Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7](I)=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[CH:1]1([N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[CH:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnc2c1c(I)cn2C1CCC1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
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: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2C1CCC1

Procedure:
Following the general procedure for the Suzuki coupling, 7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (142.5 mg, 0.4536 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (150.2 mg, 0.4533 mmol), Na2CO3 (120 mg, 1.13 mmol) and Pd(PPh3)4 (32 mg, 0.028 mmol) in DMF (10 mL)/water (2 mL). The crude material was purified by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-12)→1% MeOH in CH2Cl2 (13-37)→2% MeOH in CH2Cl2 (38-61)], yielding the title compound as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ=1.88-2.00 (m, 2H), 2.44-2.56 (m, 2H), 2.56-2.65 (m, 2H), 5.27 (brs, 2H), 5.35 (quint, J=8.6 Hz, 1H), 7.35 (s, 1H), 7.46-7.51 (m, 1H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.8, 8.2 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 8.17-8.22 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.28-8.31 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=15.03 (−), 31.11 (2C, +), 48.26 (+), 101.15 (Cquart), 115.99 (Cquart), 118.99 (+), 120.86 (+), 125.97 (Cquart), 127.42 (+), 127.55 (2C, +), 128.26 (+), 128.48 (+), 128.87 (2C, +), 129.52 (+), 136.49 (Cquart), 136.55 (+), 139.43 (Cquart), 148.52 (Cquart), 150.79 (Cquart), 151.97 (+), 156.97 (Cquart), 158.12 (Cquart). MS (ES+): m/z 392.1 (17) [MH+], 338.2 (22) [MH+-cyclobutene]. HPLC: tR=3.0 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]4[CH:25]=CC=[CH:22][CH:21]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1OC[O:37]C1CO>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH:20]4[CH2:21][CH2:22][O:37][CH2:25]4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Reactant: OCC1COCO1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OC1CCOC1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed glycerol formal (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase PHLC to give tetrahydro-3-furanyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (2 mg, 0.004 mmol). 1H NMR (CDCl-d) δ 2.06(m, 4H), 3.66(m, 2H), 3.92(m, 3H), 4.07(m, 6H), 4.79(m, 1H), 4.83(d, J=6.3 Hz, 1H), 4.96(m, 1H), 5.04(d, J=6.3 Hz, 1H), 6.15(vbs, 2H), 6.96 (s, 1H), 7.05(m, 2H), 7.53(s, 1H), 8.15(d, J=8.2 Hz, 1H), 8.22(s, 1H). LC/MS MH30 =471 and 1,3-dioxolan-4-ylmethyl N-(4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)carbamate(6.0 mg, 0.013 mmol). 1H NMR (CDCl-d) δ 2.06(m, 4H), 3.66(m, 2H), 3.75(m, 1H), 3.92(m, 3H), 4.03(m, 1H), 4.13(m, 1H), 4.34(m, 2H), 4.94(s, 1H), 4.97(m, 1H), 5.10(s, 1H), 5.32(bs, 2H), 6.97(s, 1H), 7.03 (m, 2H), 7.06(d, J=8.2 Hz, 1H), 7.38(s, 1H), 8.15(d, J=7.9 Hz, 1H), 8.31(s, 1H). LC/MS MH30 =471.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:21])([F:20])[C:8]([C:11]1[NH:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)([OH:10])[CH3:9].[N+:22]([O-])([OH:24])=[O:23]>C(OCC)C>[F:21][C:7]([F:6])([F:20])[C:8]([C:11]1[NH:15][C:14]2[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:13]=2[N:12]=1)([OH:10])[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: CC(O)(c1nc2ccccc2[nH]1)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(O)(c1nc2ccc([N+](=O)[O-])cc2[nH]1)C(F)(F)F
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To stirred concentrated sulfuric acid (11 mL) was added 1,1,1-trifluoro-2-benzimidazol-2-ylpropan-2-ol (3.00 g) under a nitrogen atmosphere while maintaining the temperature at 5° C. The reaction mixture was treated with a nitrating reagent (3.5 mL) containing concentrated nitric acid and concentrated sulfuric acid (1.5 mL), while maintaining the reaction temperature below 35° C., and was then stirred for 1 hour at ice bath temperature. The reaction mixture was then poured onto ice, neutralized to pH 7-8, extracted with diethyl ether, and dried. The solvent was evaporated to leave a gold oil. Trituration of the oil with diethyl ether provided the title compound as a white solid (0.80 g); mp 73°-75° C., resolidified mp 173°-174° C.; NMR (250 MHz): 1.68 (s,3), 7.62 (s,1), 7.78 (broad d,1), 8.19 (dd,1), 8.52 (s,1), 13.4 (s,1); MS: m/z=276 (M+1). Analysis for C10H8F3N3O: Calculated C, 43.65; H, 2.93; N, 15.27; Found: C, 43.32; H, 3.02; N, 15.03.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](Cl)=[O:35]>O1CCOCC1>[Cl:9][C:6]1[CH:5]=[C:4]([F:10])[C:3]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:2]([NH:1][C:34]([C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)=[O:35])[C:7]=1[OH:8]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1COCCO1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2NC(=O)c2ccc3ccccc3c2)c1=O
Yield: 84.4 %

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.50 g, 1.4 mmol) and 2-naphthoyl chloride (0.27 g, 1.4 mmol) were dissolved in 1,4-dioxane (10 ml) and the solution heated under reflux for 4 hr. Solvent was evaporated under reduced pressure and the product purified by column chromatography on silica gel (eluent, hexane-ethyl acetate, 8:2) to furnish the title compound (0.60 g).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([C:26]2[O:27][C:28]([CH2:31]Cl)=[N:29][N:30]=2)[CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([C:26]2[O:27][C:28]([CH2:31][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH:1]3[CH2:2][CH2:3]3)=[N:29][N:30]=2)[CH:23]=[N:22][CH:21]=1
Reactant: ClCc1nnc(-c2cncc(Br)c2)o1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2nnc(-c3cncc(Br)c3)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-bromo-5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridine: 1H NMR (400 MHz, CDCl3) δ 9.05 (d, J=1.7 Hz, 1H), 8.82 (d, J=1.9 Hz, 1H), 8.39 (m, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 6.52 (s, 1H), 5.80 (s, 2H), 2.06 (m, 1H), 1.19 (m, 2H), 0.92 (m, 2H); MS (ES) m/z 488 (M+1, isotope for Br) and 490 (M+1, isotope for Br).
Reaction SMILES: [CH2:1]([C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:15]([C:26]1[CH:27]=[N:28][C:29]([C:32]2[CH:37]=[CH:36][C:35](O)=[C:34]([F:39])[CH:33]=2)=[N:30][CH:31]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.N1(C2C=CC=CN=2)CCCC1>[CH2:1]([C:7]1[S:11][C:10]([C:12]([O:14][C:35]2[CH:36]=[CH:37][C:32]([C:29]3[N:30]=[CH:31][C:26]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:27][N:28]=3)=[CH:33][C:34]=2[F:39])=[O:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)c(F)c2)nc1
Reactant: CCCCCCc1ccc(C(=O)O)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCCCCCCCCc1cnc(-c2ccc(OC(=O)c3ccc(CCCCCC)s3)c(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
1.0 g (4.72×10-3 mol) of 5-hexylthiophene-2-carboxylic acid, 1.62 g (4.72×10-3 mol) 4-(5-undecyl-2-pyrimidinyl)-2-fluorophenol, N,N'-dicyclohexylcarbodiimide (DCC) and 0.03 g of pyrrolidinopyridine were dissolved in 30 ml of dichloromethane, followed by stirring overnight at room temperature. After the reaction, the insoluble matter was filtered off, followed by distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (ethanol/ethyl acetate) to obtain 1.86 g of a pure product (Yield: 3.2%) ##STR84##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]([OH:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a solution of 1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (2.5 g, 7.56 mol) in acetonitrile (25 mL) was Cs2CO3 (3.93 g, 12.06 mol) with stirring at RT. After 15 min, MeI (2.34 g, 16.48 mol) was added. The reaction mixture was stirred at rt for 14 h. The reaction was monitored by TLC. When SM was finished, reaction mixture was filtered through celite pad and filtrate was concentrated. Column chromatography of crude material afforded product 1,4-di-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate (29) as white solid (2.35 g, 90%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[S:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>>[Cl:15][C:16]1[CH:25]=[C:24]([NH:26][C:12]([C:6]2[S:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: CC(C)c1cc(C(=O)O)sc1C(C)C
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cc1Cl
Yield: 34.2 %

Procedure:
In the same manner as that of Example 24, 4,5-diisopropylthiophene-2-carboxylic acid (80 mg, 0.377 mmol) and methyl 2-chloro-4-aminobenzoate (126 mg, 0.679 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [n-hexane-ethyl acetate (40:1)] and recrystallized to obtain methyl 2-chloro-4-[(4,5-diisopropylthiophene-2-carbonyl)amino]benzoate (49 mg, 34%) as colorless prisms.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[F:23][C:24](=[CH2:28])[C:25](Cl)=[O:26]>C(OCC)C>[F:23][C:24](=[CH2:28])[C:25]([O:8][C:3]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)([C:2]([F:1])([F:14])[F:15])[C:4]([F:7])([F:6])[F:5])=[O:26]
Reactant: C=C(F)C(=O)Cl
Reactant: OC(c1ccco1)(C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)OC(c1ccco1)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
A solution of 20 g (0.085 mol) of hexafluoro-2-(2-furyl)-2-propanol and 8.65 g (0.085 mol) of triethylamine in 25 ml of dry diethyl ether was added dropwise with stirring at a temperature of 20° C. to a solution of 9.8 g (0.09 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 25 ml of dry diethyl ether in the course of 30 minutes. The reaction mixture was then stirred at a temperature of 20° C. for a further 4 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.005 g of hydroquinone monomethyl ether. 15.9 g (61 percent of theory) of hexafluoro-2-(2-furyl)-2-propyl α-fluoroacrylate having a boiling point of 55° to 57° C. (under 8 mbar were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][CH2:11][S:12][CH:13]([F:15])[F:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:21])=[N-]>C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([O:18][CH3:21])=[O:17])[CH2:10][CH2:11][S:12][CH:13]([F:14])[F:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCSC(F)F)C(=O)O
Solvent: CCOCC
Product: COC(=O)[C@H](CCSC(F)F)NC(=O)OC(C)(C)C

Procedure:
To a solution of N-tert-butoxycarbonyl-S-difluoromethylhomocysteine in diethyl ether (1 mL) was added a solution of diazomethane in ether until a faint yellow color persisted. The excess reagent was quenched by addition of glacial acetic acid, and the reaction was concentrated. The residue was purified by silica gel chromatography eluting with 20% EtOAc/hexane to afford a colorless oil (400 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5](/[CH:9]=[CH:15]/[N:16]([CH3:18])[CH3:17])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 96 %

Procedure:
A solution of 10.3 g (50 mmol) of 4,5-dichloro-2-nitrotoluene (Helv. Chim. Acta 1936, 19, 434-439) in a mixture of 11.9 g (100 mmol) N,N-dimethylformamide dimethylacetal in DMF (25 ml) was heated at 100° C. for 16 h. The dark reaction mixture was concentrated in vacuo, the residue diluted with methylene chloride and washed twice with water. The organic solution was dried over MgSO4, concentrated in vacuo affording 12.6 g (48 mmol, yield 96.5%) of the title compound as dark red to crude crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>C1COCC1>[F:22][C:3]1[C:2]([NH:1][C:32](=[O:36])[C:33]([CH3:35])=[CH2:34])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[C:9]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: C=C(C)C(=O)Cl
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3F)c12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1F
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(3-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (6.5 mg, 0.022 mmol) and DIPEA (12 μL, 0.066 mmol) in THF (220 μL) at room temperature was added methacryloyl chloride (3.5 mg, 0.033 mmol) and the solution was stirred for 1 hour. The reaction was concentrated and the residues, dissolved in 2 mL of DMSO, were purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. Lyophilization of the desired fractions afforded a colorless solid. LRMS (ESI) calc'd for C19H18N4O3F [M+H]+: 369, found 369.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:17](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:18][N:19]2[C:24]=1[C:23]([CH3:25])=[N:22][N:21]=[C:20]2[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1>>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:17]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[CH:4][N:5]=2)=[N:18][N:19]2[C:24]=1[C:23]([CH3:25])=[N:22][N:21]=[C:20]2[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4cnccn4)nnc(C)c3c2-c2ccccc2F)cc1
Reactant: Cn1ncnc1CO
Product: Cc1nnc(-c2cnccn2)n2nc(OCc3ncnn3C)c(-c3ccccc3F)c12

Procedure:
This compound was prepared using the procedure described in example 7, step e, using (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (prepared as described in EP-A-170073) instead of (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol, and using toluene-4-sulfonic acid 3-(2-fluorophenyl)-4-methyl-7-(pyrazin-2-yl)pyrazolo[1,5-d][1,2,4]triazin-2-yl ester instead of toluene-4-sulfonic acid 3-tert-butyl-7-(2,6-difluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester. Data for the title compound: 1H NMR (400 MHz, CDCl3) δ 2.54 (3H, s), 3.84 (3H, s), 5.54 (1H, d, J=13 Hz), 5.58 (1H, d, J=13 Hz), 7.21 (1H, m), 7.26 (1H, m), 7.36 (1H, td, J=7.4, 1.8 Hz), 7.46 (1H, m), 7.84 (1H, s), 8.85 (2H, m), 9.48 (1H, d, J=1.4 Hz); MS (ES+) m/e 418 [MH]+. Anal. Found C, 57.37; H, 3.73; N, 28.99%. C20H16FN9O.0.3 H2O.0.07 C6H14 requires C, 57.19; H, 4.13; N, 29.40%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH3:7][C:8]1([CH3:30])[C:28]2[C:11](=[CH:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[O:25][CH3:26])=[N:15][C:14]=3[CH:27]=2)[NH:10][C:9]1=[O:29].C(N(CC)CC)C>CN(C)C=O>[CH3:7][C:8]1([CH3:30])[C:28]2[C:11](=[CH:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH:24][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:20][C:19]=4[O:25][CH3:26])=[N:15][C:14]=3[CH:27]=2)[NH:10][C:9]1=[O:29]
Reactant: COc1cc(N)ccc1-c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.26 g. (11 mmol) methanesulphonyl chloride were slowly added dropwise to a solution of 3.6 g. (10 mmol) 7,7-dimethyl-2-(2-methoxy-4-aminophenyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one hydrochloride and 2.2 g. (22 mmol) triethylamine in 50 ml. dimethylformamide. After stirring for 2 hours at 25° C., the dimethylformamide was distilled off under a high vacuum. The residue was worked up with water and filtered off with suction. Subsequently, it was recrystallised from ethanol to give 2.9 g. (72.5% of theory) of the title compound; m.p. >300° C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:10][C@H:9]([OH:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31](O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(C(OCC)=O)=NC(OCC)=O>>[C:31]([O:11][C@H:9]1[CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:10]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccccc1
Reactant: O[C@H]1C[C@@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(O[C@H]1C[C@H](c2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of cis-3-phenylcyclobutanol (Eckehard, V. D.; et al. Chem. Ber., 1993, 126, 2759., 4.6 g, 30.2 mmol), triphenylphosphine (3.3 g, 59.1 mmol) and benzoic acid (7.6 mg, 62.3 mmol) was added diethyl azodicarboxylate (DEAD) (10.9 g, 62.3 mmol) at room temperature. The resulting mixture was stirred at room temperature for 40 min, then the mixture was concentrated. The residue was dissolved in diethyl ether (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL), water (50 mL), and brine (50 mL). The organic layer was dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (10:1) to afford 6.52 g (86%) of the title compound as a pale yellow oil: 1H-NMR (CDCl3) δ 7.71–7.20 (10H, m), 5.49–5.41 (1H, m), 3.82–3.72 (1H, m), 2.78–2.64 (4H, m).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH3:9].[I:14][C:15]1[C:23]([I:24])=[C:22]([C:25]([O-:27])=[O:26])[C:21]([I:28])=[C:20]([I:29])[C:16]=1[C:17]([O-:19])=[O:18]>CN(C=O)C>[I:14][C:15]1[C:23]([I:24])=[C:22]([C:25]([O:27][CH:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH3:9])=[O:26])[C:21]([I:28])=[C:20]([I:29])[C:16]=1[C:17]([O:19][CH:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH3:9])=[O:18]
Reactant: CCCCC(C)Br
Reactant: O=C([O-])c1c(I)c(I)c(C(=O)[O-])c(I)c1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCC(C)OC(=O)c1c(I)c(I)c(C(=O)OC(C)CCCC)c(I)c1I
Temperature: 76 °C
Reaction time: 22 h
Yield: 31 %

Procedure:
Cesium carbonate (1.63 g, 5.0 mmol) and 2-bromohexane (2.0 ml, 16 mmol) were added to a flask containing a stirred mixture of 2,3,5,6-tetraiodoterephthalate acid (1.4 g, 2.0 mmol) and dry DMF (20 ml). The reaction flask was immersed in an oil bath which was warmed to 76° C. over a period of 0.5 hr. After stirring under an atmosphere of N2 for 22 hrs, the reaction was allowed to cool, diluted with DMF, filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up into EtOAc (200 ml), washed with saturated aqueous sodium bicarbonate (2×50 ml), water (50 ml) and brine (50 ml), dried (Na2SO4), filtered and evaporated in vacuo. Flash column chromatography (silica, 1:19; Et2O:hexanes) provided bis (2-hexyl) 2,3,5,6-tetraiodoterephthalate (0.52 g, 44%) as a light yellow solid. Mp 114°-115° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][C:18]2[CH:20]=[CH:21][C:22]([F:23])=[C:16]([F:15])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(F)c(F)c1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)c(F)c2)CC1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 3,4-difluoroaniline (3.09 g) was treated in the same manner as described in Preparation Example 37 to give light brown prism crystal of the title compound.