Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[C:21](=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CO>[OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:21])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COc1cc([N+](=O)[O-])c(C(=O)O)cc1O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(O)c(OC)cc1[N+](=O)[O-]
Yield: 87 %

Procedure:
To a solution of 5-hydroxy-4-methoxy-2-nitrobenzoic acid [Sinha J. Ind. Chem. Soc., 47, 925 (1970)] (83.0 g, 0.39 mol) in MeOH (250 ml) was added concentrated H2SO4 (20 ml) and the reaction mixture was heated to reflux for 16 h. On cooling, the reaction mixture was poured into aqueous potassium carbonate solution and acetic acid was added until pH 4 was reached. The mixture was extracted with chloroform, the organic layer washed twice with H2O and dried over MgSO4. Evaporation under reduced pressure afforded the subtitle compound as yellow crystals (77.0 g, 87%). Rf 0.30 (benzene/acetone 4/1, v/v); m.p. 146-9° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:42])[CH2:37][CH2:38][C:39](Cl)=[O:40]>ClCCl>[O:40]=[C:39]1[CH2:38][CH2:37][C:36](=[O:42])[N:1]1[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)CCC(=O)Cl
Reactant: Nc1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1NCc1ccnc(N2C(=O)CCC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
193 mg (0.5 mmol) of 2-[(2-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is mixed in 20 ml of dichloromethane with 0.21 ml (1.5 mmol) of triethylamine, and it is mixed at room temperature drop by drop with a solution of 93 mg (0.6 mmol) of succinic acid dichloride in 3 ml of methylene chloride. After stirring overnight at room temperature, it is diluted with methylene chloride and washed in succession with water, saturated sodium bicarbonate solution and saturated common salt solution. Then, the organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on Isolute (Separtis Company) with a gradient of methylene chloride:ethanol=100:0 to 95:5. 120 mg (51% of theory) of 2-{[2-(2,5-dioxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamide is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[N:11]=[C:10]([N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH3:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: CNc1ccc(OC)cc1
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(N(C)c2nc(Cl)nc3ccc(OC)cc23)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
A mixture of 2,4-dichloro-6-methoxy-quinazoline (0.5g, 2.18 mmol), (4-methoxyphenyl)-methylamine (0.35 g, 2.61 mmol) and sodium acetate (0.21 g, 2.61 mmol) in 8 mL of solvent (THF:water=1:1) was stirred at 60-70° C. for 3 h. The reaction mixture was concentrated and the resulting solid was dissolved in ethyl acetate and transferred to the silica gel pad (30mg) and washed with 40% ethyl acetate/hexane as eluent. The filtrate was concentrated under reduced pressure to give 0.7 g of the clean product (98% yield). 1H NMR (DMSO): δ 7.6 (d, 1H), 7.36-7.31 (m, 3H), 7.08-7.05 (dd, 2H), 6.2 (d, 1H), 3.79 (s, 3H), 3.5 (s, 3H), 3.28(s, 3H). LC/MS: 330, (M+1).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:40][CH:41]([CH3:43])[CH3:42])[CH:21]2[CH2:26][CH:25]([CH2:27]OS(C)(=O)=O)[CH2:24][N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:44]1[CH:48]=[CH:47][N:46]=[CH:45]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:40][CH:41]([CH3:42])[CH3:43])[CH:21]2[CH2:26][CH:25]([CH2:27][N:44]3[CH:48]=[CH:47][N:46]=[CH:45]3)[CH2:24][N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)C1CC(COS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C1
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)C1CC(Cn2ccnc2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 24 h
Yield: 45.1 %

Procedure:
tert-Butyl 3-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (100 mg) and imidazole (30 mg) were dissolved in N,N-dimethylacetamide (4 ml), cesium carbonate (130 mg) was added and the mixture was stirred at 60° C. for 1 day. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object compound (43.1 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=C.C1C[O:41]CC1.O.I([O-])(=O)(=O)=O.[Na+]>CCOC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:41]
Reactant: C=Cc1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(C=O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 50 %

Procedure:
A suspension of 6-(N-(3-chloro-4-vinylphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (890 mg, 1.65 mmol) in 1:1 THF/water (36 mL) was treated with a solution of osmium tetroxide (2.5% in t-butanol, 0.415 mL, 0.033 mmol) and stirred for a few minutes. The resulting solution was treated with sodium periodate (883 mg, 4.13 mmol) and the reaction mixture was stirred for 16 h at rt. The reaction mixture was diluted with EtOAc and washed with 1:1 water/brine (1×), then brine (1×). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane, filtered and the filtrate was purified by flash chromatography (silica gel, gradient of 0 to 50% EtOAc in hexanes) to afford the title compound (0.45 g, 50%) as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 10.23 (s, 1H), 8.45-8.53 (m, 1H), 8.04 (s, 1H), 7.94-8.01 (m, 2H), 7.86 (d, 1H), 7.35-7.46 (m, 3H), 7.31 (dd, 1H), 7.24-7.29 (m, 1H), 3.57 (s, 3H), 2.84 (d, 3H), 1.89-1.98 (m, 1H), 0.68-1.02 (m, 3H), 0.42-0.58 (m, 1H). LCMS (m/z, ES+)=541 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([CH2:25][OH:26])[CH:24]=1)[O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:34][S:35]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH:24]=1)[O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])(=[O:37])=[O:36]
Reactant: COC(=O)CCOCCOCCOCCOc1cc(CO)cc(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCOCCOCCOCCOc1cc(COS(C)(=O)=O)cc(COS(C)(=O)=O)c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 3-(2-(2-(2-(3,5-bis(hydroxymethyl)phenoxy)ethoxy)ethoxy)ethoxy)propanoate (263b) (145 mg, 0.389 mmol) in anhydrous dichloromethane (5.5 ml) was added triethylamine (0.163 ml, 1.168 mmol). The mixture was cooled to −5° C. and methanesulfonyl chloride (0.076 ml, 0.973 mmol) was added slowly. After stirring for one hour at −5° C. the reaction was quenched with cold water and extracted with cold ethyl acetate. The organic extracts were washed with cold water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 3-(2-(2-(2-(3,5-bis((methylsulfonyloxy)methyl)phenoxy)ethoxy)ethoxy)ethoxy)propanoate. MS (m/z). found 551.1 (M+Na)+. To a stirred mixture of methyl 3-(2-(2-(2-(3,5-bis((methylsulfonyloxy)methyl)phenoxy)ethoxy)ethoxy)ethoxy)propanoate (206 mg, 0.390 mmol) and compound 8 (287 mg, 0.974 mmol) in anhydrous DMF (3.9 ml) was added potassium carbonate (269 mg, 1.949 mmol). The reaction was allowed to stir at room temperature for 18 hours. The mixture was quenched with water and extracted three times with dichloromethane. The organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash silica gel chromatography (5% MeOH/CH2Cl2) followed by preparative reverse phase HPLC (C18 column, eluted with CH3CN/H2O) gave compound 263c (110 mg, 30%) as a white solid. 1H NMR (400 Hz, CDCl3): δ 8.18 (d, J=8.0 Hz, 2H), 7.77 (m, 2H), 7.49 (s, 2H), 7.19 (m, 4H), 7.02 (m, 2H), 6.89 (s, 2H), 6.87 (s, 1H), 6.75 (s, 2H), 5.10 (m, 4H), 4.39 (m, 2H), 4.05 (m, 2H), 3.90 (s, 6H), 3.77 (m, 2H), 3.67 (t, J=6.4 Hz, 2H), 3.64 (m, 2H), 3.59 (s, 3H), 3.70-3.54 (m, 8H), 3.40 (m, 2H), 2.51 (t, J=6.4 Hz, 2H); MS (m/z). found 965.3 (M+H2O+Na)+, 983.3 (M+2H2O+Na)+.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[CH2:18]([Cl:21])[C:19]#[CH:20].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[ClH:21].[F:17][C:3]([F:2])([F:16])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:20][C:19]#[CH:18])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: C#CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C#CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 15 h

Procedure:
3.2 g (0.012 mol) of N-(3-trifluoromethyl-phenyl)-piperazine hydrochloride, 0.9 g (0.012 mol) of propargyl chloride and 2.5 g (0.024 mol) of sodium carbonate were heated at 60° C. in 50 ml of absolute acetonitrile while stirring. Over a period of 15 hours, an additional 0.34 g (0.0046 mol) of propargyl chloride and 0.5 g (0.0046 mol) of sodium carbonate were added. The inorganic salts were removed by suction filtration, and the filtrate was evaporated under reduced pressure. The evaporation residue was dissolved in toluene, and the product solution was extracted with the calculated quantity of dilute hydrochloric acid. The aqueous phase was made alkaline with soda, and the base was extracted with ether. After drying with sodium sulfate, the organice phase was evaporated under reduced pressure, and the base was converted into its hydrochloride in conventional manner. White crystals from acetonitrile, melting point 218°-219° C. (decomposition). Yield: 2.7 g (73.8% of theory). The existence of these compounds was confirmed by elemental and spectrum analysis.
Reaction SMILES: [H-].[K+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[CH2:18](Br)[CH:19]=[CH2:20].C(O)(=O)C>O1CCCC1.O>[CH3:3][O:4][C:5](=[O:17])[CH:6]([CH2:20][CH:19]=[CH2:18])[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: C=CCBr
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C=CCC(C(=O)OC)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A mixture of 35% potassium hydride oil suspension (6.04 g, 35% w/w/, 53 mmols of potassium hydride) in 240 mL of sieve dried tetrahydrofuran was cooled to 0° C. The cold mixture was treated with homoterephthalic acid dimethyl ester (10.0 g, 48 mmols). The mixture was stirred at 0° C. for one hour. Allyl bromide (6.41 g, 53 mmols) was added and the mixture was stirred at 0° C. for 30 minutes, then at room temperature for 16 hours. The resulting mixture was treated with 4.8 mL of 50% acetic acid, then poured into 480 mL of water. The mixture was extracted with ether (2 ×250 mL). The ether extracts were combined, dried over magnesium sulfate, and concentrated to a brown oil. Chromatography on 250 g of flash silica gel (10% ether in hexane eluent) gave the product IV-1a as a pale yellow oil, 10.5 g (89% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>C(O)(=O)C>[C:22]1([CH3:25])[CH:23]=[CH:24][C:19]([N:18]2[C:10](=[O:11])[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:6]3[C:7]2=[O:9])=[CH:20][CH:21]=1
Reactant: O=C1OC(=O)c2c1cc([N+](=O)[O-])cc2[N+](=O)[O-]
Reactant: Cc1ccc(N)cc1
Solvent: CC(=O)O
Product: Cc1ccc(N2C(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3C2=O)cc1
Yield: 85.1 %

Procedure:
2 kg (8.4 mols) of 3,5-dinitrophthalic anhydride and 897 g (8.4 mols) of p-toluidine in 6.2 l of glacial acetic acid are kept under reflux for 3 hours. After cooling, the mixture is filtered, the residue is rinsed with 2 l of water and then suspended in 25 l of water, and the product is filtered off and dried at 100° C. in vacuo. 2,339 g (85% of theory) of N-(p-toluyl)-3,5-dinitrophthalimide are obtained; melting point: 182°-3° C.
Reaction SMILES: [F:1][C:2](I)([F:7])[C:3]([F:6])([F:5])[F:4].C[Mg]Br.C([O:14][C:15]([C:17]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)([OH:24])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)=O)C.[Cl-].[NH4+]>CCOCC.O>[OH:24][C:17]([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)([C:15](=[O:14])[C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: CCOC(=O)C(O)(Cn1cncn1)c1ccc(F)cc1
Reactant: FC(F)(F)C(F)(F)I
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: O=C(C(O)(Cn1cncn1)c1ccc(F)cc1)C(F)(F)C(F)(F)F
Reaction time: 0.5 h
Yield: 55 %

Procedure:
Gaseous pentafluoroethyl iodide (5 g., 0.02M) was passed into a flask containing dry ether (40 ml.) at -70° and fitted with a dry-ice condenser. A 3 molar solution of methylmagnesium bromide (5.8 ml., 0.017M) was then added over 5 minutes keeping the temperature between -70° and -65°. The mixture was then stirred at -70° for 1/2 hour. 1-Ethoxycarbonyl-1-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol (1.3 g., 0.0047M) in dry ether (10 ml.) was then added over 10 minutes keeping the temperature at -65° or below. The mixture was then stirred at -70° for 1 hour and was then allowed to warm to -25° over 11/2 hours. A solution of ammonium chloride (5 g.) in water (30 ml.) was then added. The ether layer was separated and the aqueous layer was extracted further with ether (2×40 ml.). The ether layers were combined, dried (MgSO4) and evaporated to give the crude title compound as an oil. The oil was purified by chromatography on silica (230-400 mesh) eluting with ethyl acetate:60°-80° petrol (4:1, by volume) to give the title compound, 1.2 g (55% yield). The compound was recrystallised from cyclohexane, m.p. (after said recrystallisation) 128°-132°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CN1CCOCC1.[CH3:13][O:14][C:15]([C:17]1[N:18]=[C:19]([CH3:29])[S:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)=[O:16].O>C(Cl)Cl>[CH3:13][O:14][C:15]([C:17]1[N:18]=[C:19]([CH3:29])[S:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH:23]=1)=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1nc(C)sc1-c1cccc(N)c1
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1nc(C)sc1-c1cccc(NS(C)(=O)=O)c1

Procedure:
Methanesulfonyl chloride (5.27 mmol) and 4-methylmorpholine (4.86 mmol) are added successively to a solution of 5-(3-amino-phenyl)-2-methyl-thiazole-4-carboxylic acid methyl ester (4.05 mmol) in DCM (50 mL). After stirring for 2 h water is added, the layers are separated and the aq. layer is extracted once with DCM. The combined organic layers are washed with citric acid (10% solution in water), dried over MgSO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS: tR=0.84 min; [M+H]+=327.2.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O>O>[F:16][C:17]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[C:7]([C:8]3[N:9]=[C:10]([NH:14][CH3:15])[N:11]=[CH:12][N:13]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: O=C(O)c1cc(O)ccc1F
Reactant: CNc1ncnc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1ncnc(-c2cccnc2Oc2ccc(F)c(C(=O)O)c2)n1
Temperature: 130 °C

Procedure:
To [4-(2-chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-methyl-amine (6.90 g, 31.1 mmol), 2-fluoro-5-hydroxybenzoic acid (4.9 g, 31.1 mmol) and Cs2CO3 (20.3 g, 62.2 mmol) was added DMSO (25 mL). The mixture was heated overnight at 130° C. in a sealed tube. The cooled mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified (pH˜4) with TFA and the resulting solid was filtered, washed with water and dried to yield 2-fluoro-5-[3-(4-methylamino-[1,3,5]triazin-2-yl)-pyridin-2-yloxy]-benzoic acid. MS m/z=342 [M+1]+. Calc'd for C16H12FN5O3: 341.30.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])=[CH:7][CH:6]=1)[CH3:3].[NH2:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[C:25]([Cl:30])[N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[Cl:30][C:25]1[CH:26]=[C:27]([O:21][CH:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:8]2[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=2)[C:17]([F:18])([F:20])[F:19])[N:28]=[C:23]([NH2:22])[N:24]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CN(C)Cc1ccc(-c2ccccc2C(O)C(F)(F)F)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C)Cc1ccc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)o1
Temperature: 110 °C
Yield: 38.5 %

Procedure:
The mixture of 1-[2-(5-dimethylaminomethyl-furan-2-yl)-phenyl]-2,2,2-trifluoro-ethanol (225 mg, 0.75 mmol), 2-amino-4,6-dichloro-pyrimidine (111 mg, 0.67 mmol), cesium carbonate (978 mg, 3.01 mmol) and 1,4-dioxane (3 ml) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature; 10 ml of ethyl acetate was added. The mixture was then filtered through Celite, the filtrate was concentrated to give 110 mg of 4-chloro-6-{1-[2-(5-dimethylaminomethyl-furan-2-yl)-phenyl]2,2,2-trifluoro-ethoxy}-pyrimidin-2-ylamine, yield 87%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccccc1I
Product: O=C(Cl)Cc1ccccc1I

Procedure:
A solution of 13.32 g (0.05 mol) of 2-iodophenylacetic acid in 75 ml thionyl chloride is refluxed for 2 hours, and the volatiles removed under vacuum. Toluene is added (3 times) and the solvent removed under vacuum after each addition to give 2-iodophenylacetyl chloride as a gum. To the preceding compound (0.05 mol) in a mixture of 100 ml of toluene-dichloromethane (1:1) is added 11 g (0.05 mol) of 2-iodoaniline and (0.10 mol) of diisopropylethylamine. The mixture is stirred at room temperature overnight and the solvent removed. The residue is dissolved in dichloromethane and the solution washed with 1N HCl, saturated sodium bicarbonate, brine and dried (Na2SO4). The solvent is removed and the residue recrystallized from methanol-ether to give 16.0 g of light brown crystals, m.p. 160°-163° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8](S)=[N:9][C:10](C)=[C:5]2[C:4]([C:13]2[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[N:3]1.[CH3:21][NH2:22]>C(O)C.C(OCC)(=O)C>[CH3:21][NH:22][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[C:5]=12
Reactant: CN
Reactant: Cc1nc(S)nc2c1c(-c1ccc([N+](=O)[O-])o1)nn2C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ncnc2c1c(-c1ccc([N+](=O)[O-])o1)nn2C

Procedure:
A mixture of 3.0 grams of 1-methyl-4-methyl-mercapto-3-(5-nitro-2-furyl)-1H-pyrazolo [3,4-d] pyrimidine, 50 millitres of a 33% solution of methylamine in ethanol and 20 milliliters of ethyl acetate was heated at reflux for 1hour and cooled. The crystalline product formed was collected, washed with ethanol and dried. Recrystallisation from ehtyl acetate gave 4-methylamino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo [3,4-d]pyrimidine having melting point 280° C. identical to the product obtained in Example 13.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl.N12CCCN=C1CCCCC2>ClCCl>[C:1]([O:5][C:6]([C:7]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:15]2[C:16](=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=2)[NH:22][C:34]1=[O:36])=[O:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(Br)cc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C1(C(=O)OC(C)(C)C)C(=O)Nc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 130.2 %

Procedure:
2-(2-Amino-4-bromo-phenyl)-malonic acid di-tert-butyl ester (10.00 g, 25.9 mmol) and diisopropylethyl amine (22.6 ml, 129.6 mmol) were dissolved in 100 ml of anhydrous dichloromethane (DCM) under an atmosphere of dry N2. The solution was cooled to 0° C. and triphosgene (2.82 g, 9.50 mmol) was added portionwise over a period of 15 minutes. After the addition was complete, the reaction mixture was warmed to ambient temperature and stirred for 1.5 hours after which time 1,8-diazabicyclo[5.4.0]undec-7-ene (19.4 ml, 129.5 mmol) was added and the mixture was stirred for an additional 1 hour. The reaction mixture was then partitioned between water and DCM. The DCM layer was then washed 3 times with 10% aqueous NaHSO4, dried over MgSO4, filtered and concentrated under vacuum to give a green foam. The green foam was stirred in hexanes overnight. The precipitate was collected and washed with hexanes, dried under vacuum to give 5.10 g of the titled compound as a white solid.