Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].Cl.O>C(O)C>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]2[N:12]=[C:11]([CH:22]([C:23]([F:25])([F:26])[F:24])[OH:27])[NH:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(-c2nc(C(=O)C(F)(F)F)[nH]c2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc(C(O)C(F)(F)F)[nH]c2-c2ccc(OC)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3.8 g (10 mmoles) of the compound of Example 9 in 50 ml ethanol chilled to 0°-5°, was added 1.0 g (25 mmoles) sodium borohydride all at once. After 0.5 hour at that temperature, the cooling was discontinued, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was then chilled to 0°-10° C., and 40 ml of 2 N HCl was cautiously added, followed by another 40 ml of water. Most of the ethanol was removed under vacuo. The crystalline product was collected by filtration, washed with water, and air dried. Recrystallization from acetonitrile yielded 3.9 of the title compound, m.p. 242°-245°. The infrared and NMR spectra were consistent with the assigned structure.
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25]>C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:24]2[NH:25][C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cccc(-c2nc(C(=O)OC(C)(C)C)c(-c3ccncc3)[nH]2)c1
Yield: 31.2 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(4-pyridyl)propionate (3.2 g) and 3-methoxybenzylamine (2.1 g) were dissolved in toluene (120 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 10 to give tert-butyl 2-(3-methoxyphenyl)-5-(4-pyridyl)imidazole-4-carboxylate (1.4 g), melting point 197-199° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](OS(C(F)(F)F)(=O)=O)[C:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:33][NH:34][CH2:35][CH2:36][OH:37]>>[C:23]([O:22][C:20]([C:6]1[C:7]([N:34]([CH2:35][CH2:36][OH:37])[CH3:33])=[N:8][C:9]2[C:4]([C:5]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: CNCCO
Product: CN(CCO)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 92 step A from tert-butyl 6-chloro-4-phenyl-2-(trifluoromethylsulfonyloxy)quinoline-3-carboxylate (prepared in analogy to example 91 step A to C, 100 mg, 0.21 mmol) and 2-(methylamino)ethanol (0.164 ml, 2.05 mmol). Pale yellow solid (65 mg, 77%). MS (ESI): 413 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[C:12]([C:15]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][N:18]([CH2:27][CH3:28])[C:17](=[O:29])[C:16]=1[N+]([O-])=O)(=[O:14])[CH3:13].Cl>C1COCC1.C(OCC)(=O)C>[C:12]([C:15]1[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:19][N:18]([CH2:27][CH3:28])[C:17](=[O:29])[C:16]=1[NH:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11])(=[O:14])[CH3:13]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1c(Cl)cncc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2c(Cl)cncc2Cl)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
To a stirred suspension of 50 mg (1.25 mmol) of sodium hydride in 5 ml of THF, 100 mg (0.62 mmol) of 4-amino-3,5-dichloropyridine in 5 ml of THF was added. The mixture was allowed stirring 30 minutes at room temperature and then cooled to 0° C. 150 mg (0.52 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 10 ml of THF was added. The reaction was allowed to warm to room temperature and to continue stirring for 12 hours. The mixture was acidified with 2N HCl to pH 2. Ethyl acetate was added and the organic layer was washed with water, brine, dried over Na2SO4 anhydride and evaporated. The residue obtained (210 mg) was purified by column chromatography (silica gel, hexane/ethyl acetate 1:1) to yield the title compound (35 mg, 16.7% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[CH3:15][NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27]>>[C:10]([O:9][C:8](=[O:14])[NH:7][CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([NH:16][CH3:15])=[C:18]([N+:26]([O-:28])=[O:27])[CH:19]=2)[CH2:2]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: CNc1ccc(C(=O)N2CCCC(NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]

Procedure:
Prepared similarly to intermediate 20 from tert-butyl piperidin-3-ylcarbamate (available from, for example, Apollo Scientific Ltd) and 4-(methylamino)-3-nitrobenzoic acid.
Reaction SMILES: [Cl:1]Cl.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+]([O-])=O)[C:5]=1[Cl:13].[OH-].[Na+]>>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:1])[C:5]=1[Cl:13]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: ClCl
Agent: [Na+]
Agent: [OH-]
Product: Clc1cccc(Cl)c1Cl
Temperature: 170 °C
Yield: 0.8 %

Procedure:
Chlorine gas (400 mg, 573 millimoles) was bubbled into a solution of benzenephosphorusdichloride (789 microliters, 573 millimoles) in BPOD (10 ml) at room temperature. The initially clear colorless solution became warm and turned pale yellow, but remained clear. To this mixture was added 1,2-dichloro-3-nitrobenzene (1.0 g, 573 millimoles) and then the reaction mixture was heated to 170° C. for 5 hours. The cooled reaction mixture was then poured onto crushed ice/water (100 ml) and neutralized with 50% aqueous sodium hydroxide. After extracting with ether, the ether extracts were dried and concentrated in vacuo to yield 1,2,3-trichlorobenzene (880 mg, 94 weight %).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[C:9]([CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:10][C:11]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:12]([CH:22]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[N:18][CH:17]=1)=[O:14].[CH3:38][N:39]1[CH:43]=[C:42](B(O)O)[CH:41]=[N:40]1>COCCOC.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>[CH3:38][N:39]1[CH:43]=[C:42]([C:8]2[C:9]([CH2:31][N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:10][C:11]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:12]([CH:22]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[N:18][CH:17]=2)=[O:14])[CH:41]=[N:40]1
Reactant: Cn1cc(B(O)O)cn1
Reactant: O=C(Nc1ccnnc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1
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
Product: Cn1cc(-c2cc(C(=O)Nc3ccnnc3)c(OCc3ccccc3)cc2CN2CCOCC2)cn1
Temperature: 120 °C

Procedure:
Na2CO3 (0.25 ml, 0.25 mmol) and palladium tetrakis (8.61 mg, 7.45 μmol) was added to 5-bromo-4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]-N-4-pyridazinylbenzamide (may be prepared as described in Example 1; 60 mg, 0.12 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (18.76 mg, 0.149 mmol) in 1,2-dimethoxyethane (3 ml). The mixture was heated at 120° C. in a microwave for one hour and the solvent was removed in vacuo. The residue was purified by MDAP to yield the title compound as a white solid. 8 mg.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:18])[CH2:11][CH:12]1[S:17][CH2:16][CH2:15][CH2:14][S:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>C1COCC1>[CH2:23]([O:18][C@@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][CH:12]1[S:17][CH2:16][CH2:15][CH2:14][S:13]1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: O[C@@H](COCc1ccccc1)CC1SCCCS1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@@H](COCc1ccccc1)CC1SCCCS1
Reaction time: 0.2 h

Procedure:
A solution of (R)-1-benzyloxy-3-[1,3]dithian-2-yl-propan-2-ol (22.1 g) in THF (300 mL) was cooled to 0° C. 60% sodium hydride (4.35 g) was added, followed by stirring. After 12 minutes, allyl bromide (10 mL) was added and then the ice bath was removed. The mixture was further stirred at room temperature. After stirring overnight, the reaction solution was added to a mixture of ice and t-butyl methyl ether, and the organic layer was separated. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to silica gel chromatography to obtain the title compound (24.7 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11]3)[C:4]=2[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:14][CH2:13][C@H:12]([NH:15][C:23](=[O:25])[CH3:24])[CH2:11]3)[C:4]=2[CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: N[C@H]1CCN(c2cccc3c2CCO3)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CCN(c2cccc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-N-(2,3-dihydrobenzofuran-4-yl)-3-(amino)pyrrolidine (0.1 mmol) and triethylamine (0.15 mmol) were dissolved in CH2Cl2. Acetylchloride (0.12 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The organics were then washed with 1 N HCl, NaHCO3, and brine. The organic solution was dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography eluting with 4% methanol in CH2Cl2 to yield the title compound.
Reaction SMILES: Cl.[CH:2]([NH:5][OH:6])([CH3:4])[CH3:3].C(OCC)C.[OH-].[Na+].[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([CH3:22])=[CH:17][C:16]=1[N:23]=[C:24]=[O:25]>O>[OH:6][N:5]([CH:2]([CH3:4])[CH3:3])[C:24]([NH:23][C:16]1[CH:17]=[C:18]([CH3:22])[C:19]([CH3:21])=[CH:20][C:15]=1[CH3:14])=[O:25]
Reactant: CC(C)NO
Reactant: Cc1cc(C)c(N=C=O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(C)c(NC(=O)N(O)C(C)C)cc1C
Reaction time: 0.17 h
Yield: 67.7 %

Procedure:
A solution of N-isopropylhydroxylamine hydrochloride (1.85 g, 16.5 mmol) in water (5 mL) was combined with diethyl ether (50 mL) then cooled in an ice bath. A solution of sodium hydroxide (0.72 g, 18 mmol) in water (10 mL) was added over a 10 minute period. The reaction mixture was stirred for 10 minutes then 2,4,5-trimethylphenyl isocyanate (2.42 g, 15 mmol) was added as a solid. The reaction mixture was stirred at ambient temperature for 18 hours. A white solid was isolated by filtration then recrystallized from hexanes/ethyl acetate to provide 2.4 g of the desired product as a white crystalline solid, m.p. 176.2°-176.8° C. Analysis: Calculated for C13H20N2O2 : %C, 66.07; %H, 8.53; %N, 11.85; Found: %C, 65.85; %H, 8.35; %N, 11.68.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:16])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[F:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.COC(C)(C)C>[CH2:14]([O:13][C:11]([C:10]1[C:9]([CH3:16])=[N:8][N:7]2[C:2]([O:1][CH2:26][C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=3[F:18])=[CH:3][C:4]([CH3:17])=[CH:5][C:6]=12)=[O:12])[CH3:15]
Reactant: OCc1cccc(F)c1F
Reactant: CCOC(=O)c1c(C)nn2c(O)cc(C)cc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOC(=O)c1c(C)nn2c(OCc3cccc(F)c3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 180 mg (0.768 mmol) of 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester from Example 8A in 7 ml of dry tetrahydrofuran was admixed with 221.5 mg (1.537 mmol) of (2,3-difluorophenyl)methanol (CAS 75853-18-8), 423.2 mg (1.614 mmol) of triphenylphosphine and 0.32 ml (1.614 mmol) of diethyl azodicarboxylate. The resulting mixture was stirred at room temperature for 1 h, some of the solvent was drawn off under reduced pressure and the residue was admixed with 5 ml of tert-butyl methyl ether. The resulting precipitate was filtered off and dried under reduced pressure, which gave 190 mg (67% of theory, 97% pure) of the target compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH:7]=[CH:6][C:5]=1[OH:31])[CH2:2][CH3:3].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:31][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)[O:16][C:17]=2[CH3:18])=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3])[CH3:38]
Reactant: CCCc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1OCC(=O)OCC
Temperature: 55 °C

Procedure:
A mixture of 2-propyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl) ethoxy]phenol (0.90 mmol) (see Ex. 60, part B), ethyl 2-bromoethanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-2-propylphenoxy}ethanoic acid ethyl ester, 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=8.3 Hz, 2H), 7.67 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.44 (t, J=7.5 Hz, 2H), 7.36 (t, J=7.3 Hz, 1H), 6.72 (brs, 1H), 6.64 (brs, 2H), 4.59 (s, 2H), 4.54 (q, J=7.3 Hz, 2H), 4.20 (t, J=6.6 Hz, 2H), 2.97 (t, J=6.8 Hz, 2H), 2.58-2.61 (m, 2H), 2.38 (s, 3H), 1.61 (sextet, J=7.3 Hz, 2H), 1.27 (t, J=7.3 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11](OC)=[N:10][S:9]2(=[O:19])=[O:18])[CH:5]=[CH:6][CH:7]=1.[Si:21]([O:28][CH2:29][CH2:30][C@H:31]([NH2:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:39][C@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[F:38])[CH2:30][CH2:29][O:28][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])=[N:10][S:9]2(=[O:19])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](N)c1ccccc1F
Reactant: COC1=NS(=O)(=O)C(C)(c2cccc(Br)c2)C(C)(C)O1
Solvent: ClCCl
Product: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2F)=NS(=O)(=O)C1(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 64.7 %

Procedure:
A solution of 188 mg of 5-(3-bromophenyl)-2-methoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 157 mg of (S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propylamine in 2 ml of methylene chloride was stirred at room temperature for 3 hours and the conversion was checked by LCMS. Since no reaction had taken place yet, the solvent was concentrated by rotary evaporation and the residue with addition of 0.25 ml of methylene chloride was stirred at room temperature for 17 hours. Subsequently, the reaction mixture was stirred at 50° C. for 4 hours. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (206 mg) with a molecular weight of 613.7 g/mol (C27H38BrFN2O4SSi); MS (ESI): m/e=614 (M+H+).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH:20](=[O:22])[CH3:21]>O1CCCC1>[Br:13][C:14]1[C:19]([CH:20]([OH:22])[CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Brc1ccccn1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)c1cccnc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
Butyllithium (1.6M in hexanes, 26.7 mL, 42.7 mmol) was added over 15 minutes to a solution of diisopropylamine (6.0 mL, 42.8 mmol) in tetrahydrofuran (45 mL) at 0 to 5° C. under nitrogen, then stirred for 30 minutes. This solution was cooled to −78° C. and 2-bromopyridine (3.45 mL, 35.8 mmol) was added. The reaction was stirred at −78° C. for 1 hour. Acetaldehyde (2 mL, 35.6 mmol) was added and the reaction stirred at −78° C. for 1 hour then quenched with saturated ammonium chloride solution and allowed to warm to room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 0-10% diethyl ether/dichloromethane, to give 1-(2-bromopyridin-3-yl)ethanol (2.65 g, 37%). 1H NMR (400 MHz, CDCl3) δ8.27 (1H, dd, J=2.0, 4.7 Hz), 7.92 (1H, dd, J=2.0, 7.4 Hz), 7.31 (1H, dd, J=4.7, 7.8 Hz), 5.19 (1H, q, J=6.3 Hz), 2.18 (1H, s), 1.51 (3H, d, J=6.4 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]1[C:6](=[CH:7][C:8](=[O:34])[C:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:10]1)[O:5]2.CC1C=C(C)N=C(C)C=1.[CH3:44][C:45]([O:47][CH2:48][CH:49]1[O:54][C@H:53](Br)[CH:52]([O:56][C:57]([CH3:59])=[O:58])[C@@H:51]([O:60][C:61]([CH3:63])=[O:62])[C@H:50]1[O:64][C:65]([CH3:67])=[O:66])=[O:46]>ClCCl.C(=O)([O-])[O-].[Ag+2]>[CH2:16]([C:9]1[C:8](=[O:34])[CH:7]=[C:6]2[C:11](=[N:12][C:13]3[C:4]([O:5]2)=[CH:3][C:2]([O:1][C@@H:53]2[O:54][C@H:49]([CH2:48][O:47][C:45](=[O:46])[CH3:44])[C@H:50]([O:64][C:65](=[O:66])[CH3:67])[C@H:51]([O:60][C:61](=[O:62])[CH3:63])[C@H:52]2[O:56][C:57](=[O:58])[CH3:59])=[CH:15][CH:14]=3)[CH:10]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC(=O)OCC1O[C@H](Br)C(OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CCCCCCCCCCCCCCCCCCc1cc2nc3ccc(O)cc3oc-2cc1=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CCCCCCCCCCCCCCCCCCc1cc2nc3ccc(O[C@@H]4O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)cc3oc-2cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-hydroxy-2-octadecyl-3H-phenoxazine-3-one ("octadecylresorufin) (220 mg, 0.47 mmole), powdered, activated 4Å molecular sieves (0.5 g), sym-collidine (125 μL, 0.95 mmole), and silver carbonate (155 mg, 0.56 mmole) in dry dichloromethane (20 mL) is allowed to stir at room temperature, under an atmosphere of dry nitrogen gas, in the dark for 1 hour. To this mixture is added 1-bromo-2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside (389 mg, 0.95 mmole), slowly with stirring, and the resulting heterogenous solution allowed to stir as above for 72 hours. After this time the reaction mixture is filtered through a pad of diatomaceous earth. The precipitate is washed with chloroform (5×10 mL) and the combined organic filtrates are extracted with 1M aqueous HCl (1×75 mL), saturated aqueous sodium bicarbonate solution (1×75 mL), 1M sodium thiosulfate (1×75 mL), and water (1×75 mL). The organic layer is dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure, and dried in vacuo to an orange-brown powder (440 mg). An analytical sample of the title compound can be isolated by preparative t.l.c. (20×20 cm SiO2 plate; eluent=9:1 chloroform:ethylacetate) with the bright-orange product eluting at the highest Rf (0.44), (50 mg from 200 mg applied).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:4][C:3]=1I.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:4][C:3]=1/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Cc1cc(-n2cnnn2)cc(I)c1N
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(-n2cnnn2)cc(C)c1N

Procedure:
To a solution of 1-(4-amino-3-iodo-5-methylphenyl)tetrazole (5 g) in acetronitrile (80 cm3) was added ethyl acrylate (2 g), triethylamine (2 g) and palladium acetate (0.1 g). The mixture was heated under reflux for 11/2 hours, cooled and then partitioned between water (100 cm3) and dichloromethane (100 cm3). The aqueous phase was re-extracted with more dichloromethane (100 cm3) and the combined organic phases were dried (MgSO4), filtered and evaporated in vacuo. The residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane: methanol, 20:1. Combination and evaporation of appropriate fractions gave a solid which on recrystallisation from ethyl acetate/methanol afforded yellow needles of trans-ethyl 3-(2-amino-3-methyl-5-[tetrazol-1-yl]phenyl)prop-2-enoate, m.p. 210°-211°, (3.45 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:20]4=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[C:20]4=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]4[CH2:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
Platinum(IV) oxide (9.7 mg) was added to a solution of 9-(3′-methoxybiphenyl-4-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (17.4 mg) in THF (dry) (15 mL) and MeOH (15 mL) and the mixture was stirred at 50° C. under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Silica-gel was added to the filtrate and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (6.5 mg) as colorless gum.