.59 (s, 1H), 7.93 (s, 1H), 7.81 (m, 2H), 7.50 (m, 2H), 7.36 (m, 2H), 7.10 (m, 2H), 6.66 (s, 1H), 6.38 (s, 1H), 1.66 (d, 3H). (M+H)+=468.0.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]([F:32])([CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])[CH2:18]O.N1C=CC=CC=1>ClCCl>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][CH2:18][C:17]([F:32])([F:16])[CH2:20][N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26])(=[O:10])=[O:11]
Reactant: O=C1c2ccccc2C(=O)N1CC(F)(F)CO
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)COS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triflic anhydride (1.1 ml, 6.6 mmol) was added to a cold (0° C.) solution of 2,2-difluoro-3-phthalimido-1-propanol (1.4 g, 6 mmol), pyridine (0.5 ml, 6.6 mmol) in anhydrous dichloromethane (30 ml). The mixture was stirred 1 h at 0° C. and, after usual work-up, the product was purified by flash chromatography on silica gel (ethyl acetate:hexane; 20:80) (1.7 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[H-].[Na+].[CH3:15][O:16][C:17](=O)[O:18]C.Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[C:17]([O:16][CH3:15])=[O:18]
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)c1ccc(Br)cc1
Temperature: 30 °C
Reaction time: 1.17 h

Procedure:
At 40° C. a solution of 4-bromophenylacetic acid methyl ester (52 g) in THF (100 mL) is carefully added over a period of 40 min to a suspension of NaH (15.6 g) in dry THF (450 mL). Stirring is continued for 70 min without heating and the temperature drops to 27° C. The evolution of gas has stopped before dimethylcarbonate (76.42 mL) is added dropwise while the temperature of the mixture is maintained at 29-31° C. Stirring is continued for 22 h at rt. The mixture is cooled to −10° C. and then carefully neutralized to pH 6-7 with aq. HCl before bulk of the THF is removed in vacuo. The residue is dissolved in EA (700 mL), washed three times with 1 N aq. HCl and once with brine, dried over MgSO4. Most of the EA is evaporated before hexane is added. The product crystallizes over night at 4° C. The crystals are collected, washed with hexane and dried to give 2-(4-bromophenyl)-malonic acid dimethyl ester (45.9 g) as pale yellow crystals. 1H-NMR(D6-DMSO): 3.66 (s, 6H), 5.07 (s, 1H), 7.30-7.34 (m, 2H), 7.55-7.59 (m, 2H).
Reaction SMILES: [C:1]([O:10]C1C=CC=CC=1)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:4])=[CH:20][CH:19]=1
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Reactant: Nc1ccc(F)cc1
Product: O=C(Nc1ccc(F)cc1)c1ccccc1O

Procedure:
The 4′-fluoro-salicylanilide was prepared by condensing phenyl salicylate with 4-fluoroaniline then purified as described in Example 2a. The ligand mixture was then prepared from 4′-fluoro-salicylanilide and 1,1′-bi-2-naphthol using the procedure described in Example 5a. 31P NMR (121.77 MHz): several peaks between 117.1-117.7 ppm.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([NH:11][C:12]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([CH3:23])=[N:17]2)(=[O:10])[CH3:9]>[Pd].[Pt]>[C:8]([NH:11][C:12]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][CH:16]([CH3:23])[NH:17]2)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1c(F)ccc2nc(C)ccc12
Agent: [Pd]
Agent: [Pt]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(F)ccc2c1CCC(C)N2

Procedure:
The nitro group is reduced catalytically, for example in the presence of palladium on charcoal. If this reaction is carried out in the presence of acetic anhydride the product is the novel compound 5-acetamido-6-fluoroquinaldine. This intermediate is further reduced catalytically in the presence of platinum on charcoal to provide the novel compound 5-acetamido-6-fluorotetrahydroquinaldine.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([OH:25])=O)=[CH:21][N:22]=2)[CH2:14][CH2:13]1)=[O:10].[NH2:26][NH2:27]>CN(C=O)C>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([NH:26][NH2:27])=[O:25])=[CH:21][N:22]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C(=O)O)s3)CC2)c(Cl)c1Cl
Reactant: NN
Solvent: CN(C)C=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C(=O)NN)s3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylic acid (Example 227, 100 mg, 0.240 mmol) was dissolved in DMF (1 ml) and hydrazine (500 μL, 16.0 mmol). The mixture was stirred at room temperature for 2 h. The mixture was filtered and purified by semi-preparative reverse phase HPLC eluting with acetonitrile/water (0.1% TFA) (36 mg).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]O.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:36]I>C1(C)C=CC=CC=1.CCCCCC>[I:36][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: II
Reactant: CC(C)CCCC(C)CCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)CCCC(C)CCI
Reaction time: 18 h
Yield: 69.9 %

Procedure:
To a stirring solution of 43 (5 g, 32 mmol), imidazole (2.59 g, 38 mmol, 1.2 eq) and triphenylphosphine (9.11 g, 35 mmol, 1.1 eq) in toluene (100 ml) under nitrogen was added iodine (10.44 g, 41 mmol, 1.3 eq). The reaction mixture was stirred for 18 hours then filtered. The filtrate was washed with 5% sodium thiosulfate solution (3×100 ml) then dried (Na2SO4) and concentrated in vacuo to give a white solid. This solid was taken up in hexane (20 ml), cooled and filtered. The filtrate was then concentrated in vacuo to give 45 (6 g, 71%) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9]2[N+:10]([O-:18])=[CH:11][CH:12]=[C:13]([N+]([O-])=O)[CH:14]=2)=[CH:5][CH:4]=1.[OH:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][CH:28]([C:32]([OH:34])=[O:33])[CH2:29]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:21][C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][CH:28]([C:32]([OH:34])=[O:33])[CH2:29]4)=[CH:24][CH:23]=3)[CH:12]=[CH:11][N+:10]=2[O-:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNc2cc([N+](=O)[O-])cc[n+]2[O-])cc1
Reactant: O=C(O)C1CCc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Oc3ccc4c(c3)CC(C(=O)O)CC4)cc[n+]2[O-])cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of N-(4-methoxybenzyl)-4-nitropyridin-2-amine 1-oxide (25.6 g, 0.0929 mol), 7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (17 g, 0.088 mol) and cesium carbonate (92 g, 0.28 mol) in DMF (200 mL, 3 mol) was heated with stirring at 80° C. overnight. The reaction mixture was allowed to cool and then concentrated to small volume and 200 ml of water was added. The solution was acidified with conc. HCl to pH=4. The aqueous solution was removed and the remaining organic solution was washed with water (3×). The residue was treated with 1N NaOH (150 ml) and extracted with DCM (3×). The aqueous solution was acidified with conc. HCl. A precipitate formed and was filtered, washed with water (3×), and dried to give 7-({2-[(4-methoxybenzyl)amino]-1-oxidopyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (33 g, 89%) as a brown solid. 1H NMR (d6-DMSO, 400 MHz) δ: 12.40 (s, 1H); 8.03 (d, 1H); 7.80 (t, 1H); 7.20 (d, 2H); 7.12 (d, 1H); 6.82 (d, 2H); 6.76 (m, 2H); 6.20 (s, 1H); 6.10 (d, 1H); 4.30 (d, 1H); 3.70 (s, 3H); 2.80 (m, 4H); 2.65 (m, 1H); 2.08 (m, 1H); 1.74 (m, 1H) LCMS ES+ 421.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].[CH2:35]([O:37][C:38](=[O:48])[CH2:39][C:40]1[CH:45]=[C:44](Br)[CH:43]=[CH:42][C:41]=1[F:47])[CH3:36]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:35]([O:37][C:38](=[O:48])[CH2:39][C:40]1[CH:45]=[C:44]([C:21]2[CH:20]=[CH:19][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:34])=[CH:23][CH:22]=2)[CH:43]=[CH:42][C:41]=1[F:47])[CH3:36]
Reactant: CCOC(=O)Cc1cc(Br)ccc1F
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)Cc1cc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)ccc1F

Procedure:
Following the procedure described in Example 17, Step 2, {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester, (5-bromo-2-fluoro-phenyl)-acetic acid ethyl ester, and (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) were reacted to provide (4′-{-4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-4-fluoro-biphenyl-3-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([NH:15]C(=O)C)[CH:12]=[CH:13][CH:14]=2)=[C:4]([NH:19][C:20]2[C:29]3[C:24](=[N:25][C:26]([CH2:30][CH2:31][CH3:32])=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:3]=1.Cl.[OH-].[Na+]>O>[NH2:15][C:11]1[CH:10]=[C:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[NH:19][C:20]2[C:29]3[C:24](=[N:25][C:26]([CH2:30][CH2:31][CH3:32])=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCCc1ccc2c(Nc3cc(C)ccc3Sc3cccc(NC(C)=O)c3)ccnc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3cccc(N)c3)ccnc2n1
Temperature: 100 °C
Yield: 66.3 %

Procedure:
The title compound was prepared by treating the product of Example 199d (1.20 g, 2.71 mmol) with 10 mL of a 50% solution of HCl in water. This reaction mixture was heated to 100° C. for 1 hr. At this time the reaction mixture was cooled to room temperature and made basic with 2N NaOH. This was then extracted with CH2Cl2, which was then dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (720 mg, 66%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[N:12]=[N+:13]([O-:25])[C:14]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][CH2:21][O:22]4)=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO.CC[O:30]C(C)=O>>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[N:12]=[N+:13]([O-:25])[C:14]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][CH2:21][O:22]4)=[CH:17][C:15]=3[N+:16]=2[O-:30])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)OCCC3
Reactant: CCOC(C)=O
Solvent: CO
Product: [O-][n+]1nc(NCCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)OCCC3

Procedure:
H2O2 (70%, 0.74 mL, ca. 14.7 mmol) was added dropwise to a stirred solution of TFM (2.1 mL, 14.7 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 243 (509 mg, 1.5 mmol) and TFA (0.57 mL, 7.4 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 243 (80 mg, 16%) and (ii) 1,4-dioxide 244 (75 mg, 16%) as a red solid: mp (MeOH/EtOAc) 173-176° C.; 1H NMR δ 8.33 (br t, J=4.9 Hz, 1H, NH), 8.01 (s, 1H, H-5), 7.62 (s, 1H, H-10), 4.31 (br dd, J=5.3, 5.2 Hz, 2H, H-8), 3.83 (br t, J=4.6 Hz, 4H, 2×CH2O), 3.62-3.68 (m, 2H, CH2N), 3.03-3.08 (m, 2H, H-6), 2.58 (br dd, J=6.2, 6.0 Hz, 2H, CH2N), 2.50 (m, 4H, 2×CH2N), 2.07-2.13 (m, 2H, H-7), 1.84-1.91 (m, 2H, CH2); 13C NMR δ 154.5, 148.7, 136.1, 133.2, 129.9, 117.3, 105.2, 67.1, 66.9 (2), 57.8, 53.8 (2), 41.6, 26.1, 24.4, 21.3. Anal. calcd for C17H23N5O3.¼H2O: C, 55.8; H, 6.5; N, 19.1. Found: C, 55.8; H, 6.5, 18.8%.