Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:13](=[S:14])[NH:12][N:11]=[C:10]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:22][C:23]#[N:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][NH:12][C:13]=2[S:14][CH2:22][C:23]#[N:24])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2C(=S)NN=C2c2ccccc2)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(-c3ccccc3)n[nH]c2SCC#N)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.4 %

Procedure:
To a solution of 4-(3-methoxyphenyl)-3-phenyl-1H-pyrazole-5(4H)-thione (0.200 g, 0.708 mmol) in DMF (5.0 mL) was added 2-bromoacetonitrile (0.047 mL, 0.708 mmol) and K2CO3 (0.098 g, 0.708 mmol). The mixture was stirred at 25° C. for 72 h, quenched with water (40.0 mL), extracted with EtOAc (4×50.0 mL) and washed with brine. The combined organics were dried over MgSO4, filtered, and concentrated to give a brown oil. This brown oil was purified by silica gel flash chromatography to give the title compound as a white solid (0.158 g). LCMS m/z=332.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 3.67 (s, 2H), 3.74 (s, 3H), 6.82-6.89 (m, 3H), 7.23-7.29 (m, 1H), 7.34 (s, 5H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[ClH:15].[CH3:16][O:17][C:18]1[C:26]2[O:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22]=2[C:21]([C:29]2[C@@H:38]3[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([C:40]3[CH:45]=[CH:44][C:43]([C:46](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:47])=[CH:42][CH:41]=3)[N:30]=2)=[CH:20][CH:19]=1>>[ClH:15].[ClH:15].[CH3:16][O:17][C:18]1[C:26]2[O:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22]=2[C:21]([C:29]2[C@@H:38]3[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([N:4]4[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][N:9]5[CH2:10][CH2:11][O:12][CH2:13][CH2:14]5)[CH2:6][CH2:5]4)=[O:47])=[CH:42][CH:41]=3)[N:30]=2)=[CH:20][CH:19]=1
Reactant: C1CN(CCN2CCOCC2)CCN1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(CCN5CCOCC5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2

Procedure:
Prepared from intermediate product A2 and 4-(2-piperazin-1-yl-ethyl)-morpholine as described for compound 8. M.p. 271° C. (decomposes).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[NH:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[CH:9]=[CH:8]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Cl:3][C:7]1[N:12]=[N:11][C:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[CH:9][CH:8]=1
Reactant: CCCCOC(=O)c1ccc(=O)[nH]n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCOC(=O)c1ccc(Cl)nn1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a mixture of phosphorus oxychloride (20 ml) and acetonitrile (40 ml) heated at reflux was added a solution of n-butyl 6-oxo-1,6-dihydropyridazine-3-carboxylate (20 g) in acetonitrile (80 ml). The reaction was heated at reflux for 30 minutes, cooled and added to an ice cooled solution of K2CO3 (87.8 g) in water (600 ml) with vigorous stirring. The product was filtered off, washed with water and dried at 60° C. to give n-butyl 6-chloropyridazine-3-carboxylate (17.5 g, 80% yield), mpt 110°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=[O:12])=[CH:5][C:4]=1[C:17](=[O:30])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:17](=[O:30])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=1
Reactant: COC(=O)C(C)(C)Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CC(C)(C)C(=O)O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Yield: 71.1 %

Procedure:
Using methyl 3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]-2,2-dimethylpropanoate (300 mg, 0.708 mmol; Example 47), ethanol (5 ml) and 10% aqueous solution of sodium hydroxide (2 ml) and conducting the procedure similar to Example 22, 206 mg (90%) of the title compound were obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@:14]12[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:15]1[C@@H:16]1[C@@:29]([CH3:32])([CH2:30][CH2:31]2)[C@@:28]2([CH3:33])[C@@H:19]([C@:20]3([CH3:46])[C@@H:25]([CH2:26][CH2:27]2)[C:24]([CH3:35])([CH3:34])[C:23]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:13].C(=O)([O-])[O-].[K+].[K+].O1CCO[CH2:62][CH2:61]1>C(#N)C>[CH2:61]([N:7]([CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:53])[CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@:14]12[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:15]1[C@@H:16]1[C@@:29]([CH3:32])([CH2:30][CH2:31]2)[C@@:28]2([CH3:33])[C@@H:19]([C@:20]3([CH3:46])[C@@H:25]([CH2:26][CH2:27]2)[C:24]([CH3:35])([CH3:34])[C:23]([C:36]2[CH:37]=[CH:38][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:44][CH:45]=2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:13])[CH3:62]
Reactant: C1COCCO1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCCNCCCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCCN(CC)CCCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(4-methoxy-4-oxobutylamino)propylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (10 mg, 0.014 mmol) and potassium carbonate (5.69 mg, 0.041 mmol) in dioxane (1 mL) and acetonitrile (1.000 mL) was heated up at 78° C. for 3 hours, LCMS indicated the formation of desired product. The reaction mixture was quenched with distilled water (2 mL), extracted with DCM (3×2 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a colorless oil (10 mg, 96%). LCMS: m/e 757.50 (M+H)+, 2.73 min (method 1).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:20]([CH2:22][NH2:23])[OH:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:21][CH2:20][CH2:22][NH:23][S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: NCCO
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCCO)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of Example 9 (110 mg; 0.33 mmol; 1 eq.), is dissolved in DCM (10 ml). Ethanolamine (39.9 mg; 0.65 mmol; 2 eq.) and DIEA (0.17 ml; 0.98 mmol; 3 eq.) are added. After one hour, the solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, Compound (11) is obtained as white-off solid (36.5 mg; 30%). 1H NMR (DMSO-d6) δ 2.15 (s, 3H), 2.43 (s, 3H), 2.91 (m, 2H), 3.41 (m, 2H), 4.72 (t, J=6 Hz, 1H), 7.21 (d, J=4.5 Hz, 1H), 7.54 (d, J=4.5 Hz, 1H), 7.88 (br s, 1H), 12.25 (br s, 1H). M−(ESI): 360.11; M+(ESI): 362.06. HPLC, Rt: 2.36 min (purity: 97.5%).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][CH:24]=[CH2:25])=[C:17]([CH3:26])[CH:16]=2)=[O:11])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.C(OCC)C>[CH2:23]([O:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([C:14]2[O:11][C:10]([C:8]3[S:9][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=3)=[N:12][N:13]=2)=[CH:16][C:17]=1[CH3:26])[CH:24]=[CH2:25]
Reactant: C=CCOc1c(C)cc(C(=O)NNC(=O)c2ccc(CC(C)C)s2)cc1C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCOc1c(C)cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc1C
Yield: 76.5 %

Procedure:
A solution of 4-allyloxy-3,5-dimethyl-benzoic acid N′-(5-isobutyl-thiophene-2-carbonyl)-hydrazide (1.40 g, 3.62 mmol) and Burgess reagent (1.12 g, 4.71 mmol) in THF (15 mL) is stirred at 110° C. for 3 min under microwave irradiation. The mixture is diluted with diethyl ether, washed with water, dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-(4-allyloxy-3,5-dimethyl-phenyl)-5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazole (1.02 g) as a colourless oil; LC-MS: tR=1.21 min, [M+1]+=369.15.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(Cl)(Cl)Cl>[CH2:38]([C:39]1[N:13]([CH2:12][CH2:11][CH2:10][N:9]([CH3:8])[CH3:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=1)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CN(C)CCCNc1ccccc1N
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2ccccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Triethylamine (0.62 ml) was added to a solution containing N-[3-(dimethylamino)propyl]-1,2-benzenediamine (0.78 g) in chloroform (4 ml) and then stearoyl chloride (1.22 g) was added thereto while being cooled with ice. After being stirred for 2 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (3.33 ml) was added to a solution containing the residue (1.93 g) in n ethanol (20 ml). After being stirred for 5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (1.73 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1), thereby yielding the entitled compound (1.53 g) as pale brown wax.
Reaction SMILES: [Cl:1][C:2]([C:4]([Cl:6])=[CH2:5])=[CH2:3].[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH:9]=[CH:8]1>C1(C)C=CC=CC=1>[Cl:1][CH:2]1[C:4]([Cl:6])=[CH:5][CH:9]2[C:10]([O:12][C:7](=[O:13])[CH:8]2[CH2:3]1)=[O:11]
Reactant: C=C(Cl)C(=C)Cl
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C2CC(Cl)C(Cl)=CC12
Yield: 61.7 %

Procedure:
A 500 mL reaction flask was charged with 34.5 g of 2,3-dichlorobutadiene and 27.5 g of maleic anhydride. 200 mL of toluene was added, along with a small amount of BHT (0.5 g). The solution was heated to reflux until the reaction was complete. The toluene was removed and the product recrystallized from ethyl acetate/hexanes to give 38.25 g (61.8%) of 4,5-dichlorotetrahydrophthalic anhydride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:22][PH:23]([O-])([O-:27])[O:24][CH2:25][CH3:26].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:12]([CH3:15])([S@:10]([NH:9][C@@H:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:23]([CH3:22])(=[O:27])[O:24][CH2:25][CH3:26])=[CH:3][CH:4]=1)=[O:11])[CH3:14]
Reactant: CC(C)(C)[S@](=O)N[C@H](c1ccccc1)c1ccc(Br)cc1
Reactant: CCO[PH](C)([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)c1ccc([C@@H](N[S@](=O)C(C)(C)C)c2ccccc2)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
To (S)—N—((R)-(4-bromophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide, 22-a, (16 g, 43.83 mmol), ethyl methylphosphite (9.47 g, 87.67 mmol) and Et3N (13.3 g, 132 mmol) in THF (200 ml) was added PdCl2(dppf) (1.6 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into dichloromethane and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (petroleum ether:ethyl acetate=1/1) to provide the crude product, 22-b, (9.5 g, 55%).
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)C.[CH:13]1([C:18](O)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+]>C(O)C>[CH:13]1([C:18]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:12])=[CH:10][CH:9]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(O)C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NC(=O)C2CCCC2)cc1

Procedure:
4-Aminobenzoic acid ethyl ester was reacted by method E with cyclopentanecarboxylic acid, and the resulting ester was hydrolyzed by boiling with sodium hydroxide in aqueous ethanol. The product with the molecular weight of 233.27 (C13H15NO3); MS (ESI): 234 (M+H+) was obtained in this way.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:19])[N:11]2[C:16]=1[C:15]([NH:17][CH3:18])=[N:14][CH:13]=[N:12]2.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:18][NH:17][C:15]1[C:16]2=[C:8]([C:3]3[CH:4]=[N:5][N:6]([CH3:7])[C:2]=3[C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:32])([F:31])[F:20])=[CH:23][CH:24]=3)[N:9]=[C:10]([CH3:19])[N:11]2[N:12]=[CH:13][N:14]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CNc1ncnn2c(C)nc(-c3cnn(C)c3Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CNc1ncnn2c(C)nc(-c3cnn(C)c3-c3ccc(C(F)(F)F)cc3)c12

Procedure:
5-(5-Bromo-1-methyl-1H-pyrazol-4-yl)-N,7-dimethylimidazo[5,1-f][1,2,4]triazin-4-amine (500 mg, 1.55 mmol), [4-(trifluoromethyl)phenyl]boronic acid (590 mg, 3.11 mmol), sodium carbonate (329 mg, 3.10 mmol), tetrakis(triphenylphosphine)palladium(0) (179 mg, 0.155 mmol) and ethanol (10 mL) were combined in a microwave vessel. The reaction was subjected to microwave irradiation at 130° C. for 45 minutes at 200 W. The reaction was dried over sodium sulfate, filtered and concentrated in vacuo. Purification via silica gel chromatography (Eluant: 20% tetrahydrofuran in dichloromethane) provided the product as a light yellow solid. Yield: 423 mg, 1.13 mmol, 73%. LCMS m/z 388.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.62 (s, 3H), 2.99 (d, J=4.9 Hz, 3H), 3.96 (s, 3H), 5.46-5.53 (m, 1H), 7.60 (br AB quartet, JAB=8 Hz, ΔvAB=48 Hz, 4H), 7.73 (s, 1H), 7.90 (s, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][O:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6][CH2:5]1.CN(C)C=O.Cl[C:22]1[N:31]=[C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]3[O:40][CH2:41][O:42][C:36]=3[CH:35]=2)[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([Cl:43])[CH:28]=2)[N:23]=1>O>[C:10]1([CH:7]2[O:6][CH2:5][CH:4]([O:3][C:22]3[N:31]=[C:30]([NH:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]5[O:40][CH2:41][O:42][C:36]=5[CH:35]=4)[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Cl:43])[CH:28]=4)[N:23]=3)[CH2:9][O:8]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: OC1COC(c2ccccc2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2nc(OC3COC(c4ccccc4)OC3)nc(NCc3ccc4c(c3)OCO4)c2c1
Temperature: 80 °C
Yield: 27.8 %

Procedure:
100 mg of sodium hydride was added to a mixture comprising 300 mg of 5-hydroxy-2-phenyl-1,3-dioxane and 5 ml of dimethylformamide. The obtained mixture was heated to 80° C. After the bubbling had been discontinued, 300 mg of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline was added in a crystalline state. The obtained mixture was heated at 140° C. for 2 hours and cooled, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The extract was purified by silica gel column chromatography using an ethyl acetate/benzene mixture to give 118 mg of 2-(2-phenyl-1,3-dioxan-5-yl)oxy-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. 100 mg of this compound was hydrolyzed with concentrated hydrochloric acid/ethanol by a conventional process to give 60 mg of the title compound through rearrangement.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][O:14][CH3:15]>CN(C)C=O.C(OCC)(=O)C>[CH3:15][O:14][CH2:13][CH2:12][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCn1ccc([N+](=O)[O-])n1
Yield: 84.7 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 300 mg, 2.65 mmol) was dissolved in anhydrous N,N-dimethylformamide (6.6 mL) and a 60% dispersion of sodium hydride in mineral oil (106 mg, 2.66 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min, 1-bromo-2-methoxy-ethane (250 μL, 2.66 mmol) was added. The reaction continued to stir under nitrogen for 16 h. The solution was diluted with ethyl acetate (100 mL), washed with 1.0 M aqueous hydrochloric acid solution (25 mL), water (25 mL), saturated aqueous brine solution (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) afforded 1-(2-methoxy-ethyl)-3-nitro-1H-pyrazole (384 mg, 85%) as a white solid: H1-NMR (400 MHz, CDCl3) δ 3.34 (3H, s), 3.77 (2H, t, J=4.4 Hz), 4.36 (2H, t, J=4.8 Hz), 6.87 (1H, d, J=2.8 Hz), 7.54 (1H, d, J=2.4 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:32])[CH2:30][OH:31])[C@@H:25]([OH:33])[C@H:24]3[OH:34])=[C:16]([NH:35][CH2:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:15]=2)[CH2:10]1.[N:50]([C:53]1[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=1)=[C:51]=[O:52]>C1COCC1>[C:44]1([CH:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:36][NH:35][C:16]2[N:15]=[C:14]([N:11]3[CH2:12][CH2:13][C@@H:9]([NH:8][C:51]([NH:50][C:53]4[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=4)=[O:52])[CH2:10]3)[N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[C@@H:23]2[CH2:27][C@H:26]([NH:28][C:29](=[O:32])[CH2:30][OH:31])[C@@H:25]([OH:33])[C@H:24]2[OH:34])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C=Nc1cccnc1
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)C1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 50 °C

Procedure:
A solution of N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide trifluoroacetate (0.2 g, 0.28 mmol) in dry THF (10 ml) is treated with TEA (113 mg, 1.12 mmol) followed by 3-isocyanato-pyridine (38 mg, 0.31 mmol). The reaction mixture is heated at 50° C. overnight. The solvent is removed in vacuo and purification by reverse phase column chromatography (Isolute™ C18, 10-50% acetonitrile in water—0.1% TFA) affords the product. The product is further purified by dissolving in MeOH and treating with saturated sodium bicarbonate solution. The mixture is passed through a pre-washed (400 ml MeOH followed by 400 ml water) eluting with 0.5% ammonia 880: water (100 ml) followed by water (400 ml) and finally MeOH to afford the title compound. (MH+ 693.4)
Reaction SMILES: [CH:1]1[N:10]2[C:4]([CH:5]=[CH:6][O:7][C:8]3[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:9]=32)=[CH:3][CH:2]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:8]3[O:7][CH:6]=[CH:5][C:4]4[N:10]([CH:1]=[CH:2][CH:3]=4)[C:9]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)-n1cccc1C=CO2
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)-n2cccc2C=CO3)ncc1Cl

Procedure:
Title compound was prepared from 6-Oxa-10b-aza-benz[e]azulen-9-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1223c. Product was obtained as a tan solid. LCMS 479.10 (M+H), HPLC purity 99%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.38 (s, 1H), 9.35 (s, 1H), 8.52 (bd, 1H), 8.20 (s, 1H), 7.46 (m, 2H), 7.39-7.32 (m, 3H), 7.26 (s, 1H), 7.03 (s, 2H), 6.88 (d, J=9.0 Hz, 1H), 6.54 (d, J=5.9 Hz, 1H), 6.29 (m, 1H), 6.21 (s, 1H), 6.06 (d, J=5.9 Hz, 1H), 2.73 (d, J=4.3 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH2:7]
Reactant: COc1ccccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1N
Yield: 16.1 %

Procedure:
0.35 g of tert-butyl-N-(2-methoxyphenyl)carbamate (theoretically 2 mmol/g) bonded on solid support 8 is reacted with 0.5 ml (7 mmol, 10 eq) of a 20% solution of TFA/CH2Cl2 at room temperature for 1 hour. The resin is filtered on a scintered filter and rinsed with CH2Cl2 and MeOH. Then, the filtrate is concentrated under vacuum, taken up in CH2Cl2, washed with a saturated aqueous NaHCO3 solution. After drying on MgSO4 and evaporation of the solvent, 31.1 mg of 2-methoxyaniline is obtained and characterized by the 1H NMR spectrum and compared with the commercial product (yield: 36%). An IR control of the resin showed that the cleavage was not complete (presence of a carbonyl band at 1729 cm−1). The resin was then reacted again with 10 equivalents of a 20% solution of TFA/CH2Cl2 for 15 hours at room temperature. After an identical treatment, 13.8 g of pure 2-methoxyaniline were obtained (overall yield: 52%).