Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9].C([O:17][C:18]1[N:23]=[C:22]2[NH:24][CH:25]=[N:26][C:21]2=[CH:20][CH:19]=1)C1C=CC=CC=1>>[OH:17][C:18]1[N:23]=[C:22]2[N:24]([CH:2]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[O:9])[CH:25]=[N:26][C:21]2=[CH:20][CH:19]=1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: O=C1CCCCCC1Cl
Product: O=C1CCCCCC1n1cnc2ccc(O)nc21

Procedure:
From 2-chlorocycloheptanone and 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine, prepared in a similar manner as the one described in Example 1.11, the title compound was obtained. LCMS m/z=246.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.50 (m, 1H), 1.70-2.10 (m, 5H), 2.25-2.40 (m, 2H), 2.55-2.65 (m, 1H), 2.75-2.85 (m, 1H), 5.67 (dd, J1=9.5 Hz, J2=4.3 Hz, 1H), 6.77 (d, J=8.7 Hz, 1H), 8.08 (d, J=8.7 Hz, 1H), 8.88 (s, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.C(N(CC)CC)C.[O:20](S(C(F)(F)F)(=O)=O)[S:21]([C:24]([F:27])([F:26])[F:25])(=O)=[O:22]>ClCCl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:12][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:20])=[CH:10][CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Oc1ccc(-n2cncn2)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc(-n2cncn2)cc1)C(F)(F)F
Reaction time: 5 h

Procedure:
1.0 g of 4-[1,2,4]triazol-1-yl-phenol was dissolved in 10 ml of dichloromethane, and 1.72 ml of triethylamine was added thereto. 1.56 ml of Tf2O was added to the mixture and stirred for 5 hr. The reaction was terminated by using water, and the resulting mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under a reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:8]2)=[CH:4][CH:3]=1.C1([O:23][C:24](=O)[NH:25][C:26]2[S:27][C:28]([CH2:31][CH3:32])=[N:29][N:30]=2)C=CC=CC=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][CH2:13][NH:14][C:24]([NH:25][C:26]3[S:27][C:28]([CH2:31][CH3:32])=[N:29][N:30]=3)=[O:23])[CH2:8]2)=[CH:15][CH:16]=1
Reactant: CCc1nnc(NC(=O)Oc2ccccc2)s1
Reactant: NCCCN1CC(Cc2ccc(Cl)cc2)C1
Solvent: CS(C)=O
Product: CCc1nnc(NC(=O)NCCCN2CC(Cc3ccc(Cl)cc3)C2)s1

Procedure:
A solution of 3-[3-(4 chloro-benzyl)-azetidin-1-yl]-propylamine (0.100 mg, 0.418 mmol) and (5-ethyl-[1,3,4]thiadiazol-2-yl)-carbamic acid phenyl ester (0.11 mg, 0.439 mmol) in DMSO is stirred at room temperature for 18 hours then partitioned between ethylacetate and water. The organic phase is washed with brine and dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography using 5% methanol in DCM as eluent to afford 1-{3-[3-(4-chloro-benzyl)-azetidin-1-yl]-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-urea. [M+H] 394.1
Reaction SMILES: ClC1C=C([C@@H](O)CN(CCC2C=CC([C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[C:28](C)[C:27]=3C)=CC=2)C(=O)OC(C)(C)C)C=CC=1.OO.Cl([O-])=[O:40].[Na+]>C(#N)C.C(OCC)(=O)C>[C:32]([OH:33])(=[O:40])[C:29]1[CH:28]=[CH:27][CH:26]=[CH:31][CH:30]=1
Reactant: Cc1c(C=O)ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)c1C
Reactant: [O-][Cl+][O-]
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4′-formyl-2′,3′-dimethyl-1,1′-biphenyl-4-yl)ethyl)carbamate in acetonitrile (2.5 ml) and pH 4 buffer solution (sodium dihydrogenphosphate) (1.3 ml) was added 30% hydrogen peroxide solution (60 μl) and 80% sodium chlorite (128 mg) below 10° C. The reaction mixture was stirred at 40° C. for 1.5 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a benzoic acid product. To a solution of the product in tetrahydrofuran (1.0 ml) was added 4N hydrochloride in dioxane (1.18 ml), and the mixture was stirred at room temperature for 12 hours. The resultant solid was collected by filtration and dried to give 4′-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2,3-dimethyl-1,1′-biphenyl-4-carboxylic acid hydrochloride (140 mg).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH3:5][O:6][C:7](=[O:27])[C:8]1[CH:13]=[C:12]([C:14](=[O:16])[CH3:15])[C:11](F)=[C:10]([F:18])[C:9]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26].CC(C)=O>CCOC(C)=O.O>[CH3:5][O:6][C:7]([C:8]1[C:9]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[C:10]([F:18])[C:11]2=[N:1][O:16][C:14]([CH3:15])=[C:12]2[CH:13]=1)=[O:27]
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
Sodium azide (128 mg, 1.95 mmol) was added to a mixture of 5-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (6) (601 mg, 1.59 mmol) in 3:1 acetone:water (16 ml) and heated to reflux. After 16 hours, the reaction mixture was cooled to room temperature, and diluted with EtOAc and water. The organic layer was washed with water, dried (MgSO4) and concentrated. The resulting residue was diluted with water (8 mL) and heated to reflux. After 5 hours, the mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried (MgSO4) and concentrated. Purification by flash column chromatography using the Biotage system (20% EtOAc in hexanes) provided the desired product (55) (410 mg, 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:37][O:38][CH2:39][CH2:40][CH2:41][NH2:42]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:42][CH2:41][CH2:40][CH2:39][O:38][CH3:37])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COCCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Product: COCCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and [3-(methyloxy)propyl]amine using methods similar to Example 563 to provide an orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (d, J=3.58 Hz, 4 H), 1.64 (d, J=7.16 Hz, 2 H), 1.69-1.75 (m, 2 H), 1.77-1.82 (m, 2 H), 2.38-2.44 (m, 2 H), 3.24-3.26 (m, 3 H), 3.34-3.47 (m, 8 H), 4.15-4.25 (m, 4 H), 7.11-7.18 (m, 2 H), 7.40 (dd, J=8.63, 5.69 Hz, 2 H), 8.00 (s, 1 H), 8.56 (d, J=1.26 Hz, 1 H), 10.34 (t, J=5.90 Hz, 1 H), 17.19 (s, 1 H); ES+ MS: 539 (M+H+).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:23])[CH:9]([C:17]2[S:21][N:20]=[C:19]([CH3:22])[N:18]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH2:24]>N1C=CC=CC=1.N1CCCCC1>[C:1]1([NH:7][C:8](=[O:23])[CH:9]([C:17]2[S:21][N:20]=[C:19]([CH3:22])[N:18]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[S:24])[NH2:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1nsc(C(CCCCCC#N)C(=O)Nc2ccccc2)n1
Reactant: S
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cc1nsc(C(CCCCCC(N)=S)C(=O)Nc2ccccc2)n1
Temperature: 50 °C
Reaction time: 120 h

Procedure:
To a stirred mixture of 7-cyano-2-(3-methyl[1,2,4]thiadiazol-5-yl)heptanoic acid phenylamide (2021044) (0.55 g, 1.7 mmol) in pyridine (120 mL) and piperidine (30 mL) was slowly bubbled hydrogen sulphide for 15 min. The resultant mixture was then stoppered and stirred at 50° C. for five days. The solvent was removed under reduced pressure, water (150 mL) was added to the residue, and the resultant solution was extracted with dichloromethane (3×150 mL). The crude product (1.6 g) was purified by preparative liquid chromatography to afford 2-(3-methyl-[1,2,4]thiadiazol-5-yl)-7-thiocarbamoyl heptanoic acid phenylamide (2021036) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>CCOCC>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:31]([F:30])=[CH:32][CH:33]=2)[N:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.28 ml of triethylamine and 0.14 ml of 4-fluorobenzoyl chloride are mixed together then the reaction medium is agitated at ambient temperature for 2 hours. Then ether is added, followed by separating, drying, taking up in water, extracting with methylene chloride, drying and evaporating the solvents. In this way 283 mg of expected product is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.[CH3:28][C:29]1[S:33][C:32]([C:34]([OH:36])=[O:35])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:27][O:26][C:17]1[CH:18]=[C:19]([O:22][CH2:23][O:24][CH3:25])[CH:20]=[CH:21][C:16]=1[C:4]1[C:3]([CH2:2][O:36][C:34]([C:32]2[S:33][C:29]([CH3:28])=[CH:30][CH:31]=2)=[O:35])=[C:12]2[C:7]([NH:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[NH:11]2)=[CH:6][CH:5]=1
Reactant: COCOc1ccc(-c2ccc3c(c2CCl)NC(=O)C(C)(C)N3)c(OC)c1
Reactant: Cc1ccc(C(=O)O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1ccc(-c2ccc3c(c2COC(=O)c2ccc(C)s2)NC(=O)C(C)(C)N3)c(OC)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A mixture of 8-chloromethyl-7-(2-methoxy-4-methoxymethoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 10, 238 mg, 0.609 mmol), 5-methyl-2-thiophenecarboxylic acid (133 mg, 0.936 mmol), and potassium carbonate (261 mg, 1.89 mmol) was suspended in anhydrous N,N-dimethylformamide (5 mL) and stirred at 80° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL). It was washed with water (100 mL) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (264 mg) as a yellow amorphous product. (Yield 87%)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([CH:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][O:19][C:18]2[CH:27]=[CH:28][C:29]([C:31]([O:33]C)=[O:32])=[CH:30][C:17]1=2)=[O:15])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:31]([C:29]1[CH:28]=[CH:27][C:18]2[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH:16]([C:14]([NH:13][C:5]3[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=3[CH:10]([CH3:11])[CH3:12])=[O:15])[C:17]=2[CH:30]=1)([OH:33])=[O:32]
Reactant: COC(=O)c1ccc2c(c1)C(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1c2ccccc2COc2ccc(C(=O)O)cc21
Temperature: 25 °C
Yield: 92.5 %

Procedure:
After 0.58 g of 6,11-dihydro-N-(2,6-diisopropylphenyl)-2-methoxycarbonyldibenz[b,e]oxepin-11-carboxamide (Compound 24) obtained in Example 24 was dissolved in 24 ml of methanol, 6 ml of 5 N sodium hydroxide was added to the solution. The mixture was heated under reflux for 5 minutes. After completion of the reaction, the mixture was cooled to room temperature and 4N hydrochloric acid was added thereto to adjust pH to 3. The mixture was extracted with ethyl acetate. After washing with saturated sodium hydroxide aqueous solution, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to dryness to obtain 0.52 g of Compound 25.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.[C:25]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34][Cl:35])=[CH:32][CH:31]=1)([CH2:28][CH3:29])([CH3:27])[CH3:26]>O>[ClH:35].[C:25]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:2]([CH2:3][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][CH:5]=2)[CH3:1])=[CH:32][CH:31]=1)([CH2:28][CH3:29])([CH3:27])[CH3:26]
Reactant: CCC(C)(C)c1ccc(CCl)cc1
Reactant: CNCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(C)c1ccc(CN(C)Cc2cccc3ccccc23)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 1.03 g of N-methyl-1-naphthylmethylamine, 0.7 g of sodium carbonate and 10 ml of dimethylformamide was added 1.3 g of 4-tert-pentylbenzyl chloride and was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with benzene, and the benzene solution was washed with water. After distilling away benzene, 1.5 ml of concentrated hydrochloric acid was added and then an excess of concentrated hydrochloric acid was removed. A small amount of acetone was added and 1.33 g of formed white crystal was filtrated. White crystal of N-(4-tert-pentylbenzyl)-N-methyl-1-naphthylmethylamine hydrochloride (Compound of Example 12) was obtained by recrystallization from acetone.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:14][C@@H:15]1[C:24]2[C:19](=[CH:20][C:21]([Cl:26])=[CH:22][C:23]=2[Cl:25])[NH:18][C@@H:17]([C:27]([O:29]C)=[O:28])[CH2:16]1)=[O:13])=[N+]=[N-].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>C(OCC)(=O)C.[Pd]>[ClH:25].[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:14][C@@H:15]1[C:24]2[C:19](=[CH:20][C:21]([Cl:26])=[CH:22][C:23]=2[Cl:25])[NH:18][C@@H:17]([C:27]([OH:29])=[O:28])[CH2:16]1)=[O:13]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)Cc2ccccc2CN=[N+]=[N-])c2c(Cl)cc(Cl)cc2N1
Agent: [Pd]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: Cl
Product: NCc1ccccc1CC(=O)N[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Reaction time: 18 h

Procedure:
To a solution of trans-4-(2-azidomethylphenyl)methylcarbonylamino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (0.3 g, 0.67 mmol) in ethyl acetate (30 ml) was added ditertiary-butyldicarbonate (0.22 g, 1.0 mmol) and 10% palladium on carbon and this mixture was hydrogenated under 50 psi pressure for 18 hours. The mixture was filtered and the solvent was removed under vacuum to yield the crude product, which was purified by flash chromatography (using ethyl acetate in hexane as eluent) followed by recrystallisation from ethyl acetate/hexane to give the title compound, m.p. 224°-225° C.; δ (360 MHz, DMSO) 1.38 (1H, ddd, J=13.2, 12.6 and 3.8 Hz, CHACHBHCCHD), 2.18 (1H, dm, J=13.2 Hz, CHACHBHCCHD), 3.50 (2H, s, NHCOCH2Ar), 3.73 (3H, s, CO2CH3), 3.95 (1H, dd, J=12.6 Hz, CHACHBHCCHD), 4.17 (2H, d, J=5.7 Hz, ArCH2NH), 5.00 (1H, m, CHACHBHCCHD), 6.70 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.87 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.92 (1H, s, ArNH), 7.19 (4H, m, ArH), 8.50 (1H, d, J=6.9 Hz, CHDNHCOCH2); m/e (EI+) 522 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH:27](O)([CH3:29])[CH3:28]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([CH2:15][C:16]([O:18][CH:27]([CH3:29])[CH3:28])=[O:17])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 5-benzyloxy-2-nitrophenylacetic acid (4.0 g) and conc. sulphuric acid (0.6 ml) in isopropyl alcohol (40 ml) was stirred under reflux for 1 day. After removal of solvent by evaporation, the resulting residue was dissolved with ethyl acetate. The ethyl acetate extract was washed successively with aqueous sodium hydrogen carbonate solution, water, and brine, and was dried over magnesium sulfate, and concentrated under reduced pressure to give isopropyl 5-benzyloxy-2-nitrophenylacetate (4.20 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)=[N:5][N:4]=[N:3]1.N1C(C)=CC=CC=1C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].Cl>ClCCl>[C:26]1([O:25][C:23](=[O:24])[NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[CH:8]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cn1nnnc1-c1cccc(N)c1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
In a dry flask of 1-methyl-5-(3-aminophenyl)-tetrazole (24.0 g, 137 mmol) was dissolved in dichloromethane (1.4 L) and 2,6-lutidine (44.1 g, 411 mmol) was added. Phenyl chloroformate (21.2 g, 136 mmol) was added in 4 portions over 15 minutes, then the reaction was stirred for 1.5 hours. The reaction was poured into 1N aqueous hydrochloric acid (200 mL) and the mixture was extracted with dichloromethane three times (200 mL). The combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude brown material was dissolved in hot toluene, filtered, and allowed to precipitate at 0° C. to give 34.1 g of a white solid. The filtrate was concentrated and recrystallized from toluene again to give an additional crop of off-white crystals (3.44 g, 93% total). 1H NMR (300 MHz, CDCl3), δ: 10.51 (bs, 1H), 8.01 (s, 1H), 7.71 (dt, J=7, J′=2, 1H), 7.55 (m, 2H), 7.41 (m, 2H), 7.24 (m, 2H), 4.14 (s, 3H).
Reaction SMILES: CCCCCC.[H-].[Na+].[OH:9][CH2:10][C:11]1[O:12][CH:13]=[CH:14][CH:15]=1.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([Cl:26])([Cl:25])[Cl:24])[CH:20]=[C:19](Cl)[N:18]=1>C(COC)OC.O>[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([Cl:24])([Cl:25])[Cl:26])[CH:20]=[C:19]([O:9][CH2:10][C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:18]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Reactant: OCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCCCCC
Product: Clc1cc(C(Cl)(Cl)Cl)cc(OCc2ccco2)n1
Temperature: 50 °C
Yield: 58.3 %

Procedure:
To 5.5 grams (0.115 mole) of hexane washed sodium hydride in 100 mls of dimethoxyethane was added over a 25 minute period, 11.28 grams (0.115 mole) of 2-(hydroxymethyl)furan dissolved in 30 mls of dimethoxyethane. An additional 25 mls of dimethoxyethane was added and the mixture heated to 50° C. for about 10 minutes. To this mixture was added 26.54 grams (0.1 mole) of 2,6-dichloro-4-(trichloromethyl)pyridine dissolved in 100 mls of dimethoxyethane. The mixture was heated under reflux (83° C.) for about 2.5 hours and the reaction mixture added to 600 mls of water and extracted with methylene chloride. The methylene chloride was evaporated from the extract leaving a black oil. This oil was distilled under reduced pressure to obtain 19.05 grams of the desired 2-chloro-6-(2-furanylmethoxy)-4-(trichloromethyl)pyridine product. The product, an oil, had a refractive index of n 25/d = 1.5722 and upon analysis was found to have carbon, hydrogen, nitrogen and chlorine contents of 41.19, 2.50, 4.23 and 42.49 percent, respectively, as compared with the theoretical contents of 40.40, 2.16, 4.28 and 43.37 percent, respectively, as calculated for the above named compound.
Reaction SMILES: [F:1][C:2]1[CH:15]=[N:14][C:5]2[N:6]=[CH:7][C:8](=[O:13])[N:9]([CH2:10][CH:11]=C)[C:4]=2[CH:3]=1.I([O-])(=O)(=O)=[O:17].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:15]=[N:14][C:5]2[N:6]=[CH:7][C:8](=[O:13])[N:9]([CH2:10][CH:11]=[O:17])[C:4]=2[CH:3]=1
Reactant: C=CCn1c(=O)cnc2ncc(F)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=CCn1c(=O)cnc2ncc(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Fluoro-1-(2-propen-1-yl)pyrido[2,3-b]pyrazin-2(1H)-one (163 mg, 0.795 mmol) was dissolved in 1,4-dioxane (5 ml) and water (5 ml). Sodium periodate (426 mg, 1.99 mmol) was added, followed by osmium tetroxide (0.17 ml of 4% aqueous solution). The mixture stirred at rt for 2 h, and then treated with water (20 ml) and extracted with 20% MeOH/DCM (3×100 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated to give (7-fluoro-2-oxopyrido[2,3-b]pyrazin-1(2H)-yl)acetaldehyde (existing mostly as the methyl hemiacetal) as an impure brown oil (193 mg, 117%).
Reaction SMILES: B(O)(O)[C@H]1N(C([C@@H](N)C(C)C)=O)CCC1.CS(O)(=O)=O.[CH3:21][O:22][C:23](=[O:30])[CH2:24][C@H:25]([CH2:28][F:29])[CH2:26]Br.[CH2:31]([O:33][C:34](=[O:44])[CH2:35][NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:32]>C(#N)C>[CH3:21][O:22][C:23](=[O:30])[CH2:24][C@H:25]([CH2:28][F:29])[CH2:26][N:36]([CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:44]
Reactant: COC(=O)C[C@H](CF)CBr
Reactant: CCOC(=O)CNCc1ccccc1
Agent: CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O
Agent: CS(=O)(=O)O
Solvent: CC#N
Product: CCOC(=O)CN(Cc1ccccc1)C[C@@H](CF)CC(=O)OC
Temperature: 25 °C
Yield: 100.1 %

Procedure:
In a 2.5-1 four-necked flask equipped with a mechanical stirrer, a reflux condenser, a Pt-100 thermometer, and an argon in/outlet, bromide 2 (110 g, 519 mmol) was dissolved in acetonitrile (880 ml). To this solution was added N-benzylglycine ethyl ester (256 g, 1.30 mol) and the reaction mixture was refluxed for 71 hours, slowly turning dark red during this time. After cooling to room temperature, the mixture was concentrated under reduced pressure. The dark red oil was filtered over silica gel (800 g) using EtOAc:heptane 1:9 as eluent, giving the crude title compound 3 (169 g) as yellow oil which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cnc(-c2ccccc2)c1
Yield: 65.5 %

Procedure:
Reaction of 4-phenylimidazole (400 mg, 2.78 mmol), NaH (60%, 108 mg, 2.70 mmol), and SEMCl (520 uL/2.94 mmol) followed by column chromatography on silica gel (hexane/EtOAC 1:1) gave the title compound (500 mg, 67%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ0.00 (s, 9H), 0.92 (t, 2H, J=9.0 Hz), 3.54 (t, 2H, J=9.0 Hz), 5.27 (s, 2H), 7.17 (s, 1H), 7.37-7.47 (m, 3H), 7.56 (d, 2H, J=9.0 Hz), 7.68 (s, 1H). ES-MS m/z 275 (M+H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[C:9]([F:19])[CH:8]=1.[C:20](=[O:22])=[O:21]>C1COCC1.O>[CH:15]1([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:20]([OH:22])=[O:21])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C=O
Reactant: Fc1cc(Br)ccc1COC1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(COC2CCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6 M in hexane; 7.0 ml) was added to a solution of 4-bromo-1-cyclobutoxymethyl-2-fluorobenzene (2.6 g) in THF (50 ml) at −78° C. After 15 minutes, dry ice (4.4 g) was added. After warming to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The aqueous phase was acidified and again extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The product with the molecular weight of 224.23 (C12H13FO3); MS (ESI): 225 (M+H+) was obtained in this way.