Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[CH2:13][CH2:14]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]C(Br)(Br)Br>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[CH2:13][CH2:14][Br:35]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cccc2c1CCCC2CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc2c1CCCC2CCBr
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
To a solution of 2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethanol (0.20 g) and triphenylphosphine (0.42 g) in dichloromethane (10 ml) was added tetrabromomethane (0.90 g) at 5° C. The solution was stirred at 5° C. for 1.5 hours and evaporated in vacuo. To the residue, ethyl acetate was added and the insoluble material was filtered off. The ethyl acetate solution was evaporated in vacuo. The residue was chromatographed (n-hexane) over silica gel to afford 2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl bromide (0.18 g) as a colorless oil.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][CH:2]([F:5])[CH2:3][N:10]1[C:6](=[O:16])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: FC(F)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(F)F
Temperature: 120 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
An amount of 27.6 g (0.269 mol) of 2,2-difluoro-1-chloroethane and 20 g (0.135 mol) of phthalimide are dissolved in 95 g of N,N-dimethylformamide and treated with 56.3 g (0.403 mol) of potassium carbonate. The reaction mixture is stirred in an autoclave under pressure at 120° C. for 16 h. After the end of the reaction, cooling is carried out to ambient temperature and the solvent is exhaustively removed under vacuum. The remaining residue is treated with 100 ml of water and the solid is filtered off. The filter residue is washed twice with water and the product is dried under vacuum. An amount of 22.2 g of 2-(2,2-difluoroethyl)-1H-isoindole-1,3(2H)-dione with a purity of 98.4% is obtained. This corresponds to a yield of 77% of theory.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:26]2\[C:27](=[O:38])[NH:28][C:29]3[C:34]\2=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)/[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](OC(=O)C)(=[O:41])[CH3:40]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:26]2\[C:27](=[O:38])[NH:28][C:29]3[C:34]\2=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)/[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:39](=[O:41])[CH3:40])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccc(CN)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)NCc1ccc(/C(Nc2ccc(CNC(=O)OC(C)(C)C)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
Prepared analogously to Example 31 from (Z)-3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-(4-aminomethyl-phenyl)-methylidene]-5-nitro-2-indolinone and acetic anhydride in dioxane.
Reaction SMILES: FC(F)(S(O[C:17]1[CH:18]=[C:19]2[C@@:30]3([CH2:34][O:33][C:32]([NH2:35])=[N:31]3)[C:29]3[C:24](=[N:25][CH:26]=[C:27]([C:36]#[C:37][C:38]([OH:41])([CH3:40])[CH3:39])[CH:28]=3)[O:23][C:20]2=[CH:21][CH:22]=1)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.CN(C=O)C.C(NC(C)C)(C)C.[C:55]([CH:57]1[CH2:59][CH2:58]1)#[CH:56]>O.[Cu]I>[NH2:35][C:32]1[O:33][CH2:34][C@:30]2([C:29]3[C:24](=[N:25][CH:26]=[C:27]([C:36]#[C:37][C:38]([CH3:40])([OH:41])[CH3:39])[CH:28]=3)[O:23][C:20]3[C:19]2=[CH:18][C:17]([C:56]#[C:55][CH:57]2[CH2:59][CH2:58]2)=[CH:22][CH:21]=3)[N:31]=1
Reactant: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc1O2
Reactant: C#CC1CC1
Agent: [Cu]I
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(C#CC3CC3)ccc1O2
Temperature: 80 °C

Procedure:
A 0.5-2 mL vial was charged with (S)-2′-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (106 mg, 0.167 mmol), and copper(i) iodide (3.19 mg, 0.017 mmol). The vial was flushed with Ar (g), then DMF (669 μL, 0.167 mmol), diisopropylamine (469 μL, 3.35 mmol), and ethynylcyclopropane (70.8 μL, 0.836 mmol) were added in sequence to give a yellow solution. The vial was sealed and heated overnight in at 80° C. The mixture was diluted with water (15 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 40-g Redi-Sep column, eluting with 0-50% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to give (S)-4-(2′-amino-7-(cyclopropylethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yl)-2-methylbut-3-yn-2-ol as a tan solid after evaporation from DCM/hexanes.
Reaction SMILES: C(OC([CH2:6][CH2:7][NH:8][CH:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])[CH:10]([CH3:16])[C:11]([O:13]CC)=O)=O)C.CC(C)([O-])C.[K+].C(O)C>C1(C)C=CC=CC=1.O>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][CH:9]1[CH:10]([CH3:16])[C:11](=[O:13])[CH2:6][CH2:7][NH:8]1
Reactant: CCOC(=O)CCNC(Cc1ccccc1OC)C(C)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1CC1NCCC(=O)C1C
Temperature: 70 °C

Procedure:
210 g (0.6 mol) of ethyl 3-(2-ethoxycarbonylethyl)-amino-4-(2-methoxyphenyl)-2-methylbutanoate 14 are dissolved in 3 1 toluene and first about 100 mL of a solvent/water mixture are entrained. The mixture is cooled to about 70° C., combined with 80 g (0.7 mol) of potassium tert-butoxide and heated for 30 minutes to 105° C., while the ethanol formed is distilled off. Then the mixture is left to cool and the solvent is eliminated in vacuo. The residue is combined with 400 mL of ethanol and 200 mL of 40% sodium hydroxide solution and refluxed for 3 h. The alcohol is eliminated in vacuo and the aqueous phase is extracted three times with 400 mL of diethylether (ether). The combined organic phases are dried over magnesium sulfate, and the solvent is eliminated in vacuo. Yield 109 g (78%) oil.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:5]2[N:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[NH:8][C:4]=2[C:3]=1[S:17]([OH:20])(=O)=[O:18].S(Cl)([Cl:23])=O>CN(C)C=O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:5]2[N:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[NH:8][C:4]=2[C:3]=1[S:17]([Cl:23])(=[O:20])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1c(Cl)c(Cl)c(Cl)c2nc(C(F)(F)F)[nH]c12
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1c(Cl)c(Cl)c(Cl)c2nc(C(F)(F)F)[nH]c12
Temperature: 80 °C
Yield: 91 %

Procedure:
The 5,6,7-trichloro-2-trifluoromethylbenzimidazole-4-sulphonic acid (155 parts) was added to a stirred mixture of thionyl chloride (770 parts) and dimethylformamide (24 parts). A vigorous effervescence took place, and when this had subsided the mixture was slowly heated to reflux temperature (80°C) and maintained at this temperature for three hours. The reaction mixture was then cooled and the solid crystals filtered off, washed with benzene (160 parts) and dried to give 5,6,7-trichloro-2-trifluoromethylbenzimidazole-4-sulphonyl chloride (138 parts), melting point (with decompoition) 208°-209°C. Evaporation of the filtrate yielded a further 10 parts of the product, giving a total yield of 148 parts (91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27]([NH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=2)[N:14]=1)(=[O:29])=[O:28]
Reactant: Nc1cccc(COCc2ccc(Cl)cc2)n1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1cccc(COCc2ccc(Cl)cc2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-chloro-benzyloxymethyl)-pyridin-2-ylamine (0.08 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.092 g) as an off-white solid (0.082 g). MS (ESI−): 469.0 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[OH:22][CH:23]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)[CH:24]([NH2:36])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([NH:36][CH:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=2)[CH:23]([OH:22])[C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
To a solution of 4-fluoronaphthalene-1-carboxylic acid (112 mg, 0.59 mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.10 ml, 1.18 mmol) and N,N-dimethylformamide (0.01 ml) and the mixture was stirred at room temperature for 30 min. The reaction solution was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) were added (1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.39 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (147 mg, 72%).
Reaction SMILES: [CH:1]([N:4]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29]C)[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[CH2:17][C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11][C:10]1=[O:20])([CH3:3])[CH3:2].B(Br)(Br)Br.C(=O)([O-])O.[Na+].N>C(Cl)Cl>[CH:1]([N:4]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[CH2:17][C:12]2([CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:11][C:10]1=[O:20])([CH3:3])[CH3:2]
Reactant: COc1ccccc1CCN(CCCCN1C(=O)CC2(CCCC2)CC1=O)C(C)C
Agent: BrB(Br)Br
Agent: N
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)N(CCCCN1C(=O)CC2(CCCC2)CC1=O)CCc1ccccc1O
Temperature: -60 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
8-(4-{Isopropyl-[2-(2-methoxyphenyl)ethyl]-amino}butyl)-8-aza-spiro[4.5]decane-7,9-dione (550 mg, 1.2 mmol) dissolved in 10 ml methylene chloride was cooled to -60° C. under nitrogen. Boron tribromide (0.28 ml, 2.9 mmol) in 3 ml methylene chloride was added in 20 min and the mixture stirred at 10° C. overnight, poured into 5 ml cold sodium hydrogen carbonate solution. The aqueous phase was treated with 1M ammonia and extracted with methylene chloride and the solvent evaporated to yield 410 mg of an oil.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:41]O)[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N-:43]=[N+:44]=[N-:45].[Li+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>CN(C)C=O>[CH2:23]([O:22][CH:21]([CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:41][N:43]=[N+:44]=[N-:45])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(CO)OCCCCCCCC/C=C\CCCCCCCC
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCCCCC/C=C\CCCCCCCCOCC(CN=[N+]=[N-])OCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a mixture of 1.00 g (1.7 mmol) of 1,2-O-dioleylglycerol, 0.83 g (17 mmol) of lithium azide, 0.89 g (3.4 mmol) of triphenylphosphine, and 1.13 g (3.4 mmol) of carbon tetrabromide was added 10 ml of N,N-dimethylformamide in bolus and the mixture was stirred at ambient temperature for 3 hours. After completion of the reaction, the solvent was distilled off and the residue was diluted with water and extracted with ether. The ether layer was washed with water, dried, and concentrated, and the residue was purified by column chromatography (silica gel/n-hexane-ethyl acetate) to provide 1.03 g (100%) of 2,3-dioleyloxypropyl azide as oil.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][C:11]#[N:12])=[CH:8][CH:7]=1)=[O:4].[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>CN(C=O)C>[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][C:11]#[N:12])=[CH:8][CH:7]=1)=[O:4]
Reactant: N#CCc1ccc(NC(=O)CBr)cc1
Reactant: Nc1ccccc1F
Solvent: CN(C)C=O
Product: N#CCc1ccc(NC(=O)CNc2ccccc2F)cc1
Temperature: 0 °C
Yield: 73.5 %

Procedure:
A solution of 4-((bromoacetyl)amino)benzyl cyanide (8.5 g, 33.6 mmol) and 2-fluoroaniline (9.03 g, 81.3 mmol) in anhydrous DMF (60 mL) was heated to 90°-100° C. for 2 days with stirring under N2. The solution was cooled, poured into 500 mL of ice-water, and then extracted with CH2Cl2 (200 mL). The separated organic layer was dried (MgSO4) and filtered, a small amount of silica gel was added to the CH2Cl2 solution, and then the mixture was concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (2:1), afforded 7.0 g (73.5%) of the title compound, mp 111°-113° C.: 1H NMR (DMSO-d6) δ10.09 (s, 1H), 7.61 (d, J=8.4, 2H), 7.27 (d, J=8.8, 2H), 7.05 (ddd, J=9.6, J=8.0, J=1.6, 1H), 6.94 (t, J=7.1, 1H), 6.63-6.58 (m, 2H), 5.76 (bt, J=6.0, 1H): 3.96 (s, 2H), 3.93 (d, J=6.0, 2H); 13C NMR (DMSO-d6) δ168.92, 150.87 (d, J=236), 138.18, 136.37 (d, J=11.0), 128.47, 125.85, 124.72 (d, J=3.0), 119.61, 119.32, 116.24 (d, J=6.8), 114.37 (d, J=17), 112.13, 46.62, 21.79; MS (El, m/z) 283 (M+).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[NH:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2].[CH:25](=O)[C:26]([CH3:29])([CH3:28])[CH3:27].N1CCCC1>C(#N)C>[C:26]([CH:29]1[O:24][C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH:9]=[C:4]2[C:1](=[O:3])[CH2:2]1)([CH3:28])([CH3:27])[CH3:25]
Reactant: CC(C)(C)C=O
Reactant: CC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Solvent: C1CCNC1
Solvent: CC#N
Product: CC(C)(C)C1CC(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2O1
Temperature: 70 °C

Procedure:
To the product of Example 4 Step A (0.75 g, 2.09 mmol) was added pivalaldehyde (2. mL, 20.9 mmol), pyrrolidine (0.26 mL, 3.14 mmol) and acetonitrile (15 mL). The reaction was heated to 70° C. for 19 h. The reaction was then concentrated and the residue was purified directly by flash chromatography on silica gel gradient eluted with 0-35% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 426.3 (M+1), 428.3 (M+3); Rt=4.32 min.
Reaction SMILES: [CH2:1]([OH:34])[C@H:2]1[O:7][C@H:6]([O:8][CH2:9][C@H:10]2[O:15][C@H:14]([O:16][C@:17]3([CH2:26][OH:27])[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C@@H:18]3[OH:25])[C@H:13]([OH:28])[C@@H:12]([OH:29])[C@@H:11]2[OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@H:3]1[OH:33].[C:35]([O-:38])(=[O:37])[CH3:36].[Na+]>C(OC(=O)C)(=O)C>[CH2:1]([OH:34])[C@H:2]1[O:7][C@H:6]([O:8][CH2:9][C@H:10]2[O:15][C@H:14]([O:16][C@:17]3([CH2:26][OH:27])[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C@@H:18]3[OH:25])[C@H:13]([OH:28])[C@@H:12]([OH:29])[C@@H:11]2[OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@H:3]1[OH:33].[C:35]([O:38][O-:7])(=[O:37])[CH3:36]
Reactant: CC(=O)[O-]
Agent: OC[C@H]1O[C@H](OC[C@H]2O[C@H](O[C@]3(CO)O[C@H](CO)[C@@H](O)[C@@H]3O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[O-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Anhydrous raffinose (252 g, 0.50 mol) was added to 60 g anhydrous sodium acetate and stirred in 800 mL of acetic anhydride previously equilibrated to 100 degree C. Complete homogeneous solution is obtained in 30-50 minutes. The reaction is left to continue for 1-2 hours, after which the reaction mixture was poured into 4 liters of ice and left to stand for 2 hours. The raffinose peracetate precipitate formed is separated from the supernatant solution, redissolved in dichloromethane and washed three times with saturated sodium bicarbonate solution at neutral pH. The dichloromethane solution was then decolorized with 2.0 g activated charcoal and vacuum dried to give 492 g (90% yield) of raffinose peracetate white powder.
Reaction SMILES: [Si]([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][N:14]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[C:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[O:16])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>O1CCCC1>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([N:14]([CH2:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:31][CH:30]=2)[C:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[O:16])=[CH:27][CH:26]=1)#[N:29]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CN(C(=O)c2cccs2)c2ccc(C#N)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccc(N(Cc2ccc(O)cc2)C(=O)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
180 mg of N-(4-tert-butyldimethylsilyloxybenzyl)-N-(4-cyanophenyl)-2-thiophenecarboxamide was dissolved in 3.5 ml of tetrahydrofuran, and 386 mg of tetrabutylammonium fluoride was added thereto under cooling with ice, followed by stirring at room temperature for 4 hours. After the reaction mixture was poured into a saturated aqueous solution of sodium chloride, the product was extracted with diethyl ether. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by TLC (using a 19:1 mixture of chloroform and methanol as the developing solvent) to obtain 47 mg of N-(4-cyanophenyl)-N-(4-hydroxybenzyl)-2-thiophenecarboxamide.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:23]=[C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29](=O)[NH2:30])[N:21]=[C:20]3[C:16]=2[N:17]=[CH:18][N:19]3[CH2:32][CH3:33])[CH:11]=[CH:12][CH:13]=1>C1COCC1>[NH2:30][CH2:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:24]1[C:22]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH2:32][CH3:33])=[C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[CH:9]=2)[N:23]=1
Reactant: CCn1cnc2c(Nc3cccc(Cl)c3)nc(N3CCC[C@H]3C(N)=O)nc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1cnc2c(Nc3cccc(Cl)c3)nc(N3CCC[C@H]3CN)nc21
Temperature: 0 °C

Procedure:
A suspension of 230 mg (6.07 mmol) of LiAlH4 in 5 ml of abs. THF is added dropwise to a suspension of 600 mg (1.6 mmol) of 6-(3-chloro-phenyl-amino)-9-ethyl-[(S)-2-carbamoyl-pyrrolidin-1-yl]-9H-purine (cf. Example 64) in 15 ml of abs. THF, and the mixture is stirred at 80° C. for 24 h. Thereafter, 10 ml of ice/water are cautiously added dropwise and the reaction mixture is poured onto 50 ml of ice/water. The mixture is extracted three times with ethyl acetate (100 ml each time). The combined organic extracts are washed with aqueous sodium bicarbonate solution, water and saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure. The resulting crude product (oil) is purified by means of column chromatography (silica gel), digestion in diethyl ether/hexane and RP-MPLC (medium pressure chromatography, Lichroprep® RP-18 (irregular silica gel support material, Merck, Darmstadt, Germany)). 2-[(S)-2-Aminomethyl-pyrrolidin-1-yl]-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine is obtained as an oil; FAB-MS: (M+H)+=372, HPLC: tret (grad20/2)=11.25 minutes; [α]D20=−56.1° [DMSO, c=0.51].
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]=[C:11]2[S:16][CH2:15][CH:14](O)[N:12]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>ClCCl>[CH2:1]([S:8][C:9]1[N:10]=[C:11]2[S:16][CH:15]=[CH:14][N:12]2[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CSc2nc(SCc3ccccc3)nn21
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: c1ccc(CSc2nc3sccn3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from stage (b) (7.9 g) was dissolved in dichloromethane (50 ml) and was treated with pyridine (2.7 g), then with thionyl chloride (4.2 g) in dichloromethane (5 ml) dropwise with stirring at 5°-10° C. After 3 hours stirring at room temperature, the solution was washed with water, dilute hydrochloric acid, aqueous sodium bicarbonate solution and water again, dried and run down to give the desired product as a brown oil which was recrystallise from ethanol to give pure product, mp 91°-93° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7][CH3:8])[C:3]=1[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].C(O[C:21](=[N:23][C:24](=O)[O:25]CC)[CH3:22])C>C(O)(=O)C>[C:12]1([S:9]([C:3]2[C:4]([S:7][CH3:8])=[N:5][N:6]3[C:24](=[O:25])[NH:23][C:21]([CH3:22])=[N:1][C:2]=23)(=[O:11])=[O:10])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)N=C(C)OCC
Reactant: CSc1n[nH]c(N)c1S(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Product: CSc1nn2c(=O)[nH]c(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 35.8 %

Procedure:
A solution of 0.54 g (2 mol) of 5-amino-3-methylthio-4-phenylsulphonyl-pyrazole and 0.54 g (3.4 mmol) of ethyl 1-ethoxy-ethylidene-carbamate in acetic acid was stirred at 100° C. for 3 hrs. After cooling to RT the precipitate was filtered off, washed off with a copious amount of Et2O and dried in a high vacuum at 45° C. There was obtained 0.41 g (61%) of 8-benzenesulphonyl-2-methyl-7-methylsulphanyl-3H-pyrazolo[1,5-a][1,3,5]-triazin-4-one white crystals, m.p.>300° C.
Reaction SMILES: [F:1][C:2]1([F:12])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:4]=2[O:3]1.F[C:14]1[C:19]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1>>[F:12][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:14]3[C:19]([C:20]4[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]([CH2:28][C:29]5[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=5)[CH2:37][C:38]5[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=5)[N:21]=4)=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][C:4]=2[O:3]1
Reactant: Nc1ccc2c(c1)OC(F)(F)O2
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc4c(c3)OC(F)(F)O4)n2)cc1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 2,2-difluorobenzo[d][1,3]dioxol-5-amine (0.055 g, 0.320 mmol) (Apollo Scientific Limited) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.095 g, 0.213 mmol), and isolated as a brown oil (100%). 1H NMR (400 MHz, d6-DMSO) δ 11.98 (br. s., 1H); 8.79 (d, J=7.6 Hz, 1H); 8.35 (br. s., 1H); 7.92 (br. s., 1H); 7.20-7.29 (m, 5H); 7.16 (d, J=8.4 Hz, 1H); 6.83-6.97 (m, 5H); 4.81 (d, J=7.4 Hz, 4H); 3.72 (d, J=12.7 Hz, 6H); 2.57 (br. s., 3H). m/z (ESI, +ve ion) 599.0 (M+H)+.