Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([CH3:12])[N:5]=1)=[C:2]=S.C(N(CC)CC)C.Cl.Cl.[NH2:22][CH2:23][C:24]1([OH:32])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[N:26]12[CH2:31][CH2:30][CH:29]([CH2:28][CH2:27]1)[C@@:24]1([O:32][C:2]([NH:1][C:4]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([CH3:12])[N:5]=3)=[N:22][CH2:23]1)[CH2:25]2
Reactant: NCC1(O)CN2CCC1CC2
Reactant: Cc1nc(N=C=S)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NC2=NC[C@@]3(CN4CCC3CC4)O2)ccc1C#N
Temperature: 70 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To 6-isothiocyanato-2-methylnicotinonitrile (0.25 g, 1.43 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.5 mL, 3.666 mmol) and 3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.33 g, 1.46 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.67 mL, 4.28 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)-6-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)-2-methylnicotinonitrile (0.09 g, 0.3 mmol, 21% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.11 (s, 1H), 7.87 (d, J=7.93 Hz, 2H), 6.69 (s, 1H), 3.89 (d, J=10.38 Hz, 2H), 3.63 (d, J=10.38 Hz, 3H), 3.00 (s, 5H), 2.72-2.80 (m, 4H), 2.64-2.69 (m, 5H), 2.60 (s, 7H), 2.00 (d, J=2.14 Hz, 3H), 1.91 (s, 1H), 1.87 (s, 2H), 1.58 (s, 5H), 1.42-1.50 (m, 2H). MS (LC/MS) R.T.=0.48; [M+H]+=298.13.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.Br[CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([OH:16])=[O:15].CC(C)=O.C(O)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([OH:16])=[O:15])=[N:7][C:6]=2[CH:11]=1
Reactant: Sc1nc2cc(Cl)ccc2s1
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: CC#N
Product: O=C(O)C(Sc1nc2cc(Cl)ccc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
50.0 g. (0.248 m) 5-chloro-2-mercaptobenzothiazole and 53.0 g. (0.248 m) α-bromophenylacetic acid are dissolved in 1.51. acetone and the solution is heated for 4 hours in the presence of 50 ml. glacial acetic acid. The solution is concentrated to a smaller volume (about 200 ml) and the residual solid (90 g.) is collected. The resulting salt is suspended in 1 l of water and the mixture is stirred at room temperature overnight. The collected solid is recrystallized from 2.5 l. acetonitrile to give a total of 64 g (85% yield) of title compound melting at 190°-2° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2([C:13]([OH:15])=O)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:17](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:40]([O:47][C:48]1[CH:57]=[C:56]2[C:51]([C:52]([O:58][C:59]3[CH:64]=[CH:63][C:62](N)=[CH:61][C:60]=3[F:66])=[CH:53][CH:54]=[N:55]2)=[CH:50][CH:49]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[CH2:40]([O:47][C:48]1[CH:57]=[C:56]2[C:51]([C:52]([O:58][C:59]3[CH:64]=[CH:63][C:62]([N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8]([C:10]4([C:13]([NH2:17])=[O:15])[CH2:11][CH2:12]4)=[O:9])=[CH:61][C:60]=3[F:66])=[CH:53][CH:54]=[N:55]2)=[CH:50][CH:49]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)ccc23)c(F)c1
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OCc5ccccc5)ccc34)c(F)c2)CC1
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
To a solution of 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (1.14 g, 5.6 mmol) in dry CH2Cl2 (8 mL) was added HATU (2.11 g, 5.6 mmol) at 0° C. After stirring for 10 minutes, a solution of the 4-(7-(benzyloxy)quinolin-4-yloxy)-3-fluorobenzenamine (1.0 g, 2.8 mmol) and Et3N-(0.7 g, 6.9 mmol) in dry CH2Cl2 (5 mL) was added. The reaction mixture was stirred at 40° C. for 24 hrs, quenched with water (10 mL), and extracted with CH2Cl2 (30 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was chromatographed with a silica gel column (1:1 (v/v) EtOAc/n-hexane) to afford the title compound as a white solid (1.3 g, 85%).
Reaction SMILES: O1CCCC1.[H-].[Na+].Cl[CH2:9][C:10]([CH3:12])=[CH2:11].[CH2:13]([O:15][CH2:16][CH2:17][OH:18])[CH3:14]>O.C(O)C>[CH2:9]([O:18][CH2:17][CH2:16][O:15][CH2:13][CH3:14])[C:10](=[CH2:11])[CH3:12]
Reactant: CCOCCO
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)COCCOCC
Temperature: 25 °C

Procedure:
Into a 22 liter flask equipped with a reflux condenser, mechanical stirrer, addition funnel and nitrogen gas inlet, was placed 12.5 liters of dry tetrahydrofuran and 1958 grams of a 60% oil dispersion of sodium hydride. The mixture was stirred and heated to a gentle reflux, then 2.99 Kg of 3-chloro-2-methyl propene was added as one portion. Next, 2.79 Kg of 2-ethoxyethanol was added dropwise during 3.5 hours with no external heating of the resulting exothermic reaction. Refluxing was continued for two additional hours, then the solution was cooled to room temperature. Excess sodium hydride was decomposed by carefully adding ethanol then enough water to dissolve the resulting salts. The organic layer was separated and distilled through a vigreaux column at 156°-158° C. The yield of product was 3490 grams and was 99.4% pure by G.L.P.C. analysis.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]([O:17][CH3:18])=[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:6]=1)=[O:4].[CH2:23]([O:25][C:26]1[CH:27]=[C:28]2[C:32](=[C:33]([F:38])[C:34]=1[O:35][CH2:36][CH3:37])[C:31]([NH2:39])=[N:30][CH2:29]2)[CH3:24]>O1CCCC1>[BrH:1].[C:19]([C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:30]2[CH2:29][C:28]3[C:32](=[C:33]([F:38])[C:34]([O:35][CH2:36][CH3:37])=[C:26]([O:25][CH2:23][CH3:24])[CH:27]=3)[C:31]2=[NH:39])[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]=1[O:17][CH3:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1c(N2CCOCC2)cc(C(=O)CBr)cc1C(C)(C)C
Reactant: CCOc1cc2c(c(F)c1OCC)C(N)=NC2
Solvent: C1CCOC1
Product: Br
Product: CCOc1cc2c(c(F)c1OCC)C(=N)N(CC(=O)c1cc(N3CCOCC3)c(OC)c(C(C)(C)C)c1)C2
Temperature: 6 °C
Yield: 91.3 %

Procedure:
2-Bromo-1-(3-tert-butyl-4-methoxy-5-morpholinophenyl)ethanone (550 g, 1.485 mol) was dissolved in tetrahydrofuran (3 L) and subjected to clarifying filtration. A solution of 5,6-diethoxy-7-fluoro-3H-isoindol-1-ylamine (300 g, 1.254 mol) in tetrahydrofuran (4.5 L) was added dropwise to the above solution in 3 portions (100 g/1.5 L×3 times) while stirring at the ambient temperature of 6° C. After completion of the dripping, crystals were deposited. After stirring for 18 hours, the deposited crystals were collected by filtration and washed with ice-cooled tetrahydrofuran (1.2 L) to give 696.5 g of the captioned compound as wet crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)Cl)=[CH:5][CH:4]=1.[C:21]([NH:24][CH2:25][C:26](=[S:28])[NH2:27])(=[O:23])[CH3:22]>C(O)C>[C:21]([NH:24][CH2:25][C:26]1[S:28][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:27]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)NCC(N)=S
Reactant: COc1ccc(C(=O)C(Cl)c2ccc(OC)cc2)cc1
Solvent: CCO
Product: COc1ccc(-c2nc(CNC(C)=O)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
A mixture of 1,2-bis(4-methoxyphenyl)-2-chloroethanone (5.99 g) and 2-(acetylamino)ethanethioamide (3.00 g) in ethanol (30 ml) was refluxed for 2 hours. After allowing to cool to room temperature, the solvent was evaporated in vacuo, and the residue was dissolved in chloroform (200 ml) and aqueous solution of sodium hydrogencarbonate (200 ml). The separated organic layer was washed with water and brine, dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo. The resulting residue was dissolved in diethyl ether, added ethanol solution of hydrogen chloride, and the resulting precipitate was collected by filtration. The resulting crude compound was recrystallized with ethanol 10 ml). And the resulting crystal was collected by filtration, washed with ethanol and diethyl ether, and dried to give 2-acetylaminomethyl-4,5-bis(4-methoxyphenyl)thiazole (2.52 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15]([CH2:18][CH3:19])=[CH:16][CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[C:20]1([CH3:27])[C:25]([OH:26])=[CH:24][CH:23]=CC=1.B(F)(F)F.O(CC)[CH2:33][CH3:34]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15]([CH2:33][CH3:34])([C:18]3[CH:23]=[CH:24][C:25]([OH:26])=[C:20]([CH3:27])[CH:19]=3)[CH2:16][CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: Cc1ccccc1O
Reactant: CCOCC
Reactant: CC=C(CC)c1ccc2cc(C(=O)OCC)oc2c1
Agent: FB(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(O)c(C)c3)cc2o1
Yield: 55.4 %

Procedure:
6-(1-Ethyl-propenyl)-benzofuran-2-carboxylic acid ethyl ester (2.01 g, 7.78 mmol) and o-cresol (1.26 g, 11.7 mmol) and BF3—OEt2 (1.10 g, 7.78 mmol) in CH2Cl2 are reacted analogous to Example 30-C to give the title compound (1.58 g, 55%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])N1CC(=O)CC(S)C1.CC(OC(CP(OC)(OC)=O)=O)(C)C.[H-].[Na+].ClCCl>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19]
Reactant: COC(=O)C(c1ccccc1Cl)N1CC(=O)CC(S)C1
Agent: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1Cl
Reaction time: 0.33 h
Yield: 133 %

Procedure:
The crude (2-chlorophenyl)-(3-mercapto-5-oxopiperidin-1-yl)-acetic acid methyl ester (0.36 g, 1.14 mmol) was dissolved in THF (5 mL, argon sparged) and added to a mixture of tert-butyl P,P-dimethylphosphonoacetate (0.50 g, 2.23 mmol) and 60% sodium hydride (0.075 g, 1.87 mmol) in THF (4 mL, argon sparged), at room temperature under an argon atmosphere. After 20 minutes, dichloromethane (25 mL, argon sparged) was added and the mixture was washed with water (25 mL, argon sparged). The dichloromethane solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining yellow oil was purified by column chromatography on silica gel (15 g), eluting with heptane-ethyl acetate (4:1, argon sparged) to provide 3-tert-butoxycarbonylmethylene-5-mercaptopiperidin-1-yl)-(2-chlorophenyl)-acetic acid methyl ester (0.28 g, 59% yield) as a clear gel that was kept under an argon atmosphere at low temperature to prevent oxidation to the disulfide. 1H NMR (300 MHz, CDCl3/TMS): δ=7.60-7.15 (m, 4H), 5.55 (m, 1H), 4.77 (m, 1H), 3.67 (s, 3H), 3.20-2.00 (m, 7H), 1.41 (m, 9H). 13C NMR (75 MHz, CDCl3/TMS): δ=170.63 (2×), 165.26 (2×), 151.09 (3×), 134.64, 133.11 (4×), 129.83 (5×), 127.21, 118.35 (2×), 80.32 (2×), 67.57 (5×), 57.28 (6×), 52.28, 42.49-40.14 (8×), 34.54, 28.38 (2×). HRMS (DIP-CI): Calculated for (M+H+): 412.1349, found 412.1312.
Reaction SMILES: [C:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl>[O-2].[O-2].[Mn+4].O1CCCC1>[C:1]([C:5]1[NH:6][CH:7]=[C:8]([CH:10]=[O:11])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(CO)c[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C=O)c[nH]1

Procedure:
A 7.7 gm. portion of 2-tert-butyl-4-imidazolemethanol is added to 100 ml. of chloroform and 100 ml. of tetrahydrofuran and heated gently. A 25 gm. portion of manganese dioxide is added and the mixture is reacted as described in Example 22 giving the desired product as white crystals, m.p. 194°-195° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[N+:6]=1[O-:12])(=[O:3])[CH3:2].[SH-:13].[Na+].Cl>C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([SH:13])[N+:6]=1[O-:12])(=[O:3])[CH3:2]
Reactant: [SH-]
Reactant: CC(=O)Nc1cccc(Br)[n+]1[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1cccc(S)[n+]1[O-]
Yield: 79 %

Procedure:
2 gms (0.0087 mole) of 2-acetamido-6-bromopyridine-1-oxide was suspended in 35 ml (0.035 mole) of 1M aqueous sodium hydrosulfide and 30 ml of ethanol and agitated at 60° C for 5 hours and at room temperature one night. Concentrated hydrochloric acid was added dropwise to the cold yellow solution and the precipitated solid filtered, giving a 79% yield of 2-acetamido-6-mercaptopyridine-1-oxide. This impure product was purified by recrystallization from 2-propanol and hot filtration to remove a small amount of contaminating sulfur to give pale yellow crystals, m.p.=172.8°-173.5° C.
Reaction SMILES: CN(C)C(=O)C.[N:7]1[C:12]2[NH:13][CH:14]=[CH:15][C:11]=2[C:10]([NH2:16])=[N:9][CH:8]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>O>[C:17]1(=[O:22])[N:16]([C:10]2[C:11]3[CH:15]=[CH:14][NH:13][C:12]=3[N:7]=[CH:8][N:9]=2)[C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ncnc2[nH]ccc12
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1ncnc2[nH]ccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
To a 250 mL three-neck round bottom flask equipped with an overhead stirrer, nitrogen inlet, and thermocouple was charged 50 mL of dry N,N-dimethylacetamide followed by 5.0 g of 7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (3-1) [J. Davoll, J. Chem. Soc., 131-138 (1960)] and 11.6 g of phthalic anhydride. The resulting mixture was heated to 80° C. for 8 h and then cooled to 10° C. Water (40 mL) was added while maintaining the temperature below 15° C. The resulting slurry was aged for 4 h, then filtered, and the filter washed with 20 mL of 1:1 (v/v) dimethylacetamide/water followed by 30 mL of water. The cake was sucked dry, then washed with 50 mL of ethyl acetate. The solid was dried at 40° C. under vacuum with a nitrogen sweep to give 8.1 g of 4-phthalimido-7H-pyrrolo[2,3-d]pyrimidine (3-2); m.p. 276-277° C.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]3[N:22]=[C:23]([CH:26]=[CH:27][C:28]4[CH:29]=[CH:30][C:31]([S:34]([F:39])([F:35])([F:36])([F:37])[F:38])=[CH:32][CH:33]=4)[O:24][CH:25]=3)=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
25.0 mg (0.100 mmol) 95% sodium hydride were given to a solution of 216 mg (0.100 mmol) 4-(4-[Imidazol-1-yl]-butyl)-phenol in 5.0 ml DMF and stirred for 15 min. 346 mg (0.100 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued overnight. After addition of 10 ml water the resulting precipitate was isolated and washed with 2×10 ml water, 2×10 ml methanol and with diethyl ether. Yield 411 mg (78%). MS: M=526.2 (ESI+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CO>[Br:12][C:7]1[CH:6]=[C:5]([O:8][CH3:9])[C:4]([O:10][CH3:11])=[CH:3][C:2]=1[NH2:1]
Reactant: [Br-]
Reactant: COc1ccc(N)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N)c(Br)cc1OC
Reaction time: 0.33 h
Yield: 52.7 %

Procedure:
Following the procedure reported in JACS 1996, 118, 1028-1030, 4-aminoveratrole (3.06 g, 20.0 mmol) was dissolved in a mixture of dichloromethane (80 ml) and methanol (40 ml) at room temperature. Tetrabutylammonium tribromide (1.15 eq, 11.09 g) was added and the mixture was allowed to stir for 20 minutes. The mixture was extracted with saturated aqueous sodium sulfite solution. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 10:1 to 7:3 Hexanes/Ethyl Acetate) to give 2-bromo-4,5-dimethoxy-aniline 1.403 g (30%) of a yellow oil.
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]([C@H:6]([C:12]([OH:14])=[O:13])[C@H:7]([OH:11])[CH2:8][CH2:9][NH2:10])[CH2:2]1.NN=CS(O)(=O)=O.[NH:22](CCC[C@H](N1CCC1=O)C(O)=O)[C:23](N)=[NH:24]>>[OH:11][CH:7]([CH2:8][CH2:9][NH:10][C:23]([NH2:24])=[NH:22])[CH:6]([N:3]1[CH2:2][CH2:1][C:4]1=[O:5])[C:12]([OH:14])=[O:13]
Reactant: N=C(N)NCCC[C@@H](C(=O)O)N1CCC1=O
Reactant: NCC[C@@H](O)[C@@H](C(=O)O)N1CCC1=O
Agent: NN=CS(=O)(=O)O
Product: N=C(N)NCCC(O)C(C(=O)O)N1CCC1=O
Yield: 53 %

Procedure:
Proclavaminic acid (84.5 mg, 0.42 mmol) was treated aminoiminomethane-sulphonic acid in the fashion described above for the preparation 5-guanidino-2-(2-oxoazetidin-1-yl)pentanoic acid (Compound B) to give 3-hydroxy-5-guanidino-2-(2-oxoazetidin-1-yl)pentanoic acid as a white solid (62 mg, 53%), (Found: C, 38.76; H, 6.83; N, 19.54. C9H16N4O4. 2H2O requires: C, 38.57; H, 7.19; N, 19.99% (FAB; thioglycerol) MH+ 245, C9H16N4O4 requires 245; νmax.(KBr) 3 363, 1 719, 1 673, and 1 600cm-1, δH(400 MHz; D2O) 1.73-1.93 (2H, m, 4-H), 3.07(2H, t, J=4.0 Hz, 3'-H), 3.41 (2H, t, J=6.5 Hz, 5-H), 3.42-3.60 (1H, m), 3.60-3.68 (1H, m) 4'-H), 4.12 (1H, d, J=5.4 Hz, 2-H), 4.22 (1H, m, 3-H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])[CH:6](O)[C:7]([CH3:9])=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:19]([O:24]C)([O:22][CH3:23])[O:20][CH3:21]>>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])/[CH:6]=[C:7](\[CH3:9])/[CH2:8][P:19]([O:22][CH3:23])([O:20][CH3:21])=[O:24])[CH3:2]
Reactant: C=C(C)C(O)C(NC=O)C(=O)OCC
Reactant: COP(OC)OC
Agent: O=S(Br)Br
Product: CCOC(=O)C(/C=C(\C)CP(=O)(OC)OC)NC=O

Procedure:
By reaction of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite in a manner analogous to that described in Example 1, E-2-formylamino-4-methyl-5-dimethylphosphono-3-pentenoic acid ethyl ester is obtained in the form of a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.ClCCCl.[Cl:12][C:13]1[C:14]2[N:15]([C:19]([CH:23]3[CH2:26][C:25](=O)[CH2:24]3)=[N:20][C:21]=2[I:22])[CH:16]=[CH:17][N:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:12][C:13]1[C:14]2[N:15]([C:19]([CH:23]3[CH2:26][CH:25]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:24]3)=[N:20][C:21]=2[I:22])[CH:16]=[CH:17][N:18]=1
Reactant: CN1CCNCC1
Reactant: O=C1CC(c2nc(I)c3c(Cl)nccn23)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCN(C2CC(c3nc(I)c4c(Cl)nccn34)C2)CC1
Reaction time: 3 h

Procedure:
1-Methyl piperazine (5.75 mL, 0.0514 mol) in 1,2-dichloroethane (1096.7 mL, 13.892 mol) was added to 3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone (17.00 g, 0.04892 mol) and sodium triacetoxyborohydride (21.8 g, 0.0978 mol). The reaction stirred at it for 3 h. The reaction was concentrated, dissolved in CH2Cl2, and then washed with saturated NaHCO3 solution and brine. The product was dried over sodium sulfate, filtered, and concentrated in vacuo. The product was flushed through a quick silica gel plug (wetted with 100% CHCl3, eluted with 8% (7N NH3) MeOH in CHCl3), to afford the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.63 (1 H, d), 7.30 (1 H, d), 3.42 (1H, m), 2.94 (1H, m), 2.65 (4 H, m), 2.44 (8 H, m), 2.32 (3H, s); MS (ES+): m/z 431.85/433.87 (100/45) [MH+]; HPLC: tR=1.82 min. (OpenLynx, polar—5 min.).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[O:4][N:3]=1.[CH2:16]([C:23]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:16]([C:23]1([OH:29])[CH2:28][CH2:27][N:26]([C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1noc(-c2ccncc2)c1C(=O)O
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccncc2)c1C(=O)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
A suspension of 3-methyl-5-(pyridin-4-yl)-1,2-oxazole-4-carboxylic acid (0.25 g), 4-benzyl-4-hydroxypiperidine (0.35 g), HATU (0.70 g) and triethylamine (0.85 mL) in DMF (5.0 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and then purified by preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), and the obtained fraction was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.29 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([C:20]([NH2:22])=O)[CH:15]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([C:20]#[N:22])[CH:15]=1
Reactant: Cn1nc(C(N)=O)cc1CCN1C(=O)c2ccccc2C1=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cn1nc(C#N)cc1CCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.2 %

Procedure:
To a mixture of 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxamide (10.5 g, 35.2 mmol) and pyridine (5.69 mL, 70.4 mmol) in dichloromethane (200 mL) at 0° C. was added trifluoroacetic anhydride (5.47 mL, 38.7 mmol) over two minutes. The solution was stirred at 0° C. for about 20 minutes, then was allowed to warm to ambient temperature. After 2 hours, more pyridine (2.8 mL) and trifluoroacetic anhydride (1.5 mL) were added. The reaction was quenched by adding 2 M sodium carbonate (200 mL). The mixture was extracted with chloroform. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to a volume of about 50 mL. A white solid was present. Heptane (150 mL) was added, and the mixture was concentrated to a volume of about 25 mL, then hexanes were added and the solid was collected by filtration. The white solid was washed with hexanes and dried to provide 8.50 g of 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carbonitrile that contained a small amount of an impurity.