Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]4[S:28][CH:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:31]=4)=[CH:24][C:23]=3[CH:36]=1)[CH:13]=[C:12]2[CH2:37][C:38]([OH:40])=[O:39])C1C=CC=CC=1.[CH:41]([O-])=O.[NH4+].C(O)C>O>[C:32]([C:30]1[N:31]=[C:27]([C:25]2[O:26][C:22]3[CH:21]=[CH:20][C:19]([CH2:18][N:14]4[C:15]5[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=5)[C:12]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:13]4)=[CH:36][C:23]=3[CH:24]=2)[S:28][CH:29]=1)([CH3:34])([CH3:35])[CH3:33]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(CC(=O)O)c5cc(OCc6ccccc6)ccc54)ccc3o2)n1
Reactant: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(O)cc12
Reaction time: 48 h
Yield: 68.1 %

Procedure:
A mixture of 5-benzyloxy-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indole-3-acetic acid (3.0 g), 10% Pd--C (0.6 g) and ammonium formate (2.0 g) in a mixed solvents of ethanol (60 ml) and water (6 ml) was stirred under reflux for 18 hours. After removal of the catalysts by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 10% hydrogen chloride in methanol (200 ml) and the mixture was stored in refrigerator for 2 days. The resulting solution was concentrated under reduced pressure and the residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-hydroxyindole-3-acetate (1.76 g).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([OH:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:20]1([CH2:26]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO[Na]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([OH:19])[C:11]2[C:16]([C:17]=1[O:18][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccccc1
Reactant: CCCCOC(=O)c1nc(O)c2ccccc2c1O
Agent: CO[Na]
Product: CCCCOC(=O)c1nc(O)c2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.7 %

Procedure:
A mixture of 1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester (26.13 g, 100 mmol; Example D-20 b), PhCH2Br (18.2 ml, 150 mmol), MeONa (0.5 M in MeOH, 200 ml, 100 mmol) was stirred at ambient temperature for 48 h. Then the solvent was evaporated and EtOAc (100 ml) was added to the residue. The mixture was stirred vigorously for 10 min before it was filtered. The filtrate was washed with aqueous 2.5N NaOH (2×100 ml) and aqueous 2N HCl (1×100 ml). The organic phase was dried over MgSO4 and evaporated in vacuo. The residue was recrystallized from MeOH (500 ml)/water (300 ml). The resulting yellow solid was further purified by flash column chromatography on silica gel using hexanes:EtOAc:NEt3=65:30:5 as the eluent to give 10.8 g of a yellow solid. 2 g of this material were further purified by flash column chromatography on silica gel using hexanes:EtOAc:NEt3=75:20:5 as the eluent to give 1.57 g of the title compound as a slightly yellowish solid; 1H NMR (CDCl3): δ=8.88 (bs, 1H), 8.46 (d, 1H), 8.42 (d, 1H), 7.26 to 7.96 (m, 7H), 5.06 (s, 2H), 4.38 (t, 2H), 1.69 (m, 2H), 1.37 (m, 2H), 0.91 (t, 3H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=4[O:29][CH3:30])=[N:18][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:62][CH:63]1[CH2:68][CH2:67][N:66]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:65][CH2:64]1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([NH:62][CH:63]5[CH2:64][CH2:65][N:66]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:67][CH2:68]5)=[O:26])=[CH:22][C:21]=4[O:29][CH3:30])=[N:18][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-(9-Cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (Intermediate 8) (0.49 g, 1.2 mmol, 1 eq), TBTU (0.42 g, 1.3 mmol, 1.1 eq) and DIPEA (0.40 mL, 2.4 mmol, 2 eq) were stirred together in DCM (25 mL) for 30 min before addition of 4-amino-1-BOC-piperidine (0.29 g, 1.4 mmol, 1.2 eq). The RM was stirred at rt for 20 hours before diluting with DCM (30 mL) and washing sequentially with water (2×15 mL), 50% saturated aqueous sodium hydrogen carbonate (1×20 mL), saturated aqueous potassium carbonate (1×20 mL) and saturated brine (1×20 mL). Concentrated in vacuo to isolate 4-(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-BOC-piperidin-4-yl)benzamide that was used without further purification (0.71 g). Rt=3.58 min (Analytical—1).
Reaction SMILES: [CH3:1][CH:2]([C:6]([CH3:19])([C:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH3:18])[CH3:7])[C:3]([OH:5])=[O:4].[Cl:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][Cl:33])[C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[CH3:1][CH:2]([C:6]([CH3:19])([C:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH3:18])[CH3:7])[C:3]([O:5][C:27]1[CH:26]=[CH:25][C:24]([N:23]([CH2:22][CH2:21][Cl:20])[CH2:31][CH2:32][Cl:33])=[CH:29][CH:28]=1)=[O:4]
Reactant: CC1=C(C)C(=O)C(C(C)(C)C(C)C(=O)O)=C(C)C1=O
Reactant: Oc1ccc(N(CCCl)CCCl)cc1
Product: CC1=C(C)C(=O)C(C(C)(C)C(C)C(=O)Oc2ccc(N(CCCl)CCCl)cc2)=C(C)C1=O
Yield: 20 %

Procedure:
Using an analogous procedure to that described in Example 1, 2,3-dimethyl-3-(2,3,5-trimethyl-1,4-benzoquinonyl)butyric acid was reacted with 4-[bis(2-chloroethyl)amino]phenol and the product was purified by column chromatography on silica using a 8.5:1.5 mixture of petroleum ether (b.p. 40 to 60° C.) and ethyl acetate as eluent. There was thus obtained to give 4-[bis(2-chloroethyl)amino]phenyl 2,3-dimethyl-3-(2,3,5-trimethyl-1,4-benzoquinonyl)butyrate as an oil in 20% yield; NMR Spectrum: (CDCl3) 1.25 (d, 3H), 1.45 (s, 3H), 1.50 (s, 3H), 1.95 (s, 3H), 1.97 (s, 3H), 2.21 (s, 3H), 3.60 (t, 4H), 3.67 (t, 4H), 3.85 (q, 1H), 6.61 (d, 2H), 6.82 (d, 2H); Mass Spectrum: (M+Na+) 502, 504 & 506.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[OH:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:11]1([CH3:23])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[S:19](Cl)(=[O:21])=[O:20].CCOCC>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[O:9][S:19]([C:12]1[C:13]([CH3:18])=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=1[CH3:23])(=[O:21])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(O)C(=O)OC(C)(C)C
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)ON(C)C(=O)OC(C)(C)C)c(C)c1

Procedure:
A solution of 16 g. of N-t-butoxycarbonyl-N-methyl hydroxylamine and 23.8 g. of mesitylenesulfonyl chloride in 400 ml. of ether was cooled to 0° C. and treated with 15.4 ml. of triethylamine dropwise with stirring. Thirty minutes after the addition was complete, the mixture was filtered, and the filter cake was washed with 2 portions of ether. The filtrate and washings were evaporated to a heavy oil. The oil was dissolved in 40 ml. of benzene, filtered through diatomaceous earth and concentrated to dryness to give a crystalline residue of N-t-butoxycarbonyl-N-methyl mesitylenesulfonylhydroxylamine, which was used directly in the next step without characterization.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>C(Cl)Cl.O.S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:11][C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: Oc1cccc2c1CCCC2
Reactant: BrCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: BrCCCCOc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
A solution of 5,6,7,8-tetrahydronaphthalen-1-ol (4.2 g, 0.028 mol) in methylene chloride (50 ml) was mixed with a solution of sodum hydroxide (2.3 g, 0.0575 mol) in water (50 ml). After adding tetra-n-butylammonium bisulfate (9.6 g, 0.028 mol) and 1,4-dibromobutane (31 g, 0.14 mol), the reaction mixture was refluxed with vigorous stirring for 2 hrs. The reaction was cooled to room temperature, the layers separated and the organic phase washed with saturated sodium chloride solution. After drying over sodium sulfate, the organic phase was concentrated on the rotary evaporator and the residual oil heated under vacuum (0.1 mm Hg) to remove remaining 1,4-dibromobutane. The residue was chromatographed on silica gel using 100% hexane as eluent to give 8.1 g (71%) of the title compound as an oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1)=[O:10].[OH:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]=[C:23]([NH2:28])[C:22]3[N:29]=[C:30]([CH2:35][O:36][CH3:37])[N:31]([CH2:32][CH2:33][CH3:34])[C:21]=3[C:20]=2[CH:19]=1>CN(C=O)C>[CH3:37][O:36][CH2:35][C:30]1[N:31]([CH2:32][CH2:33][CH3:34])[C:21]2[C:20]3[CH:19]=[C:18]([O:17][CH2:8][C:9](=[O:10])[N:11]4[CH2:16][CH2:15][S:14][CH2:13][CH2:12]4)[CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:28])[C:22]=2[N:29]=1
Reactant: O=C(CBr)N1CCSCC1
Reactant: CCCn1c(COC)nc2c(N)nc3ccc(O)cc3c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1c(COC)nc2c(N)nc3ccc(OCC(=O)N4CCSCC4)cc3c21
Temperature: 70 °C

Procedure:
Cesium carbonate (1.7 g, 5.22 mmol, 3 eq) was added to a mixture of 4-(bromoacetyl)thiomorpholine (468 mg, 2.09 mmol, 1.2 eq, prepared according to the method described in Part C of Example 30) and 8-hydroxy-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.74 mmol, 1.0 eq) in 20 mL of DMF. The reaction mixture was heated to 70° C. and maintained for 14 hours. The reaction mixture was then cooled to ambient temperature, filtered, diluted with 50 mL of dichloromethane, concentrated under reduced pressure, and filtered to afford crude material. The crude material was purified by chromatography on a HORIZON HPFC system (eluting with a gradient of methanol/dichloromethane (20:80) in dichloromethane from 0:100 to 40:60), concentrated under reduced pressure, and crystallized from acetonitrile to afford 231 mg of 2-(methoxymethyl)-8-(2-oxo-2-thiomorpholin-4-ylethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off white solid, mp 214-216° C.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].CO[C:10](=O)[C@H:11]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>C1COCC1>[C:16]([O:15][C:13]([NH:12][CH:11]([C:10]1[O:5][N:4]=[C:1]([CH3:2])[N:3]=1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(N)=NO
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(C(Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Yield: 48.7 %

Procedure:
To a solution of acetamide oxime [2.67 g, J. Saunders et al., J. Med. Chem., 33, 1128 (1990)] in THF (125 ml) was added 60% sodium hydride (1.44 g) in oil, and the mixture was refluxed under heating for 1 hour. Then, the reaction mixture was allowed to cool, and a solution of N-tert-butoxycarbonyl-L-phenylalanine methyl ester (8.38 g) in THF (40 ml) was added at room temperature. The mixture was refluxed under heating for 20 minutes. The mixture was allowed to cool, and water (10 ml) was added, which was followed by concentration under reduced pressure. A 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1 v/v) to give 4.43 g of N-tert-butoxycarbonyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-phenylethylamine. This compound was added to a 4N hydrogen chloride-dioxane solution (50 ml), and the mixture was stirred at room temperature for 2 hours. Toluene was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ether was added to the residue for crystallization to give the title compound (3.25 g, yield 47%).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][C:4]([C:6]1[N:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=12)=[O:5].[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][C:4]([C:6]1[N:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]=12)=[O:5].[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]
Reactant: CC(C)(C)CC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC(=O)c1nc(-c2ccccc2)n2c1CNCC2
Reaction time: 2 h

Procedure:
Intermediate 26B (0.08 g, 0.20 mmol) was dissolved in DCM and TFA was added. The resulting mixture was stirred for 2 hours. The mixture was concentrated, diluted with water and acetonitrile and lyophilized to produce the desired product as a TFA salt. The residue was dissolved in methanol and filtered through a SPE SCX tube column, eluting with 2N ammonia in methanol to provide Compound 291 (0.055 g, 90%) as a free base. 1H-NMR (400 MHz, CD3OD) δ: 1.05 (s, 9H), 2.87 (s, 2H), 3.15 (t, 2H), 4.07 (t, 2H), 4.35 (s, 2H), 7.52 (m, 3H), 7.67 9 m, 2H); LCMS (+ESI) m/z 298.1 [M+H]+.
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.FC(F)(F)C(O)=O.[F:13][C:14]1[CH:15]=[C:16]([C:24]2O[CH:27]=[N:26][CH:25]=2)[CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:15]=[C:16]([C:24]2[C:2]3[CH2:3][CH2:4][CH2:5][C:1]=3[CH:27]=[N:26][CH:25]=2)[CH:17]=[CH:18][C:19]=1[C:20]([F:22])([F:23])[F:21]
Reactant: Fc1cc(-c2cnco2)ccc1C(F)(F)F
Reactant: C1=CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Fc1cc(-c2cncc3c2CCC3)ccc1C(F)(F)F
Temperature: 230 °C
Yield: 50.1 %

Procedure:
The reaction was performed on a custom-made flow system consisting of a Dionex P580 pump and a HP 6890 Series Gas Chromatography oven used as a heating source. The GC oven was equipped with a stainless steel coil reactor (53 mL volume) made from Supelco stainless steel tube (ID=2.1 mm). After heating to 230° C. using toluene as a system solvent, a mixture of cyclopentene (1.77 g, 26.0 mmol) and trifluoroacetic acid (0.30 g, 2.60 mmol) in toluene (1.0 mL), a mixture of 5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazole (0.30 g, 1.30 mmol), cyclopentene (1.77 g, 26.0 mmol) and trifluoroacetic acid (0.30 g, 2.60 mmol) in toluene (1.0 mL) and finally a mixture of cyclopentene (1.77 g, 26.0 mmol) and trifluoroacetic acid (0.30 g, 2.60 mmol) in toluene (1.0 mL) were injected onto the stainless steel coil reactor in sequential order. The system was run at a flow rate of 0.35 mL/min equaling to a nominal residence time of tR=150 min and an effective residence time of tR,eff=120 min taking the 25% volume expansion of toluene at 230° C. into account (R. E. Martin et al., Eur. J. Org. Chem. 2012, 47-52). A 750 psi back-pressure regulator with a protection guard (filled with sand/glass wool) was used at the exit of the reactor to maintain system pressure. The reaction mixture was collected in a round bottom flask, triethylamine (5 mL) was added and the solvent mixture removed under reduced pressure. Purification by flash chromatography (50 g SiO2, Telos-cartridge) eluting with a 0 to 50% EtOAc/n-heptane gradient provided the title compound (183 mg, 50%) as a slightly brown solid. MS: 282.5 (M+H)+.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:22](O)(=[O:25])[CH2:23][OH:24]>O1CCCC1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH2:6][C:7]([O:9][C:23](=[O:24])[CH2:22][OH:25])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(O)CO
Reactant: CC(=O)SCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)SCCC(=O)OC(=O)CO
Reaction time: 8 h

Procedure:
3-(Acetylthio)propanoic acid (2.96 g.) and 1,1'-carbonyldiimidazole (3.24 g.) are dissolved in 20 ml. of dry tetrahydrofuran with stirring at room temperature. After twenty minutes, a solution of glycolic acid (1.52 g.) and 2.80 ml. of triethylamine in 15 ml. of tetrahydrofuran are added. The reaction mixture is stored overnight at room temperature. The tetrahydrofuran is removed in vacuo, the crude residue taken up into ethyl acetate, washed with 1 N hydrochloric acid and three times with water, dried over magnesium sulfate and the O-(3-acetylthiopropanoyl)glycolic acid is concentrated to dryness in vacuo, yield 3.9 g. This is dissolved in ether and dicyclohexylamine is added. The dicyclohexylamine salt precipitates, yield 2.85 g., m.p. 150°-157°. The salt is converted to the free acid by adding to ethyl acetate and adding 10% potassium bisulfate solution, yield 1.5 g.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[O:11][C:12]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=2[CH:14]=1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[O:11][C:12]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=2[CH:14]=1
Reactant: Cc1cc2ccc([N+](=O)[O-])cc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2cc(CBr)oc2c1

Procedure:
N-Bromosuccinimide ("NBS") (1.11 g, 6.2 mmole) was added to a solution of 2-methyl-6-nitrobenzofuran (1.00 g, 5.65 mmole) and azobisisobutyronitrile (20 mg) in carbon tetrachloride and the mixture was heated at reflux temperature for 11/2hours in the presence of a bright light. The solvent was then evaporated and the residue dissolved in methylene chloride, washed with water, dried (MgSO4), evaporated to dryness and purified by column chromatography on silica eluting with methylene chloride/hexane (7:3). The product-containing fractions were combined and evaporated to give the title compound, yield 1.43 g. 'H-N.m.r. clearly showed that the product contained 20% of 2-dibromomethyl-6-nitrobenzofuran, however, it was not considered necessary to remove this and the product was used directly without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[Br:14]Br>C(O)(=O)C.O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CCC2
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc2c(cc1Br)CCC2
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 5-acetylaminoindane (53.0 g, 0.30 mol) in glacial acetic acid (1 L) at 10° C. was added dropwise over a period of 1 h a solution of bromine (19.0 mL, 0.37 mol). The mixture was further stirred at 10° C. for 15 min, and was then diluted with water until no more precipitate formed. The precipitate was collected, washed with water and dried under vacuum to give 61 g (80%) of the title compound.
Reaction SMILES: CC1C(C2N3C4C=CN(COCC[Si](C)(C)C)C=4N=CC3=[N:9]C=2)CC(N)C1.Cl[S:29]([NH:32][C:33](=[O:38])[O:34][CH2:35][CH2:36]Cl)(=[O:31])=[O:30].CO>C(Cl)Cl>[O:38]=[C:33]1[N:32]([S:29]([NH2:9])(=[O:31])=[O:30])[CH2:36][CH2:35][O:34]1
Reactant: O=C(NS(=O)(=O)Cl)OCCCl
Reactant: CC1CC(N)CC1c1cnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Solvent: ClCCl
Solvent: CO
Product: NS(=O)(=O)N1CCOC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.4 %

Procedure:
To a solution of 3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (0.50 g, 1.3 mmol) and 2-chloroethyl chlorosulfonylcarbamate (0.288 g, 1.297 mmol, prepared as detailed in Biorg. Med. Chem. Lett, 2006 16, 3367-3370) in DCM (16 mL) was added TEA (0.542 mL, 3.89 mmol) drop-wise. The mixture was stirred at ambient temperature for about 2 h. The solvent was removed under reduced pressure and the residue was partitioned between water and EtOAc (30 mL each). The organic layer was washed with brine (20 mL), dried over anhydrous MgSO4, filtered and concd under reduced pressure. The residue was purified by silica gel chromatography (0% DCM for 5 min, then to 6% MeOH in DCM over the next 30 min.) to yield N-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide (0.24 g, 35% yield) as an off-white solid. LC/MS (Table 1, Method a) Rt=2.42 min; MS m/z 535 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16]Br.CCOCC>CS(C)=O>[C:3]1([C:9]2([C:10]#[N:11])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CCc1ccccc1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2ccccc2)CCCC1
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To a suspension of sodium hydride (60%) (7.5 g, 187.79 mmol) in dimethyl sulfoxide (100 mL) was added dropwise a mixture of phenyl acetonitrile (10 g, 85.36 mmol) and 1,4-dibromobutane (18.43 g, 187.79 mmol) dissolved in dimethyl sulfoxide: ether (120 mL, 1:1) at 0° C. Stirring was continued for 30 min at same temperature and at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with 1N HCl (10 mL) and water (100 mL) was added. This mixture was extracted with ethyl acetate (3×100 mL), and the organic part separated and washed with water (3×100 mL) and brine (100 mL). The organic part was dried over sodium sulfate and concentrated to get a crude product which was purified on a CombiFlash column (eluted at 3% ethyl acetate in hexane) to afford 1-phenyl-cyclopentanecarbonitrile (276) (11.5 g, 78.68%) as a colorless liquid.
Reaction SMILES: [C:1]([CH2:3]C(CC1C2C(=CC=CC=2)C=CC=1)C(O)=O)#[N:2].[CH2:19]([O:21][C:22](=[O:40])[CH:23]([CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:20].ClCC#N.[H-].[Na+]>CN(C=O)C>[CH2:27]([O:26][C:24](=[O:25])[C:23]([CH2:3][C:1]#[N:2])([CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)[C:22]([O:21][CH2:19][CH3:20])=[O:40])[CH3:28]
Reactant: N#CCC(Cc1cccc2ccccc12)C(=O)O
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Agent: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC#N)(Cc1cccc2ccccc12)C(=O)OCC
Reaction time: 1 h

Procedure:
2(R,S)-Cyanomethyl-3-α-naphthylpropionic acid: 3.0 g of α-naphthylmethylmalonic acid diethyl ester and, after 30 minutes, 0.6 ml of chloroacetonitrile are added to a stirred suspension of 0.44 g of sodium hydride dispersion in 50 ml of DMF. The reaction mixture is stirred for 1 hour at 50° and then concentrated by evaporation in a high vacuum. The residue is dissolved in ethyl acetate, washed with 0.1N hydrochloric acid and water, dried over sodium sulphate, concentrated by evaporation and purified by chromatography on silica gel with toluene, yielding cyanomethyl-(α-naphthylmethyl)-malonic acid diethyl ester.