Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)O[C:4](=[O:5])[CH:3]=[CH:2]1.CC(C)=O.CCC[CH2:15][CH2:16][CH2:17][CH3:18]>C1C=CC=CC=1>[CH2:4]([O:5][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCC
Reactant: O=C1C=CC(=O)O1
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCCCOCCCC

Procedure:
Maleic anhydride can be reacted with amines to form the corresponding maleamic acid derivative. Suitably, a maleic anhydride containing polymer is reacted in solution or suspension with an amine in inert or non-reactive solvents, such as acetone, heptane, benzene or dibutylether, to provide the desired maleamic derivative.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[C:4]([CH3:10])[CH:3]=1.[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:16]2[CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:12]([CH3:11])[CH2:17]2)=[C:4]([CH3:10])[CH:3]=1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Cc1cc(N)ncc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc(N)ncc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
A mixture of 6-amino-4-methyl-3-pyridinecarbaldehyde (D99) (0.053 g, 0.39 mmol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.117 g, 0.58 mmol) and sodium tri(acetoxy)borohydride (0.206 g, 0.97 mmol) in 1,2-DCE (10 mL) was sonicated to aid dissolution of the starting material then stirred at room temperature overnight. Saturated aqueous NaHCO3 (30 mL) was added and the mixture was stirred for 24 h. The reaction mixture was extracted with DCM (3×10 mL) and the organics were dried and concentrated to give the crude title compound as an oil (0.067 g) which was used in the next step without further purification. MS (ES): MH+ 321.3, MNa+ 343.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[C:13]3=[C:23]([CH3:26])[CH:24]=[CH:25][N:12]3[N:11]=2)[C:3]=1Br.[F:28][CH:29]([F:46])[C:30]1[CH:31]=[C:32]([OH:45])[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[C:13]3=[C:23]([CH3:26])[CH:24]=[CH:25][N:12]3[N:11]=2)[C:3]=1[C:34]1[CH:33]=[C:32]([OH:45])[CH:31]=[C:30]([CH:29]([F:46])[F:28])[CH:35]=1
Reactant: Cc1ccn2nc(CNc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(O)cc(C(F)F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc(CNc3ncnc(N)c3-c3cc(O)cc(C(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 90 °C
Reaction time: 18 h
Yield: 43.4 %

Procedure:
To a solution of 2-(((6-amino-5-bromopyrimidin-4-yl)amino)methyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70 mg, 0.16 mmol) in dioxane (2 ml) were added 3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (67 mg, 0.25 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (13 mg, 0.02 mmol) and 246 μl of a 2M aqueous solution of cesium carbonate. The mixture was stirred under argon atmosphere at 90° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to obtain 34 mg (42% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:12][OH:13])[CH:7]=[C:8]([F:11])[C:9]=1[F:10].[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].Cl[C:22]1[CH:32]=[C:26]2[N:27]([CH3:31])[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:33])[N:23]=1>CN(C=O)C>[CH3:31][N:27]1[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:33])[N:23]=[C:22]([O:13][CH2:12][C:6]3[CH:5]=[C:4]([F:3])[C:9]([F:10])=[C:8]([F:11])[CH:7]=3)[CH:32]=[C:26]12.[C:16]([OH:18])([C:15]([F:20])([F:19])[F:14])=[O:17]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCCn2c1cc(OCc1cc(F)c(F)c(F)c1)nc2=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of NaH (38.3 mg, 0.956 mmol) in DMF (2 mL) was added (3,4,5-trifluorophenyl)methanol (65 mg, 0.401 mmol) at rt. The reaction mixture was stirred for 5 mins at rt, and then 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one trifluoroacetic acid salt (100 mg, 0.319 mmol) was added. The reaction mixture was stirred for another 1 h at rt, quenched with water and then filtered to give clear solution. The solution was purified by MDAP (0.3% TFA in water/MeCN) to afford the title compound as its TFA salt (16 mg, 0.036 mmol, 11.42%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27](S(C)(=O)=O)[N:26]=2)=[CH:21][C:20]1=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:36][N:37]1[CH:41]=[C:40]([NH2:42])[C:39]([CH3:43])=[N:38]1.O>C(O)(CC)C>[Si:1]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:42][C:40]3[C:39]([CH3:43])=[N:38][N:37]([CH3:36])[CH:41]=3)[N:26]=2)=[CH:21][C:20]1=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1nn(C)cc1N
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Solvent: CCC(C)O
Solvent: O
Product: Cc1nn(C)cc1Nc1nccc(-c2ccn([C@H](CO[Si](C)(C)C(C)(C)C)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Temperature: 110 °C
Yield: 66.1 %

Procedure:
(S)-1-(2-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.100 g, 0.186 mmol) and 1,3-dimethyl-1H-pyrazol-4-amine (0.413 g, 3.72 mmol) were placed in s-BuOH (2 mL), heated to 110° C. overnight, then poured into water and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by column chromatography (500:10 DCM/MeOH) to give the product (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.070 g, 66.2% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=O.[Cl:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[CH:14][CH:13]=1.O>CCO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[N:19][NH:18][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:21][CH:20]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: O=Cc1c(O)cccc1Cl
Solvent: CCO
Solvent: O
Product: O=C(NN=Cc1c(O)cccc1Cl)c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 95.5 %

Procedure:
A suspension of 2-chloro-6-hydroxybenzaldehyde (0.10 g, 0.64 mmol) and 4-chlorobenzoic acid hydrazide (0.10 g, 0.61 mmol) in EtOH (3 mL) was agitated and heated to 60° C. for 16 h. The reaction mixture was cooled to room temperature and H2O (1-2 mL) was added portionwise to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish the title compound as an off-white solid (0.18 g, 95%): mp 273-277° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 12.51 (s, 1H), 9.04 (s, 1H), 8.03-7.95 (m, 2H), 7.71-7.63 (m, 2H), 7.34 (t, J=8.2 Hz, 1H), 7.07 (dd, J=7.9, 0.9 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H); ESIMS m/z 309 ([M+H]+), 307 ([M−H]−).
Reaction SMILES: [O:1]([CH:8]([CH3:11])[CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH2:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC=CC=1>[O:1]([CH:8]([CH3:11])[CH2:9][NH:10][C:19](=[O:20])[CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(CN)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC(CNC(=O)Cc1ccccc1)Oc1ccccc1

Procedure:
2-Phenoxypropylamine (4.6 g.) was added to a mixture of phenylacetyl chloride (4.6 g.) and anhydrous sodium carbonate (3.3 g.) in dry benzene (20 ml.); there was an exothermic reaction and effervescence. The mixture was heated to reflux for 1 hour, cooled, treated with water, and then shaken. The benzene layer was separated, dried over anhydrous sodium sulphate, filtered, and diluted with light petroleum (b.p. 60°-80°) to give pure N-(2-phenoxypropyl) phenylacetamide, m.p. 94°-96°.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:10]2=[O:25])=[N:6][C:5]=1[CH3:26])(=[O:3])[CH3:2].CO[C:29](OC)([N:31]([CH3:33])[CH3:32])[CH3:30]>CN(C)C(=O)C>[CH3:32][N:31]([CH3:33])/[C:29](/[CH3:30])=[CH:2]/[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)[C:10]2=[O:25])=[N:6][C:5]=1[CH3:26])=[O:3]
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C
Solvent: CC(=O)N(C)C
Product: C/C(=C\C(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C)N(C)C
Temperature: 110 °C
Yield: 90 %

Procedure:
To a solution of 1-(5-acetyl-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)-imidazolidin-2-one (1.00 g, 2.60 mmol) in N,N-dimethylacetamide (10 mL) was added N,N-dimethylacetamide dimethyl acetal (1.0 mL, 6.15 mmol). The reaction mixture was heated for 20 hours at 110° C. The solvent was removed in vacuo, and the residue was washed with water to afford the title compound as a colorless solid in 90% yield (1.07 g): 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 5.23 (s, 1H), 4.49 (s, 2H), 3.99-3.91 (m, 2H), 3.48-3.40 (m, 2H), 2.98 (s, 6H), 2.49-2.43 (m, 6H): MS (ES+) m/z 453.1 (M+1).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[C:13]1=[O:34].C(N(CC)CC)C>ClCCl>[Si:1]([O:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:20][CH2:19]2)[C:13]1=[O:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCCN(CCO)C2=O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
tert-Butyl(dimethyl)silyl chloride (0.30 g) was added to a solution of benzyl 4-[3-(2-hydroxyethyl)-2-oxotetrahydropyrimidin-1(2H)-yl]piperidin-1-carboxylate (0.60 g) obtained in Example 39a) and triethylamine (0.28 mL) in dichloromethane (20 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (from hexane/ethyl acetate=1/1 to hexane/ethyl acetate=1/4) to obtain the title compound (0.78 g, 99%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[OH:6].[F:16][C:17]([F:23])([F:22])[S:18](Cl)(=[O:20])=[O:19]>C(OCC)C>[F:15][C:4]([F:3])([F:14])[CH:5]([O:6][S:18]([C:17]([F:23])([F:22])[F:16])(=[O:20])=[O:19])[C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: OC(c1ccc(F)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(OC(c1ccc(F)cc1)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
A dried 50 mL of flask was charged sodium hydride, 60% dispersion in mineral oil (624 mg, 15.6 mmol) under N2 and then washed with dried hexane (20 mL) twice. Dried ethyl ether (10 mL) was added and a solution of 2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethanol (90% ee) (2.5 g, 12.89 mmol) in ethyl ether (10 mL) was added at 0° C. After completion of addition, the reaction mixture was allowed to warm up to room temperature and stirred for 1 h. A solution of trifluoromethanesulfonyl chloride (3.28 g, 19.5 mmol) in ethyl ether (10 mL) was added at 0° C. After completion of addition, the reaction was allowed to warm up to room temperature and stirred for 1 h. The solvent was removed under rot-vap and diluted with hexane (150 mL) and washed with a saturated NaHCO3 n and brine. After drying with MgSO4, the organic solvent was removed to give trifluor-methanesulfonic acid 2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethyl ester (3.15 g) (90% ee) as a colorless oil which was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH:8]([C:10]1[C:11](=[O:22])[N:12]([CH3:21])[C:13]2[C:18]([N:19]=1)=[CH:17][C:16]([Cl:20])=[CH:15][CH:14]=2)[NH2:9].C(N(CC)CC)C>O1CCOCC1>[CH3:21][N:12]1[C:13]2[C:18](=[CH:17][C:16]([Cl:20])=[CH:15][CH:14]=2)[N:19]=[C:10]([NH:8][NH:9][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[C:11]1=[O:22]
Reactant: CCCCC(=O)Cl
Reactant: Cn1c(=O)c(NN)nc2cc(Cl)ccc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCC(=O)NNc1nc2cc(Cl)ccc2n(C)c1=O

Procedure:
Pentanoyl chloride (52.6 mmol) is added dropwise to a solution of 3-hydrazino-1-methyl-6-chloro-1H-quinoxalin-2-one (43.8 mmol) and triethylamine (52.6 mmol) in 500 ml. of dioxane and stirred at room temperature for 2 hours. The dioxane is removed under vacuum and the residue washed with water and ether, filtered and dried under high vacuum at 65° for 3 hours to give crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.O1C(C2C=C(N[C:34]3[N:39]=[C:38]([C:40]4[C:41]([C:49]5[CH:50]=[C:51]([NH:55][C:56](=[O:63])[CH2:57][C:58]6[S:59][CH:60]=[CH:61][CH:62]=6)[CH:52]=[CH:53][CH:54]=5)=[N:42][N:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=45)[CH:37]=[CH:36][N:35]=3)C=CC=2)=CN=C1>CC(O)C.Cl.CCOC(C)=O>[F:13][C:11]([F:14])([F:12])[C:10]([N:9]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:34]2[N:39]=[C:38]([C:40]3[C:41]([C:49]4[CH:54]=[CH:53][CH:52]=[C:51]([NH:55][C:56](=[O:63])[CH2:57][C:58]5[S:59][CH:60]=[CH:61][CH:62]=5)[CH:50]=4)=[N:42][N:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=34)[CH:37]=[CH:36][N:35]=2)[CH:3]=1)=[O:15]
Reactant: CS(=O)(=O)CCN(Cc1cccc(N)c1)C(=O)C(F)(F)F
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCN(Cc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1)C(=O)C(F)(F)F
Temperature: 180 °C
Yield: 63 %

Procedure:
A suspension of N-[(3-aminophenyl)methyl]-2,2,2-trifluoro-N-[2-(methylsulfonyl)ethyl]acetamide (68 mg, 0.21 mmol) and N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (75 mg, 0.17 mmol) (see Example 2, Step B) in i-PrOH (3 mL) was acidified with 2 drops of 12 N HCl and heated in a microwave for 15 min. at 180° C. The reaction mixture was then diluted with EtOAc, washed with saturated aqueous NaHCO3, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography to generate the title compound in 63% yield. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=6.8 Hz, 1H), 8.31 (d, J=8.6 Hz, 1H), 8.22 (d, J=5.3 Hz, 1H), 7.67-7.80 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.26-7.39 (m, 4H), 7.17 (t, J=7.7 Hz, 1H), 7.05 (s, 1H), 6.94 (t, J=6.9 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.62-6.64 (m, 2H), 6.53 (s, 1H), 4.68 (s, 2H), 3.96 (s, 2H), 3.72-3.75 (m, 2H), 3.16-3.24 (m, 2H), 2.90 (s, 3H). ES-LC/MS m/z=734 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][CH3:26])=[O:24].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH3:26][NH:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][CH:29]=[C:20]([CH2:19][N:12]2[C:13](=[O:14])[CH:9]([CH2:8][C:7]3[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[NH:10][C:11]2=[O:15])[CH:21]=1
Reactant: CNC(=O)c1cccc(CCl)c1
Reactant: O=C1NC(=O)C(Cc2ccc([N+](=O)[O-])cc2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(CN2C(=O)NC(Cc3ccc([N+](=O)[O-])cc3)C2=O)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 69.2 %

Procedure:
The product from step (a) (4.0 g), the product from step (b) (3.3 g) and anhy. K2CO3 (2.55 g) were taken up in DMF (25 ml) and stirred at room temperature for 60 hours. The mixture was poured with vigorous stirring into ice-water (175 ml) to give an oily precipitate. Ethyl acetate was added and stirring continued for 1 hour to solidify the precipitate. The latter was filtered off, washed with water, ethyl acetate and ether, and dried to give the desired product as a peach-coloured solid (4.5 g).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][O:17]4)[CH:15]=3)=[CH:9][N:8]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[N:30]1([C:2]2[C:3]3[C:10]([C:11]4[CH:12]=[N:13][N:14]([CH:16]5[CH2:21][CH2:20][CH2:19][CH2:18][O:17]5)[CH:15]=4)=[CH:9][N:8]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:29])[CH3:27])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: C1COCCN1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cnn(C3CCCCO3)c2)c2c(Cl)ncnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[Si](C)(C)CCOCn1cc(-c2cnn(C3CCCCO3)c2)c2c(N3CCOCC3)ncnc21

Procedure:
A solution of 4-chloro-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C18) (3.3 g, 7.6 mmol), morpholine (0.99 g, 11 mmol) and N,N-diisopropylethylamine (6 mL, 34 mmol) in n-butanol (15 mL) was irradiated in a microwave synthesizer at 100° C. for 30 minutes. After removal of solvents in vacuo, the residue was purified by silica gel chromatography (Gradient: 10% to 50% ethyl acetate in petroleum ether) to provide the product as a brown oil. Yield: 2.6 g, 5.4 mmol, 71%. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.17 (s, 1H), 5.62 (s, 2H), 5.44 (dd, J=6.5, 6.0 Hz, 1H), 4.08-4.15 (m, 1H), 3.71-3.79 (m, 1H), 3.62-3.67 (m, 4H), 3.58 (dd, J=8.5, 8.0 Hz, 2H), 3.33-3.39 (m, 4H), 2.06-2.19 (m, 3H), 1.62-1.79 (m, 3H), 0.93 (dd, J=8.5, 7.5 Hz, 2H), −0.04 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[CH3:23][O:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([N:9]3[C:10]4[C:6](=[CH:5][CH:4]=[CH:3][C:2]=4[CH3:1])[CH2:7][CH2:8]3)=[N:13][CH:14]=[N:15]2)=[CH:20][CH:19]=1
Reactant: Cc1cccc2c1NCC2
Reactant: COc1ccc2c(Cl)ncnc2c1
Solvent: CC(C)O
Product: COc1ccc2c(N3CCc4cccc(C)c43)ncnc2c1
Yield: 79 %

Procedure:
Utilizing a procedure analogous to that described in Example 1 this product was prepared in 79% yield from 7-methyl-indoline (1.1 eq.), and 4-chloro-7-methoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 157°-160° C. (dec); LC-MS: 292 (MH+); anal. RP18-HPLC RT: 4.30 min.).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][C@@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].F[C:28](F)(F)C(O)=O.C(OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC.Cl.O1CCC(CN)C1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:23]2[CH2:22][CH2:21][O:20][CH2:28]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN[C@@H]3CCCO3)c2n1
Agent: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Agent: Cl
Agent: NCC1CCOC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 14 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and (tetrahydro-3-furanylmethyl)amine hydrochloride.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OCC#CCN3CCCCC3)cc2)CCN(Cc2ccc(Br)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(S(=O)(=O)c2ccc(OCC#CCN3CCCCC3)cc2)CCN(Cc2ccc(Br)cc2)CC1

Procedure:
1-(4-Bromo-benzyl)-4-[4-(4-piperidin-1-yl-but-2-ynyloxy)-benzenesulfonyl]-piperdine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-[4-(4-piperidin-1-yl-but-2-ynyloxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester (4.64 g, 7.5 mmol) dissolved in THF:methanol (50:150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 3.35 g (76%); off white solid; mp 180° C.; MS: 295.9 (M+2H)2+ 590.9 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[Cl:13].[CH2:14](C([Sn])=C(CCCC)CCCC)[CH2:15]CC>C1(C)C=CC=CC=1>[Cl:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:7][C:2]=1[CH:14]=[CH2:15]
Reactant: FC(F)(F)Oc1ccc(Cl)c(Br)c1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1cc(OC(F)(F)F)ccc1Cl
Yield: 33.3 %

Procedure:
2-Bromo-1-chloro-4-(trifluoromethoxy)benzene (Description 25; 1.0 g, 3.6 mmol) and tri-n-butylvinyl tin (1.21 g, 3.8 mmol) were dissolved in toluene (20 mL) and the solution was degassed for 45 minutes with nitrogen. Tetrakis(triphenylphosphine) palladium (0) (100 mg) was then added and the solution heated at reflux for 2 hours. Once cooled, the solution was concentrated and the residue was purified by silica chromatography to give the title compound (274 mg, 1.2 mmol).