Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][N:15]([CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CO.[OH-].[Li+]>O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][N:15]([CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CCCCN(CC(NC(=O)OC(C)(C)C)C(=O)O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
(S)-methyl 2-(tert-butoxycarbonyl)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)-propanoate iv (500 mg, 1.06 mmol) was dissolved in the mixed solvent system: THF (4 mL), methanol (1 mL), and water (2 mL). Powdered lithium hydroxide (250 mg, 10.4 mmol) was added. The light yellow slurry was stirred at rt for 15 h, and then concentrated in vacuo. The residue was partitioned between ether and water. The ether phase was discarded, and the aqueous phase was treated with 1 N HCl until the pH was 4. This acidic solution was extracted with ethyl acetate four times. The combined ethyl acetate extracts were dried (MgSO4) and concentrated in vacuo to give 430 mg (89%) of 2-(tert-butoxycarbonylamino)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoic acid (Example 26) as a yellow oil. 1H NMR (CD3OD, 300 MHz) δ 1.38 (s, 9H), 1.51-1.60 (m, 2H), 1.89-1.98 (m, 2H), 3.28-3.32 (m, 2H), 3.59-3.64 (dd, J=14.95, 9.46 Hz, 1H), 3.71-3.74 (m, 1H), 4.33 (dd, J=9.61, 4.43 Hz, 1H), 4.87-4.94 (m, 2H), 5.63-5.72 (m, 1H), 7.71-7.77 (m, 3H), 8.01 (dd, J=7.48, 1.37 Hz, 1H); MS m/z 358 (M++1-Boc).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][CH2:6][C:5]([CH2:18][OH:19])([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[N+:15]([O-:17])=[O:16])[CH2:4][O:3]1.N12CCN(CC1)CC2.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.[Cl-].[NH4+]>ClCCl>[CH3:1][C:2]1([CH3:20])[O:7][CH2:6][C:5]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[N+:15]([O-:17])=[O:16])([CH2:18][O:19][S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CO)(CCn2ccnc2[N+](=O)[O-])CO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(CCn3ccnc3[N+](=O)[O-])COC(C)(C)OC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.7 %

Procedure:
25 mg (0.086 mmol equivalents) of 2,2-dimethyl-5-hydroxymethyl-5-[2-(2-nitro-1H-imidazol-1-yl)ethyl]-1,3-dioxane was dissolved in 1 mL of dichloromethane, 19 mg (0.172 mmol equivalents) of 1,4-diazabicyclo[2,2,2]octane and 19 mg (0.10 mmol equivalents) of p-toluenesulfonyl chloride were added thereto, and the mixture was stirred at room temperature (25° C.) for 4 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were dried with anhydrous magnesium sulfate and then concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=1/3) to give 18 mg (0.041 mmol equivalents) of 2,2-dimethyl-5-[2-(2-nitro-1H-imidazol-1-yl)ethyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=[O:9].[CH2:16](O)C>[Pd]>[CH3:16][O:9][C:8](=[O:10])[CH2:7][CH2:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=1
Reactant: CCO
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Agent: [Pd]
Product: COC(=O)CCc1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A mixture of 2.20 g of 3-(trifluoromethyl) cinnamic acid, 166 mg of palladium/carbon (10%, wet), and 40 ml of ethanol was stirred overnight under a hydrogen atmosphere at 1 atm. Palladium/carbon was separated by filtration, and the filtrate was concentrated under reduced pressure. 20 ml of methanol and 4 drops of concentrated sulfuric acid were added and the mixture was stirred at 60° C. for 2 hours, and then left to cool down. After concentration under reduced pressure, 20 ml of a saturated sodium bicarbonate aqueous solution was added, and the resultant was extracted with 20 ml of dichloromethane. The extract was dried with anhydrous sodium sulfate and then concentrated under reduced pressure to afford 2.40 g of the captioned compound as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[CH:12]=[CH:13][C:14]([OH:16])=[O:15])[CH3:2].CCN(C(C)C)C(C)C>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:2]
Reactant: CCc1cc(C=O)cc(C)c1C=CC(=O)O
Agent: [Pd]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CO)cc(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 3-(2-ethyl-4-formyl-6-methyl-phenyl)-acrylic acid (2.75 g, 12.6 mmol) and DIPEA (1.8 g, 13.8 mmol) in ethanol (80 mL), Pd/C (275 mg, 10% Pd, moistened with 50% water) was added. The mixture was stirred for 16 h at rt under 1 atm of H2. The catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in EA and washed with 2 N aq. HCl, followed by 1 N aq. HCl and brine. The org. extract was dried over Na2SO4, filtered and evaporated to give 3-(2-ethyl-4-hydroxymethyl-6-methyl-phenyl)-propionic acid as a white solid (2.8 g). LC-MS: tR=0.76 min.
Reaction SMILES: [NH2:1][C@H:2]([CH3:31])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:32][C@@H:33]1[CH2:38][CH2:37][O:36][C:34]1=[O:35]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][C@H:2]([NH:1][C:34](=[O:35])[C@H:33]([OH:32])[CH2:38][CH2:37][OH:36])[CH3:31])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: C[C@@H](N)COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C1OCC[C@H]1O
Product: C[C@H](COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)NC(=O)[C@H](O)CCO
Yield: 77 %

Procedure:
The procedure described in Example 63 was repeated using 5-{[(2R)-2-aminopropyl]oxy}-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 2.4, preparation of starting materials) and (R)-(+)-α-hydroxy-γ-butyrolactone to give the title compound in 77% yield; NMR spectrum (DMSO-d6) 1.22 (d, 3H), 1.46-1.60 (m, 1H), 1.72-1.86 (m, 1H), 3.38-3.51 (m, 2H), 3.83-3.93 (m, 1H), 4.20-4.40 (m, 3H), 4.42-4.55 (m, 1H), 5.29 (s, 2H), 5.39 (d, 1H), 7.14 (d, 1H), 7.21 (d, 1H), 7.30-7.40 (m, 2H), 7.47-7.55 (m, 1H), 7.58 (d, 1H), 7.72 (t, 1H), 7.87 (t, 1H), 7.97 (d, 1H), 8.01 (s, 1H), 8.46 (s, 1H), 8.59 (d, 1H), 9.74 (s, 1H); Mass spectrum MH+ 538.0.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[C:2]1([CH:1]=[N:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CCNCC1
Solvent: Cc1ccccc1
Product: C(=NC1CCNCC1)c1ccccc1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
Benzaldehyde (21.2 g; 0.2 mol) was added, dropwise, to a solution of 4-aminopiperidine (20 g; 0.2 mol) in toluene (80 ml). The solution thus obtained was stirred at room temperature. After 3 h the solvent was removed by evaporation at reduced pressure and the residue was taken up twice with toluene. 31 g N-(phenylmethylene)piperidine-4-amine was thus obtained, and was used in the subsequent reactions without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16]([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:15]2[C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].Cl[C:48](=[O:54])[C:49]([O:51][CH2:52][CH3:53])=[O:50]>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([C:48](=[O:54])[C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16]([CH2:26][NH:27][C:28]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:34])=[C:15]2[C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(NCCNC(=O)OC(C)(C)C)cc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)N(CCNC(=O)OC(C)(C)C)c1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
To a solution of tert-butyl [6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (0.50 g, 0.89 mmol) in ethyl acetate (50 ml) was added saturated aqueous sodium hydrogen carbonate (50 ml), and the mixture was vigorously stirred at room temperature. Ethyl chloroglyoxylate (0.30 g, 2.2 mmol) was added dropwise to the obtained mixture and the mixture was vigorously stirred for 30 min. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl {{2-[(tert-butoxycarbonyl)amino]ethyl}[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]amino}(oxo)acetate (0.53 g, yield 90%) as a white powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[I-:14].[Na+].I>O>[I:14][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: [I-]
Reactant: CSc1ncc(C(F)(F)F)c(Cl)n1
Agent: I
Agent: [Na+]
Solvent: O
Product: CSc1ncc(C(F)(F)F)c(I)n1
Reaction time: 48 h
Yield: 56.4 %

Procedure:
4-Chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (I13) (5.00 g, 21.9 mmol) was placed into a reaction flask then sodium iodide (9.80 g, 65.6 mmol) and hydroiodic acid (58%; 70 mL) were added. The reaction mixture was stirred for 48 hours in darkness then diluted with water (200 mL) where upon a colourless solid precipitated. The precipitate was collected by filtration and was washed with 10% NaHCO3 solution until neutral. The resulting solid was washed with water (100 mL) then suction dried for 2 hours to give the title compound (I14) (3.956 g, 57%) as a pale yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 2.58 (s, 3H). LCMS Method C: rt 6.30 min, m/z 321.0 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:3]([O:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11]([NH:14][C:15]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]2[C:18]([C@H:19]3[CH2:29][C@H:20]3[CH2:21][O:22]2)=[CH:17][CH:16]=1)(=[O:13])=[O:12])[CH3:2].FC1C=CC(S(=O)(=O)NC2C=CC3[C@H]4C[C@H]4COC=3C=2C(OC)=O)=C(C=1)CO[C@@H]1CCN(C(OC(C)(C)C)=O)C1>>[CH2:1]([C@@H:3]([O:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11]([NH:14][C:15]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]2[C:18]([C@H:19]3[CH2:29][C@H:20]3[CH2:21][O:22]2)=[CH:17][CH:16]=1)(=[O:12])=[O:13])[CH3:2]
Reactant: CC[C@H](OC1CCNC1)c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OC[C@@H]1C[C@H]21
Agent: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CO[C@@H]2CCN(C(=O)OC(C)(C)C)C2)ccc2c1OC[C@@H]1C[C@H]21
Product: CC[C@@H](OC1CCNC1)c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OC[C@@H]1C[C@H]21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 213, starting from tert-butyl (R)-3-[(1aR,7bS)-5-fluoro-2-(4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl)benzyloxy]-pyrrolidine-1-carboxylate (Intermediate 218).
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:3][C:4](OC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.S(=O)(=O)(O)O>C1COCC1>[CH3:1]/[C:2](/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:3]\[CH2:4][OH:5]
Reactant: CCCCCCCCCC(C)=CC(=O)OC
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCC/C(C)=C/CO
Yield: 99 %

Procedure:
A dry THF solution (150 ml) of the crude product, methyl 3-methyl-2-dodecenoate (2′) (E/Z mixture, 98.5 g, 0.435 mol), was added dropwise at room temperature to a stirred suspension of LiAlH4 (16.5 g, 0.435 mol) in dry THF (300 ml). The reaction mixture was heated for 2 hours under reflux. After the mixture was reverted to room temperature, water and 10% sulfuric acid were slowly added in sequence, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under vacuum to obtain crude (E)-3-methyl-2-dodecen-1-ol (85.5 g, 99%) as an E/Z mixture. The E/Z ratio of the crude alcohol mixture was found to be 96:4 as a result of 250 MHz 1H-NMR analysis. A portion (50 g) of the residue was subjected to silica gel column chromatography (hexane elution) to obtain 41.3 g (83%) of a pure E isomer (3′).
Reaction SMILES: [Br-:1].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:22]([C:25]1[CH:26]=[CH:27][C:28]([Br:31])=[N:29][CH:30]=1)(=[O:24])[CH3:23]>C1COCC1>[Br:31][C:28]1[CH:27]=[CH:26][C:25]([C:22](=[O:24])[CH2:23][Br:1])=[CH:30][N:29]=1
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 206.1 %

Procedure:
Add pyridinium tribromide (7.0 g, 22 mmol) to a solution of 5-acetyl-2-bromo-pyridine (4.0 g, 20 mmol) in THF (100 mL) at room temperature. Stir the mixture for 16 h at room temperature under a nitrogen atmosphere. Quench the mixture with saturated aqueous NaHCO3 (50 mL, pH to 7.8). Extract the mixture with EtOAc (150 mL). Wash the organic layer with brine (50 mL) and concentrate in vacuo to obtain the desired intermediate as a dark brown oil (11.5 g) that was used without further purification. MS (ES+) m/z: 280 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([N:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([N:7]2[C:11]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccnn1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccnn1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of di-tert-butyl (1-phenyl-1H-pyrazol-5-yl)imidodicarbonate (5.30 g) in methanol (100 mL) was added 1N aqueous sodium hydroxide solution (73.0 mL) at room temperature, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated and adjusted to pH 5-6 with 2N hydrochloric acid. The reaction mixture was extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.80 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14].Cl>CO.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]#[C:12][Si:13]([CH3:14])([CH3:16])[CH3:15]
Reactant: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])ccc1F
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: C[Si](C)(C)C#Cc1cc(N)ccc1F
Yield: 92.1 %

Procedure:
460 mg of iron are added to a solution of 460 mg of [(2-fluoro-5-nitrophenyl)ethynyl](trimethyl)silane in 10 ml of methanol, and the medium is adjusted to pH 4-5 with concentrated hydrochloric acid. After refluxing for three and a half hours, the medium is cooled and then filtered through silica, and concentrated to dryness under reduced pressure. The residue is taken up with diethyl ether, the insoluble material is filtered off, and then the filtrate is concentrated to dryness under reduced pressure. 370 mg of 4-fluoro-3-[(trimethylsilyl)ethynyl]aniline are obtained in the form of an orangey oil, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([N+:23]([O-])=O)=[CH:21][N:22]=3)[N:19]=2)[CH:5]=[CH:6][CH:7]=1>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([NH2:23])=[CH:21][N:22]=3)[N:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc2ccc(N3CCCCC3c3cccc(F)c3)nn12
Solvent: CCO
Product: Nc1cnc2ccc(N3CCCCC3c3cccc(F)c3)nn12
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-(2-(3-fluorophenyl)piperidin-1-yl)-3-nitroimidazo[1,2-b]pyridazine (50 mg, 0.146 mmol) and SnCl2 dihydrate (165 mg, 0.732 mmol) in 5 mL EtOH was first stirred at 70° C. for 30 minutes, then cooled to ambient temperature and concentrated. EtOAc and water (10 mL each) were added to the solid residue, followed by Na2CO3 aqueous solution (2 mL×2 N) to obtain a phase break. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers was dried with Na2SO4 and concentrated to provide the product for the next step.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[O:6][CH:7]=1.[CH3:18][S:19]([CH2:22][C:23]1[N:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH:25]=[CH:26][N:27]=1)(=[O:21])=[O:20].[H-].[Na+]>>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1/[CH:9]=[CH:8]/[C:5]1[O:6][CH:7]=[C:3]([CH2:2][O:38][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:24]3[CH:25]=[CH:26][N:27]=[C:23]3[CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:37][CH:36]=2)[N:4]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3F)n2)cc1
Yield: 55.5 %

Procedure:
Using 4-(chloromethyl)-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (274 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (300 mg) and 65% sodium hydride (39.5 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (285 mg) as a colorless crystal powder.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[C:21]([N:22]4[CH2:30][C:29]5[C:24](=[C:25]([N+:31]([O-])=O)[CH:26]=[CH:27][CH:28]=5)[C:23]4=[O:34])=[CH:20][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO.C(Cl)Cl>[NH2:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[C:23](=[O:34])[N:22]([C:21]1[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:8][CH:9]=4)[N:14]=3)[NH:19][CH:20]=1)[CH2:30]2
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4cccc([N+](=O)[O-])c4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(N4Cc5cccc(N)c5C4=O)c3n2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]-7-nitro-isoindolin-1-one (148 mg, 0.2056 mmol) suspended in EtOH (5 mL) and mixture heated to 70° C. SnCl2.2H2O (232.0 mg, 1.028 mmol) added and the mixture heated at reflux. After 1 h a further ˜200 mg SnCl2.2H2O added. After 1 h reaction mixture cooled, diluted with DCM and sat NaHCO3 added. Mixture stirred vigorously for 30 mins then passed through a phase separator cartridge. Org phase concentrated to a yellow solid (158 mg). This material deprotected using Method E Step 2 to give the title compound after purification using hplc; 1H NMR (400 MHz, DMSO) δ 1.21 (6H, d), 3.49 (1H, sep), 5.35 (2H, s), 6.22 (2H, s), 6.65 (1H, d), 6.81 (1H, d), 7.31 (1H, dd), 7.99 (2H, d), 8.43 (1H, s), 8.50 (2H, d), 9.07 (1H, s), 12.27 (1H, brs) ppm; MS (ES+) 448.0.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([F:14])[C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[C:15]1([CH3:23])[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH4-].[Na+]>>[F:14][C:10]1[C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=[C:2]([NH:1][CH2:23][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[C:11]=1[O:12][CH3:13]
Reactant: COc1c(N)cc2oc(=O)[nH]c2c1F
Reactant: Cc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Product: COc1c(NCc2cccc(C)c2)cc2oc(=O)[nH]c2c1F

Procedure:
Following the procedure of Example 13, 6-amino-4-fluoro-5-methoxy-2-benzoxazolone (Example 11) was reacted with 3-tolualdehyde and the resulting product was reduced with sodium borohydride to give the title compound: m.p. 160°-161° C.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](O)[CH:6]=[C:7](S(O)(=O)=O)[CH:8]=2)[CH:3]=1.S([O-])(O)=O.[Na+].NCCCCCCCCN>O>[CH:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)c1cc(O)c2cc(O)ccc2c1
Agent: NCCCCCCCCN
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: c1ccc2ccccc2c1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Step 4) 2,8-Dihydroxy naphthalene-6-sulfonic acid (263 parts), sodium hydrogen sulphite (259 parts), water (900 parts) and 1,8-diaminooctane (400 parts) were stirred at 80° C. for 20 hours and then a further 20 hours at 95° C. The reaction was allowed to cool over night and filtered. The resultant filter cake was stirred in water (500 parts) and 2N sodium hydroxide (750 parts) for 15 minutes. 2N Hydrochloric acid (300 parts) was added and the precipitate filtered. The filter cake was dissolved in water (500 parts) and 2N sodium hydroxide (1000 parts) by heating to 50° C. 2N Hydrochloric acid was added and the precipitate filtered off at 40° C. The filter cake was oven dried at 70° C. to produce a naphthalene intermediate (111 parts).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].O>CO>[CH3:17][S:14]([CH2:13][CH2:12][N:9]1[C:8]2[CH:18]=[CH:19][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[CH:10]1)(=[O:15])=[O:16]
Reactant: COC(=O)c1ccc2c(c1)ncn2CCS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)CCn1cnc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 1-(2-methanesulfonylethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (0.2 g, 7.09 mmol) in methanol was added LiOH (50 mg) followed by water (1 mL). The reaction mixture was allowed to stir at room temp for 2 h. it was then concentrated to remove methanol and the aqueous layer was acidified with citric acid. The precipitated product was filtered to give 1-(2-Methanesulfonyl-ethyl)-1H-benzoimidazole-5-carboxylic acid (90%). MS-ESI m/z 269 (M+1); 1H NMR (300 MHz, DMSO-d6) δ 12.6 (br, 1H), 8.4 (s, 1H), 8.2 (s, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 4.8 (t, 2H), 3.8 (t, 2H), 3.0 (s, 3H).