Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[O:22]C)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12].B(Br)(Br)Br>O>[F:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[OH:22])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccc(C)cc2OC)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(C)cc2O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
Under ice cooling, to a dichloromethane solution (10.0 ml) of methyl 3-fluoro-2′-methoxy-4′-methylbiphenyl-4-carboxylate (910 mg) was added a dichloromethane solution (1 M, 9.95 ml) of boron tribromide, followed by stirring at room temperature overnight. The reaction solution was poured into water, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the resulting residue were added methanol (30.0 ml) and ethyl acetate (3.0 ml). Under ice cooling, a hexane solution (2 M, 8.30 ml) of trimethylsilyldiazomethane was added dropwise, and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to afford methyl 3-fluoro-2′-hydroxy-4′-methylbiphenyl-4-carboxylate (137 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[N:15]12[CH2:23][CH2:22][CH2:21][C@@H:20]1[CH2:19][NH:18][CH2:17][CH2:16]2.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:18]2[CH2:17][CH2:16][N:15]3[CH2:23][CH2:22][CH2:21][C@@H:20]3[CH2:19]2)=[CH:3][C:4]=1[O:11][CH:12]([CH3:14])[CH3:13])([O-:10])=[O:9]
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1C[C@@H]2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1cc(N2CCN3CCC[C@@H]3C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 21 h
Yield: 93.9 %

Procedure:
A mixture of 1.0 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 634 mg of (R)-1,4-diazabicyclo[4,3,0]nonane and 1.04 g of potassium carbonate in 7 ml of DMSO is stirred at ambient temperature for 21 hours. The reaction medium is run into 15 ml of water and the mixture is then extracted three times with 30 ml of ethyl acetate. The organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum, so as to obtain 1.44 g of (8aR)-2-[4-nitro-3-(propan-2-yloxy)phenyl]octahydropyrrolo[1,2-a]pyrazine in the form of an orangey-coloured oily residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[BrH:11].O.BrBr>C(O)(=O)C>[Br:11][CH2:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10]
Reactant: Br
Reactant: CC(=O)c1ccc(Br)cn1
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C(CBr)c1ccc(Br)cn1
Reaction time: 1 h

Procedure:
1-(5-bromopyridin-2-yl)ethanone (200 mg, 1.0 mmol) was dissolved in Acetic acid (50 mL) and HBr in Acetic acid (48% solution, 280 uL) was added along with water (100 uL). Warmed to 70 C and added Bromine (51.5 uL, 1.0 mmol) and stirred for 1 hour. The reaction was concentrated to give the desired product (280 mg) containing a small amount of dibrominated product. This material was used as is.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([C:13]1[C:14](OS(C(F)(F)F)(=O)=O)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[CH:24]=1)=[CH:20][C:19]([Cl:32])=[CH:18][CH:17]=2)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[C:6]([O:10][C:11]([C:13]1[C:14]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[CH:24]=1)=[CH:20][C:19]([Cl:32])=[CH:18][CH:17]=2)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: C1CCNC1
Reactant: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(OS(=O)(=O)C(F)(F)F)nc3ccc(Cl)cc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(N3CCCC3)nc3ccc(Cl)cc23)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a solution of pyrrolidine (0.093 ml, 1.13 mmol) in DMSO (7 ml) was added 6-chloro-4-(3-isopropyl-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 78 step C, 400 mg, 0.76 mmol) and potassium carbonate (313 mg, 2.026 mmol) at 25° C. The resulting reaction mixture was stirred at 90° C. for 3 h. The reaction mixture was diluted with water (15 ml), and extracted with EtOAc (2×30 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (5-10% EtOAc in hexane) to afford 6-chloro-4-(3-isopropyl-phenyl)-2-pyrrolidin-1-yl-quinoline-3-carboxylic acid tert-butyl ester (250 mg, 73%) as pale yellow solid. LC-MS (ESI): LC-MS (ESI): 451 (M+H)+.
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:18][CH3:19])[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[CH:3]1.[CH2:20]([O:28][C:29](=[O:33])[CH2:30][C:31]#[N:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(OC(=O)C)(=O)C>>[CH2:12]([C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH:4]=[CH:3][C:2](=[C:30]([C:29]([O:28][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:33])[C:31]#[N:32])[CH:7]=[CH:6]2)=[CH:18][CH:19]=1)[CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCC(CCCc1ccccc1)n1ccc(=O)cc1
Reactant: CCCCCCCCOC(=O)CC#N
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCOC(=O)C(C#N)=C1C=CN(c2ccc(CCCCCC)cc2)C=C1
Temperature: 140 °C

Procedure:
In a 50 ml round bottom flask with stirbar, reflux condenser and nitrogen bubbler was placed the 4-(4-oxo-4Hpyridin-1-yl)hexylbenzene (0.638 g, 2.5 mmol), octylcyanoacetate (1.97 g, 10 mmol) and acetic anhydride (5.0 g). This mixture was heated in a 140° C. oil bath for 4.0 hours. After this period the mixture was cooled and crystalline product was isolated by suction filtration and washed well with acetic anhydride. The crude product was crystallized once from 1-propanol as yellow crystals (0.90 g, 83%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:32])[CH:20]([NH2:31])[CH2:21][C:22]1[C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[S:25][CH:26]=1>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]([C@@H:20]1[NH:31][C@H:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=2)[C:26]2[S:25][C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[C:22]=2[CH2:21]1)=[O:32]
Reactant: COC(=O)C(N)Cc1csc2ccccc12
Reactant: O=Cc1cccc(O)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H]1Cc2c(sc3ccccc23)[C@@H](c2cccc(O)c2)N1
Temperature: 40 °C
Yield: 122.3 %

Procedure:
1.45 g (11.9 mmol) of 3-hydroxy benzaldehyde and 4.2 ml (54.6 mmol) of trifluoro acetic acid are added to a solution of 2.04 g (8.7 mmol) of 2-amino-3-benzo[b]thiophen-3-yl-propionic acid methyl ester (compound B1) in 20 ml of toluene. The solution is stirred at 40° C. over night. The mixture is washed with a saturated solution of sodium hydrogen carbonate. The aqueous layer is washed with ethyl acetate and the combined organic layers are washed with 5 M hydrochloric acid and dried with magnesium sulfate. 3.61 g of a brown oil are obtained as the crude product.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:7]([CH3:19])[CH:6]=1)=[O:4].[CH:20]([N-:22][CH:23]=[O:24])=[O:21].[Na+]>C(#N)C>[CH:20]([N:22]([CH:23]=[O:24])[CH2:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:7]([CH3:19])[CH:6]=1)=[O:4])=[O:21]
Reactant: O=C[N-]C=O
Reactant: Cn1cc(C(=O)CCl)cc1C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(C(=O)CN(C=O)C=O)cc1C(=O)c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 54.6 %

Procedure:
A solution of 10 g (0.034 mole) of 2-chloro-1-[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]-ethanone and 3.8 g (0.041 mole) sodium diformylamide in 80 mL acetonitrile was heated under reflux overnight under argon. An additional 2.0 g portion of sodium diformylamide was added and reflux was continued for 1.5 hrs. After evaporation of the solvent in vacuo the residue was passed through a flash column (silica gel, 3:1 hexane:acetone the 2:1 hexane:acetone) to give 6.18 g of a solid. mp 279°-282° C. 260° C. decomp. mass spectrum (Cl--CH4) m/z=333 (M+1). NMR 300 MHz (CDCl3) d 9.0 (s, 2H); 7.8 (d, 2H); 7.55 (s, 1H); 7.45 (d, 2H); 7.1 (s, 1H); 4.85 (s, 2H); 4.1 (s, 3H).
Reaction SMILES: N[C:2]1[C:7]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][C:3]=1[S:16]([OH:19])(=[O:18])=[O:17].[Na:20].[BrH:21].N([O-])=O.[Na+]>O>[Br:21][C:2]1[C:7]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][C:3]=1[S:16]([OH:19])(=[O:18])=[O:17].[Na:20]
Reactant: Nc1c(S(=O)(=O)O)cc(S(=O)(=O)O)cc1S(=O)(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=S(=O)(O)c1cc(S(=O)(=O)O)c(Br)c(S(=O)(=O)O)c1

Procedure:
The 2-amino-benzene-1,3,5-trisulfonic acid, sodium salt can be dissolved in water and treated with 48% hydrobromic acid (5 equivalents). A solution of sodium nitrite (2 equivalents) in water can be added dropwise and stirred until the precipitation of the diazonium salt is complete. A solution of cuprous bromide (1 equivalent) in 48% hydrobromic acid (5 equivalents) can be added in one portion and the mixture stirred until gas evolution ceases followed by heating to a reflux. The solution can be evaporated and the residue dissolved in water followed by neutralization to pH 7 using sodium bicarbonate. The solids can be filtered off, the filtrate evaporated, and the solids dried under vacuum. The product can be recrystallized from water by addition of ethanol to give 2-bromo-benzene-1,3,5-trisulfonic acid, sodium salt.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20]C(C)(C)C)=O)[CH2:14][CH2:13]3)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:26][C:27]1[CH:32]=[N:31][C:30]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)=[C:29]2[NH:38][CH:39]=[C:40]([C:41](=[O:45])C(O)=O)[C:28]=12.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O1CCOCC1>[F:26][C:27]1[CH:32]=[N:31][C:30]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)=[C:29]2[NH:38][CH:39]=[C:40]([C:41](=[O:45])[C:18]([N:15]3[CH2:14][CH2:13][CH:12]([C:11]4[N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]=[N:9][N:10]=4)[CH2:17][CH2:16]3)=[O:20])[C:28]=12
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnnn2-c2ccccc2)CC1
Reactant: O=C(O)C(=O)c1c[nH]c2c(-n3ccnn3)ncc(F)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: O=C(C(=O)N1CCC(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(-n3ccnn3)ncc(F)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
Part C: To a solution of tert-butyl 4-(1-phenyl-1H-tetrazol-5-yl)piperidine-1-carboxylate (0.165 g, 0.50 mmol) in 1,4-dioxane (10 mL) at 25° C. was added 4.00 N HCl in 1,4-dioxane (10 mL), and the mixture was stirred at 25° C. for 16 h. The mixture then was concentrated under vacuum. The resulting solids were dissolved in DMF (10 mL). To this solution was added sequentially 2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.137 g, 0.50 mmol), N-methylmorpholine (0.165 mL, 1.50 mmol), and TBTU (0.176 g, 0.55 mmol), and the mixture was stirred at 25° C. for 24 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was dissolved in hot methanol, and the solution then was allowed to cool slowly to room temperature. The precipitate was recovered by filtration, washed with methanol, and dried under vacuum to provide 1-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperidin-1-yl)ethane-1,2-dione (0.142 g) as an off-white solid; mp: 257-258° C.; HRMS: 487.1740 (M+H)+ [calc'd: 487.1755]; 1H NMR (500 MHz, DMSO-D6) δ 13.06 (br s, 1H), 9.02 (s, 1H), 8.32 (d, 1H, J=1.8 Hz), 8.30 (s, 1H), 8.12 (s, 1H), 7.58 (s, 5H), 4.37 (m, 1H), 3.67 (m, 1H), 3.32 (m, 1H), 3.25 (m, 1H), 3.03 (m, 1H), 2.01 (m, 1H), 1.88 (m, 1H), 1.83-1.70 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([S:18]([N:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]1=2.Br[CH2:37][C:38]([NH2:40])=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:21]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:18]([C:15]2[CH:16]=[CH:17][C:9]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[O:1][CH2:37][C:38]([NH2:40])=[O:39])[CH2:13][CH2:12][O:11][C:10]=3[CH:14]=2)(=[O:19])=[O:20])=[CH:33][CH:32]=1
Reactant: NC(=O)CBr
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2OCC(N)=O)cc1
Temperature: 80 °C
Yield: 49 %

Procedure:
To a solution of 4-(2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (550 mg, 1.080 mmol), 2-bromoacetamide (704 mg, 5.108 mmol, Aldrich) in DMF (10 mL) was added potassium carbonate (528 mg, 3.83 mmol). The reaction mixture was heated at 80° C. for 12 h. After completion, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (50 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 0-60% ethyl acetate in hexane) to get 2-(2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)phenoxy)acetamide (300 mg, 49.0%). MS (ESI, positive ion) m/z; 567.1 (M+1)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].N1CC[O:22]CC1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][O:22][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: C1COCCN1
Product: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Yield: 80 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(methane-2-sulfonyl)-benzoic acid and morpholine and obtained in 80% yield. MS (m/e): 284.1 (MH−, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH:12]=[O:13].C(C(OC1C(OC(C(C)(C)C)=O)=C(I)C=CC=1)=O)(C)(C)C.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>C(OC(C)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[C:12]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:13]
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Reactant: CS(N)(=O)=O
Agent: CC(C)(C)C(=O)Oc1cccc(I)c1OC(=O)C(C)(C)C
Solvent: CC(=O)OC(C)C
Product: CS(=O)(=O)NC(=O)c1c[nH]c2cc(Cl)c(Br)cc12
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 5-bromo-6-chloro-1H-indole-3-carbaldehyde (445 mg, 1.72 mmol), Bis(tert-butylcarbonyloxy)iodobenzene (961 mg, 2.30 mmol) in isopropyl acetate (2 mL) was added methanesulfonamide (111 mg, 1.15 mmol). After stirring 5 minutes, Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)] (18.3 mg, 0.0230 mmol) was added and heated to 50° C. for 2 h. The reaction was filtered and the collected solid (245 mg) was identified as a mixture of the title compound and 5-bromo-6-chloro-1H-indole-3-carbaldehyde. The mixture was taken forward without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:26]=[C:11]3[N:12]=[C:13]([CH3:25])[C:14]([C@H:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O[C:31]([CH3:34])([CH3:33])[CH3:32])(=O)C.Cl(O)(=O)(=O)=O>C(Cl)Cl.CCOCC>[C:31]([O:24][C@@H:19]([C:14]1[C:13]([CH3:25])=[N:12][C:11]2[N:10]([N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:26]=2)[C:15]=1[CH:16]([CH3:18])[CH3:17])[C:20]([O:22][CH3:23])=[O:21])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C(C)C
Reaction time: 3 h
Yield: 131.9 %

Procedure:
To a stirred solution of (S)-methyl 2-(2-(3-chlorophenyl)-7-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (0.069 g, 0.185 mmol) and tert-butyl acetate (1.247 ml, 9.23 mmol) in CH2Cl2 (5 mL) was added 70% perchloric acid (0.048 ml, 0.554 mmol) at rt. After 3 h, the reaction mixture was diluted with Et2O (35 mL), washed with sat Na2CO3 (2×5 mL), brine (5 mL), dried (Na2SO4), filtered and concentrated to give colorless paste which was purified by prep-HPLC to afford (S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.0496 g, 0.244 mmol, 62.5% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ: 7.98 (t, J=1.7 Hz, 1H), 7.87 (dt, J=7.6, 1.4 Hz, 1H), 7.41-7.32 (m, 2H), 6.77 (s, 1H), 5.42 (s, 1H), 4.07 (dt, J=13.6, 6.9 Hz, 1H), 3.71 (s, 3H), 2.73 (s, 3H), 1.68 (d, J=7.0 Hz, 3H), 1.56 (d, J=7.0 Hz, 3H), 1.26 (s, 9H). LCMS (M+H) calcd for C23H29ClN3O3: 430.19. found: 430.3.
Reaction SMILES: Cl.[CH2:2]([NH2:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[N-:9]([C:12]#[N:13])[C:10]#[N:11].[Na+]>C(O)CCC>[C:10]([NH:9][C:12](=[NH:13])[NH:8][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])#[N:11]
Reactant: CCCCCCN
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CCCCCCNC(=N)NC#N
Yield: 51.5 %

Procedure:
A mixture of hexylamine hydrochloride (63.5 g.), sodium dicyanamide (44.5 g.) and butanol (200 ml.) was heated at reflux for 18 hours and then cooled. The mixture was filtered and the filtrate was evaporated to dryness. The residue was stirred with water and the insoluble solid was collected and crystallised from aqueous ethanol to give 3-cyano-1-hexylguanidine (40 g.) m.p. 103°-105°.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24]1[CH:39]=[CH:38][CH:37]=[CH:36][C:25]=1[CH2:26][NH:27][C:28](=[O:35])[C@H:29]([C@H:31]([CH2:33][CH3:34])[CH3:32])[NH2:30].C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:27]([CH2:26][C:25]3[CH:36]=[CH:37][CH:38]=[CH:39][C:24]=3[O:23][CH3:22])[C:28](=[O:35])[C@H:29]([C@H:31]([CH2:33][CH3:34])[CH3:32])[NH2:30])=[O:16])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1OC)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 79.5 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (179 mg, 0.61 mmol, 1.0 eq), L-isoleucine 2-methoxybenzylamide (308 mg, 1.23 mmol) and dichloromethane (2 mL), was treated with triethylamine (515 uL, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (783 uL, 2.0 eq), to provide 254 mg (79%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] 2-methoxybenzylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:36])[CH:10]=1.[ClH:37]>CO.CCOCC>[ClH:1].[ClH:37].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:36])[CH:10]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cc5Cl)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cc5Cl)cc4=O)cc31)CNCC2
Reaction time: 3 h
Yield: 42 %

Procedure:
tert-Butyl 7-(4-(2,4-dichlorophenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (56 mg, 0.11 mmol) was dissolved in MeOH (1 mL) and 2 N HCl in Et2O (5 mL) was added. The reaction was allowed to proceed for 3 h. The mixture was concentrated and purified by preparative HPLC. Conversion to the HCl salt (2 N HCl in Et2O) provided the title compound (22 mg, 42%) as a yellow solid: mp 321-324° C.; 1H NMR (500 MHz, CD3OD) δ 7.80 (d, J=7.0 Hz, 1H), 7.70 (s, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.62 (s, 1H), 7.54 (s, 2H), 7.13 (d, J=7.0 Hz, 1H), 6.73 (s, 1H), 6.61 (d, J=7.2 Hz, 1H), 4.54 (s, 2H), 3.80 (s, 3H), 3.72 (t, J=6.0 Hz, 2H), 3.26 (t, J=5.9 Hz, 2H); ESI MS m/z 424 [M+H]+; HPLC (Method B)>99% (AUC), tR=14.1 min.
Reaction SMILES: C1(CN[C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H]2CC[C@@H](CO)O2)CC1.C(N(CC)CC)C.C1(CC(Cl)=O)C=CC=CC=1>C(#N)C.CN(C)C1C=CN=CC=1>[N:14]1[CH:6]=[C:7]2[C:11]([NH:10][CH:9]=[N:8]2)=[N:12][CH:13]=1
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)Cc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: c1ncc2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.5 g, 1.44 mmoles) was dissolved in 20 mL acetonitrile. 4-Dimethylaminopyridine (10.2 mg, 0.08 mmoles) and triethylamine (620 μL, 4.4 mmoles) were added and the flask was chilled in an ice bath under a nitrogen atmosphere. Phenylacetyl chloride (1.11 g, 7.2 mmoles, Aldrich Chemical Co., Madison, Wis.) was added dropwise to the flask over a period of 15 minutes. The reaction was stirred at room temperature for 0.5 hours. The reaction was quenched with methanol and solvents were removed under vacuo. The residue was dissolved in 2 mL CHCL3 /CH3OH (9:1) and chromatographed on a column of silica gel (5×15 cm) in the application solvent. Additional chromatography was performed on the product containing fractions using a Chromatotron 2 mm silica gel plate developed with a hexane:acetone mixture (7:3). Lyophilization of the product containing fractions afforded 0.459 g of 6 -(cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-[(phenylacetyl)methyl]-2-furyl)]-9H-purine as an oil (78% yield): m.p. <25° C.