Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3](=O)CC(=O)C.[NH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[NH2:18].C(=O)([O-])O.[Na+]>C(O)C>[CH3:2][C:3]1[NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[N:18]=1
Reactant: Cc1cc(C)c(N)c(N)c1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c2[nH]c(C)nc2c1
Yield: 124.2 %

Procedure:
30 ml (150 mmol) of hydrogen chloride-solution (5 M in water) and 1.5 ml (14.68 mmol) 2,4-Pentandione are added to a solution of (7.34 mmol) of 2-Amino-3,5-dimethylphenylamine (example X, Step 1) in 112 ml ethanol. The reaction mixture is refluxed for 30 minutes. The solution is neutralized with saturated sodium hydrogen carbonate solution (to pH 7) and extracted with dichlormethane. The organic phases are dried over magnesium sulfate and the solvent is evaporated under vacuum to afford 2,5,7-Trimethyl-1H-benzimidazole (1.46 g) in quantitative yield.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[BH4-].[Na+].[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>O1CCOCC1.C(O)(=O)C.O>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C@H:7]([O:8][C:35]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:41])[O:9][C@@H:10]4[O:16]3)[CH2:4][CH2:3]1
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Reactant: O=C1CCC(=O)O1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: C[C@H]1[C@H](OC(=O)CCC(=O)O)O[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Artemisinin (500 mg) and polyhydroxy compound (dextrose, 2.5 g) are stirred in 1,4-dioxan (15 ml) at room temperature for 5 minutes. Sodium borohydride (2.5 g) is added slowly for 10 minutes and the reaction mixture is stirred for about 2 hours at room temperature (20-30° C.). After completion of the reaction (Checked by TLC), succinic anhydride (250 mg) and anion exchange (basic) resin (1.5 g) are added at room temperature and the reaction mixture is stirred further for 2 hours at room temperature. Cold water (50 ml) is added to the reaction mixture and pH is adjusted between 6-7 with dilute acetic acid and extracted with 40% ethyl acetate in hexane (3×25 ml). The combined extract is washed with water (50 ml). The ethyl acetate n-hexane extract is dried over anhydrous sodium sulphate and evaporation of the solvent yield 655 mg of crude artesunic acid which upon purification over silica gel (1:5 ratio) with 20-30% ethyl acetate in hexane, furnish pure artesunic acid in 93% w/w (465 mg) yield (according to CO-TLC). After drying the pure α-artesunic acid, mp 140-142° C. is chareterised by spectral analysis.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:28])=[CH:29][CH:30]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN
Reactant: CCc1sc(C2CCOCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCc1sc(C2CCOCC2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a mixture of 4-({cyclohexyl[2-ethyl-5-(tetrahydro-2H-pyran-4-yl)thiophen-3-yl]methyl}amino)benzoic acid (250 mg) synthesized above, ethyl β-alaninate hydrochloride (108 mg), 1-hydroxybenzotriazole monohydrate (108 mg) and triethylamine (98 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (135 mg), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate) to give a pale-yellow oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (158 mg, 54%) as a white solid.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[NH:19][C:20]4[C:21]([N:39]=3)=[N:22][C:23]([C:27]3[S:28][C:29]5[CH:34]=[CH:33][N:32]=[C:31]([CH:35]6[CH2:37][CH2:36]6)[C:30]=5[N:38]=3)=[C:24]([Cl:26])[CH:25]=4)[CH:12]2[O:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:26][C:24]1[CH:25]=[C:20]2[NH:19][C:18]([O:17][C@H:16]3[C@H:12]4[O:11][CH2:10][C@@H:9]([OH:8])[C@H:13]4[O:14][CH2:15]3)=[N:39][C:21]2=[N:22][C:23]=1[C:27]1[S:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH:35]3[CH2:37][CH2:36]3)[C:30]=2[N:38]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1COC2C1OC[C@H]2Oc1nc2nc(-c3nc4c(C5CC5)nccc4s3)c(Cl)cc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3nc4c(C5CC5)nccc4s3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 2-(2-(((3R,6R)-6-((tert-butyldimethylsilyl)-oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl)-4-cyclopropyl-thiazolo[4,5-c]pyridine (20.0 mg, 0.034 mmol) dissolved in anhydrous THF (0.3 mL) was added 1M TBAF in THF (0.07 mL, 0.070 mmol) and stirred at RT for 19 h. The reaction solution evaporated down under reduced pressure. Flash chromatography of the resulting residue utilizing a 4 g silica RediSep Rf® Gold column and employing a 0-15% MeOH/DCM gradient afforded the title compound. LC-MS: calculated for C21H18ClN5O4S 471.08 observed m/e: 472.01 (M+H)+ (Rt 1.02/1.8 min)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1Cl)[CH3:2].C(C1C(F)=CN=C(Cl)C=1C(O)=O)C.[CH3:27][S:28][C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1[O:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([S:28][CH3:27])[CH:30]=1)[CH3:2]
Reactant: CSc1cccc(O)c1
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Agent: CCc1c(F)cnc(Cl)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(F)cnc1Oc1cccc(SC)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A solution of ethyl-2-chloro-5-fluoro-nicotinoate (29 g, 0.143 mol) (prepared according to the method of J. Med. Chem., 1993, 36(18), 2676–88, at page 2684, column 2, 3rd compound, Ethyl 2-chloro-5-fluoropyridine-3-carboxylic acid) and 3-methylsulphanyl-phenol (20 g, 0.143 mol) (prepared according to the method of WO 98/45268, page 68, preparation 61) in dioxane (300 mL) was treated with caesium carbonate (46.5 g, 0.143 mol) at room temperature. The reaction mixture was heated to 100° C. and stirred for 48 hours. The reaction mixture was concentrated in vacuo and the residue taken up in water (600 mL) and extracted with ethyl acetate (3×250 mL). The organic layers were combined, washed with brine (200 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:toluene (99.75:0.25 to 99.5:0.5) to yield the title product as a yellow oil, 27.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[N+:3]=1[O-].P(Cl)(Cl)Cl>C(Cl)CCl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)[n+]([O-])c(Cl)c1
Solvent: ClP(Cl)Cl
Solvent: ClCCCl
Product: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Reaction time: 8 h

Procedure:
A solution of 20.9 gm (0.1 mol) of 2,6-dichloro-4-nitropyridine-1-oxide (J. Chem. Soc. B 1967, 1235) in 100 ml of ethylene chloride was heated to boiling and then 27.5 gm (0.2 mol) of phosphorus trichloride were added. The solution obtained was stirred for a further 8 hours under reflux and was then concentrated by evaporation in vacuo. The oily residue which remained was poured into ice water. The crystalline residue formed was recovered by suction filtration and washed neutral with water.
Reaction SMILES: [N:1]1[CH:7]=[CH:6][C:5](=[O:8])[N:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(Cl)Cl>[O:8]=[C:5]1[CH:6]=[CH:7][N:1]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:2][CH:3]=[N:4]1
Reactant: O=c1ccnccn1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C=CN(C(=O)OCc2ccccc2)CC=N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.8 g (42.0 mmol) [1,4]diazepin-5-one are dissolved in 60 ml DCM and at ice bath temperature successively combined with 11.0 ml (83.9 mmol) triethylamine and 6.8 ml (46.2 mmol) benzyl chloroformate. The mixture is heated to RT and kept for three hours at this temperature. Then the mixture is concentrated and combined with water. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The crude product is [purified] by column chromatography on silica gel (eluant DCM/MeOH 95:5→90:10).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][S:15][CH2:16][C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C(OCC)C.[ClH:40]>C(O)(C(F)(F)F)=O.C(OCC)C>[NH2:1][C@@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][S:15][CH2:16][C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[ClH:40]
Reactant: Cc1ccc(CSC[C@H](NC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(CSC[C@H](NC(=O)[C@H](N)Cc2ccccc2)C(=O)O)cc1
Reaction time: 0.75 h

Procedure:
5 g BOC-(D)Phe-Cys(MBzl)-OH are dissolved in 80 ml TFA and 10 ml H2O and allowed to stand for 45 minutes at room-temperature. The solution is diluted with ethyl-ether and 20 ml ethyl-ether/HCl (~5 N) are added, and the precipitate is filtered off, washed with ethyl ether and dried to yield the title compound:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C>[C:1]([NH:4][C:5]1[C:14]([N+:25]([O-:27])=[O:26])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOc1cc(NC(C)=O)ccc1C(=O)OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOc1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
A mixture of 118.6 parts of methyl 4-(acetylamino)-2-ethoxybenzoate, 200 parts of acetic acid and 156 parts of acetic acid anhydride was stirred and heated to 50° C. After cooling to 15° C. (ice-bath) there were added dropwise 47.1 parts of fuming nitric acid 100% using a bromine funnel: an exothermic reaction occured. The temperature was kept at about 20° C. by cooling in an ice-bath. Upon completion, the temperature was allowed to rise to 40° C. and stirring was continued at this temperature for one hour. If necessary the whole was cooled with ice-water to keep the temperature at about 40° C. When the exothermic reaction was ceased, the whole was allowed to cool for one hour and was further cooled to 0° C. The reaction mixture was poured onto icewater while stirring. Upon stirring for one hour, the precipitated product was filtered off and dissolved in 1950 parts of dichloromethane. The solution was washed twice with 500 parts of water, dried, filtered and evaporated. The residue was crystallized overnight at room temperature from 2-propanol. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 67.6 parts (47.9%) of methyl 4-(acetylamino)-2-ethoxy-5-nitrobenzoate; mp. 110° C. (intermediate 32).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].[C:11]([P:15](Cl)[C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])([CH3:13])[CH3:12].C1(C)C=CC=CC=1>O1CCCC1.[Cu](Cl)Cl.O>[C:11]([P:15]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: COc1ccccc1Br
Agent: Cl[Cu]Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1P(C(C)(C)C)C(C)(C)C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, a Grignard reagent solution previously prepared from 12.1 g (0.065 mol) of 2-bromoanisole and 2.1 g (0.085 mol) of metallic magnesium in 65 ml of tetrahydrofuran, and 0.13 g (0.0010 mol (corresponding to 2% by mol)) of copper(II) chloride were placed. To the contents of the flask, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride was dropwise added as it is without being dissolved in a solvent, over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at 50° C. for 3 hours. After the temperature of the reaction solution was returned to room temperature, gas chromatography analysis was carried out, and as a result, di-tert-butylphosphinous chloride was present in trace amounts. Thereafter, 65 ml of toluene and 50 ml of water were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent and a low-boiling component were distilled off under reduced pressure to obtain 11.9 g (purity: 95.0%) of the aimed di-tert-butyl(2-methoxyphenyl)phosphine was obtained. The yield was 89.7%.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:20]=4)[C:15]3=[O:32])=[CH:10][C:9]=2[F:33])[CH2:4]1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:34][N:2]([CH3:1])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[CH:20]=4)[C:15]3=[O:32])=[CH:10][C:9]=2[F:33])[CH2:4]1
Reactant: C1CCNCC1
Reactant: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(OS(=O)(=O)C(F)(F)F)ccc4C3=O)cc2F)C1
Product: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(N5CCCCC5)ccc4C3=O)cc2F)C1

Procedure:
Trifluoromethanesulfonic acid 2-[4-((R)-3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl ester was reacted with piperidine by method N. The product with the molecular weight of 436.58 (C26H33FN40) was obtained in this way; MS (ESI): 437 (M+H+).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([NH2:11])=[CH:9][N:8]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[Br:40][CH2:41][C:42]1[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](Cl)=[O:45]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([NH:11][C:44](=[O:45])[C:43]3[CH:47]=[CH:48][CH:49]=[CH:50][C:42]=3[CH2:41][Br:40])=[CH:9][N:8]([C:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1CBr
Reactant: Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12)c1ccccc1CBr
Reaction time: 8 h
Yield: 33.7 %

Procedure:
2-bromo-5-trityl-pyrrolo[2,3-b]pyrazin-7-amine (3 g, 6.588 mmol) dissolved in THF (30 mL) under N2 at rt. DIPEA (5.7 mL, 32.9 mmol) added followed by a solution of 2-(bromomethyl)benzoyl chloride (1.9 g, 8.137 mmol) in THF (10 mL). Reaction mixture stirred overnight then partitioned between EtOAc and water. Aqueous phase extracted with EtOAc. Combined organics washed with saturated NaHCO3 solution then brine, dried and concentrated. Residue taken up in DCM and purified by chromatography (0-40% EtOAc-petroleum ether gradient). Further purification by chromatography (isocratic DCM elution) gives the title compound as a yellow foam (1.45 g, 34%); 1H NMR (400 MHz, DMSO) δ 4.93 (2H, s), 7.21-7.38 (15H, m), 7.44-7.61 (3H, m), 7.62 (1H, d), 8.19 (1H, s), 8.59 (1H, s), 10.93 (1H, s) ppm; MS (ES+) 653.0.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[CH2:26][C@H:25]([CH2:27][OH:28])[CH:24]=[CH:23]2)=[C:15](Cl)[N:14]=1.[OH-].[Na+]>CO>[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[CH2:26][C@H:25]([CH2:27][OH:28])[CH:24]=[CH:23]2)=[C:15]([NH:10][C@@H:8]2[CH2:9][C@H:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:14]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(N[C@@H]2C[C@H]2c2ccccc2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1

Procedure:
A solution of trans-2-phenyl cyclopropylamine.HCl (1.02 g, 6 mmol) in methanol (10 ml) was stirred with basic ion exchange resin for 5 minutes. The resin was filtered off and the filtrate was concentrated to a colorless oil. To this was added (±)-(cis)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.549 g, 2 mmol). The resulting solution was stirred in a Parr bomb at 80° C. for 12 hours 1 N NaOH 12 ml) was added and the solvent evaporated. The residual oil was chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform to give tan crystals after crystallization from acetonitrile-methanol (0.221 g, 30%), m.p.=188-190° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:6][CH:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(C(C)=O)C>[CH2:29]([O:28][C:26]([CH2:25][O:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:6][CH:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])=[O:27])[CH3:30]
Reactant: O=[N+]([O-])c1cccc(OC2CCCCO2)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1c(OC2CCCCO2)cccc1[N+](=O)[O-]

Procedure:
A mixture of 38.4 g of 2-hydroxy-3-(tetrahydropyran-2-yloxy)-nitrobenzene, 22.2 g of potassium carbonate and 27.0 g of ethyl bromoacetate in 400 ml of methyl ethyl ketone is heated to the reflux temperature for 16 hours, whilst stirring, and then filtered; the filter residue is rinsed with 100 ml of methyl ethyl ketone. The combined filtrates are evaporated under reduced pressure. The residual yellowish oil is taken up in 400 ml of diethyl ether, the solution is clarified by filtration, with the addition of 2 g of an active charcoal formulation and the filtrate is evaporated under reduced pressure. The residual oil solidifies after some time to give a mass of crystals and gives 2-ethoxycarbonylmethoxy-3-(tetrahydropyran-2-yloxy)-nitrobenzene; melting point 65°-66°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C#CC2C[C:36]3(CCNC3)[O:35]N=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH:18]([O:35][CH3:36])[CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(C#CC2=NOC3(CCNC3)C2)c1
Reactant: CCOC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Product: CCOC(=O)N1CC(OC)C2(CC(C#Cc3cccc(Cl)c3)=NO2)C1

Procedure:
The title compound was synthesized following the method herein described for the compound of Example 112 but replacing Compound 126a for Compound 27d. After the usual work-up procedure the crude was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 8:2 to 1:1) giving the title compound. Yield: 52.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:30][CH:29]=[C:28]3[F:50])[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:58](Cl)(Cl)=[O:59]>C(#N)C.ClCCl>[C:38]([O:37][C:36]([N:35]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH:55]4[CH2:56][CH2:57]4)(=[O:54])=[O:53])[NH:1][C:58](=[O:59])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[CH:34][CH:33]=2)[C:28]([F:50])=[CH:29][N:30]=1)[C:43](=[O:44])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:42])([CH3:40])([CH3:39])[CH3:41]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c2)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C2CC2)ccc1[C@@H](C)CO
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 34.5 %

Procedure:
To a solution of 19A (135 mg, 0.168 mmol) in acetonitrile (6 mL) and dichloromethane (3 mL) at 0° C., was added phosgene solution (20% in toluene, 0.106 mL, 0.201 mmol) dropwise. The mixture was stirred at 0° C. for 40 min, then at rt for 10 min. Extra phosgene was removed by bubbling Ar for 20 min. The crude was redissolved in acetonitrile (1.0 mL) and dichloromethane (1.0 mL), and was added dropwise via syringe pump into a solution of TEA (0.187 mL, 1.340 mmol) in dichloromethane (60 mL) at rt over 3.0 h. The solution was stirred at rt over night. The solvent was removed and the crude residue was purified using a prep HPLC equipped with a C18 PHENOMENEX® Luna Axia column (30 mm×75 cm, 5μ). The desired fractions were collected and concentrated to give a mixture of diastereoisomers (114 mg). The diastereoisomers were separated by a prep chiral HPLC [(R,R)-Whelk-01 250×21.1 mm column] to give 19B (48 mg, 0.058 mmol, 34.4% yield). MS (ESI) m/z: 832.6 (M+H)+.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.[CH3:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>C1(C)C=CC=CC=1>[F:14][C:11]([F:12])([F:13])[C:5]1([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[S:3][C:2]([NH:1][C:27]([NH:26][C:24](=[O:25])[C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=2[CH3:21])=[O:28])=[N:6]1
Reactant: Cc1ccccc1C(=O)N=C=O
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: Cc1ccccc1
Product: Cc1ccccc1C(=O)NC(=O)NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) was dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g), and 2-methylbenzoylisocyanate (0.3 g) which is a starting compound was added thereto and the mixture was stirred at room temperature for 3 hours.