Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17]3[C:7]([CH2:8][C@@H:9]4[C@@H:14]([C:15]=3[CH:16]=1)[CH2:13][C@H:12]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:11][N:10]4[CH3:26])=[CH:6][NH:5]2.[C:27](O)(=O)C.CSC.B>C(O)=O>[CH2:21]([N:20]([CH2:23][CH3:24])[C:19]([NH:18][C@H:12]1[CH2:13][C@H:14]2[C@@H:9]([CH2:8][C:7]3[C:17]4[C:4](=[CH:3][C:2]([NH:1][CH3:27])=[CH:16][C:15]2=4)[NH:5][CH:6]=3)[N:10]([CH3:26])[CH2:11]1)=[O:25])[CH3:22]
Reactant: CC(=O)O
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(N)cc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: B
Solvent: O=CO
Solvent: CSC
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(NC)cc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
At -20° C., 355 mg of 3-(13-amino-6-methyl-8α-ergolinyl)-1,1-diethylurea is reacted to the N-formyl compound with the mixed anhydride of acetic acid and formic acid and the N-formyl compound is reduced with borane-dimethyl sulfide (S. Krishnamurty, Tetrahedron Letters 1982: 3315). After chromatography, 260 mg of 1,1-diethyl-3-(6-methyl-13-methylamino-8α-ergolinyl)urea is obtained.
Reaction SMILES: [C:1]1([P:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=C(C)C(OC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=C(C=[O:32])N=C1>C(O)C>[C:1]1([P:7](=[O:32])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c[nH]cn1
Solvent: CCO
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 0.961 g (10 mmol) of methyl 2-(triphenylphosphoranylidene)propionate [H. J. Bestmann and H. Schulz, Angew. Chem., 73, 27 (1961)] and 3.48 g (10 mmol) of imidazole-4-carboxaldehyde [F. L. Pyman, J. Chem. Soc., 186 (1916)] in 50 ml of absolute ethanol is stirred at room temperature for seven days. At the end of this time, the ethanol is removed in vacuo and the desired product is isolated free of triphenylphosphine oxide by chromatography on silica gel. The product thus obtained is a mixture of E and Z olefin isomers.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:16])=O>>[ClH:16].[N:2]1([CH2:8][CH2:9][CH2:10][C:11]([Cl:1])=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCN1CCCCC1
Agent: Cl
Product: O=C(Cl)CCCN1CCCCC1

Procedure:
4-Piperidinobutyric acid hydrochloride (750 mg) and 4 ml of thionyl chloride were combined and stirred at reflux for 45 min., concentrated, triturated with ether and dried to give 700 mg of light brown solid which when dissolved in dry methanol gave Rf 0.1 in system D, distinctly different from the starting acid and presumably the methyl ester. The solid was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH:49]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:50]([O:52][CH3:53])=[O:51]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH:49]([C:50]([O:52][CH3:53])=[O:51])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nn(C(C(=O)OC)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 57 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) with methyl α-bromophenyl-acetate was carried out as described in Example 3, Step A, except 3 equivalents of the alkylating agent was used. After work-up, flash chromatography of the crude product over silica gel (50 mL for 0.24 mmole, elution with 0.5% MeOH/CH2Cl2) gave the title compound in 57% yield as an oil, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) m/e 766 (M+1)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)=[O:17]
Reactant: O=C(Cl)CCCCCl
Reactant: c1ccc2c(c1)OCCO2
Product: O=C(CCCCCl)c1ccc2c(c1)OCCO2

Procedure:
Using 2,3-dihydro-1,4-benzodioxine. (10.0 g) and 5-chlorovaleryl chloride (10.4 ml) according to the same method as that, of Reference Example 1, the title compound was obtained as colorless crystals (15.1 g) having a melting point of 52 to 53° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-])=O)[CH:8]=[CH:7][CH:6]=2.[H][H]>C(O)C.C1COCC1.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c([N+](=O)[O-])cccc2cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2c(N)cccc2cn1
Yield: 94 %

Procedure:
To a solution of Example 35A (1.60 g, 8.82 mmol) in ethanol (45 mL) and THF (45 mL) was added 10% Pd/C (100 mg). The solution was hydrogenated under 1 atmosphere of hydrogen for 16 hours at ambient temperature. The mixture was filtered through a plug of Celite and the volatiles were evaporated in vacuo. The resulting solid was triturated with 1:1 CH2Cl2-hexanes and air-dried to provide the title compound (1.31 g, 8.29 mmol, 94% yield) as a light green solid. 1H NMR (300 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.78 (d, J=0.6 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 6.80 (dd, J=7.4, 1.2 Hz, 1H), 5.84 (s, 2H), 2.58 (s, 3H); MS (ESI) m/z 159 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27].Cl>O.CN(C)C=O>[CH2:27]([O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]2[CH:17]=[CH:18][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:11][CH:12]=1)[CH:26]=[CH2:25]
Reactant: CC(C)Oc1ccc(Oc2ccc(O)cc2)cc1
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(Oc2ccc(OC(C)C)cc2)cc1
Reaction time: 0.4 h
Yield: 69 %

Procedure:
To a mixture of 1.23 g of 4-(4-isopropoxyphenoxy)phenol, 1.4 g of potassium carbonate and 10 ml of N,N-dimethylformamide, 0.65 ml of allyl bromide was added dropwise at room temperature with stirring. After 24 minutes, the reaction solution was poured into water, and acidified by adding 10% hydrochloric acid. The solution was extracted with 50 ml of diethyl ether, washed in turn with 10% hydrochloric acid, an aqueous 10% sodium hydroxide and a saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.98 g of 4-(4-isopropoxyphenoxy)phenyl allyl ether (yield, 69%).
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:38]=[CH:37][CH:36]=[CH:35][C:8]=2[CH2:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]([NH:27]C(=O)OC(C)(C)C)[CH3:26])=[CH:21][CH:20]=3)[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][CH:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:13]2[N:12]=[C:11]([CH2:10][CH2:9][C:8]3[CH:35]=[CH:36][CH:37]=[CH:38][C:7]=3[C:4]3([C:1]([NH2:2])=[O:3])[CH2:6][CH2:5]3)[C:16]([CH3:17])=[CH:15][N:14]=2)=[CH:20][CH:21]=1)[CH3:26]
Reactant: Cc1cnc(Nc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)nc1CCc1ccccc1C1(C(N)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(C(C)N)cc2)nc1CCc1ccccc1C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 42 %

Procedure:
A solution of tert-butyl (1-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)ethyl)carbamate A47 (0.110 g, 0.213 mmol) in DCM (10 mL) was treated with TFA (0.33 mL, 4.3 mmol) and stirred for 6 hours at room temperature. The volatiles were evaporated in vacuo before aq. NaOH (2 M, 30 mL) was added to the residue. The aqueous phase was extracted with EtOAc (3×30 mL) and the combined organics were washed with brine and dried over MgSO4. The solvent was removed in vacuo to give an off-white solid that still contained starting material. The solid was taken up in DCM (20 mL) and treated with TFA (0.17 mL, 2.2 mmol). The mixture was stirred at room temperature for 24 hours before the volatiles were removed in vacuo. Aq. NaOH (2 M, 30 mL) was added and the aqueous phase was extracted with EtOAc (3×30 mL). The organics were combined, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The resultant white solid was dissolved in DCM and the desired product was precipitated by the addition of cyclohexane. The precipitate was isolated by vacuum filtration to give the title compound 50 (0.037 g, 42%) as a white solid. LCMS-A: rt 2.98 min; m/z 399 [M-NH2]+.
Reaction SMILES: N1(S(C2C=CC([C:14]3[CH:15]=[C:16]4[N:22]=[C:21]([CH2:23][CH2:24][CH:25]5[NH:31][C:30](=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26]5)[NH:20][C:17]4=[N:18][CH:19]=3)=CC=2)(=O)=O)CCC1.Br[C:34]1[CH:39]=[CH:38][C:37]([S:40]([N:43]([CH3:50])[CH2:44][CH:45]2[CH2:49][CH2:48][CH2:47][O:46]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1.BrC1C=C2N=C(CCC3NC(=O)CCCC3)NC2=NC=1>>[CH3:50][N:43]([CH2:44][CH:45]1[CH2:49][CH2:48][CH2:47][O:46]1)[S:40]([C:37]1[CH:38]=[CH:39][C:34]([C:14]2[CH:15]=[C:16]3[N:22]=[C:21]([CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:32])[NH:31]4)[NH:20][C:17]3=[N:18][CH:19]=2)=[CH:35][CH:36]=1)(=[O:42])=[O:41]
Reactant: CN(CC1CCCO1)S(=O)(=O)c1ccc(Br)cc1
Reactant: O=C1CCCCC(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCC5)cc4)cnc3[nH]2)N1
Agent: O=C1CCCCC(CCc2nc3cc(Br)cnc3[nH]2)N1
Product: CN(CC1CCCO1)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=O)N4)nc3c2)cc1

Procedure:
The title compound is synthesized as described for 7-(2-{6-[4-(azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepan-2-one (compound B6) from 458 mg of 4-bromo-N-methyl-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide (compound C7) and 300 mg of 7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound C1). Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-20 vol. % ethanol) yields 174 mg of the title compound as a waxy solid. ESI-MS: 512.4 (MH+). TLC: Rf=0.30 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br-:20].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:20][C:17]1[CH:18]=[C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=2)[CH:14]=[CH:15][C:16]=1[OH:19]
Reactant: [Br-]
Reactant: Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 138.3 %

Procedure:
To a solution prepared by dissolving the resulting 2.88 g of 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenol in 300 ml of chloroform, 4.80 g of tetra-n-butylammonium tribromide was slowly added with stirring under room temperature. After 12 hours, the reaction solution was concentrated, and the residue was extracted twice with 100 ml of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 2.53 g of 2-bromo-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenol (yield, 69%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[CH3:8][C:9]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:15]#[N:16])([CH3:11])[CH3:10].C(N(C)C(C)C)(C)C>C(Cl)Cl>[CH3:24][C:21]([C:18]1[CH:17]=[C:14]([CH:13]=[C:12]([C:9]([CH3:11])([CH3:10])[CH3:8])[C:19]=1[O:20][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:15]#[N:16])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(C#N)cc(C(C)(C)C)c1O
Reactant: COCCOCCl
Agent: CC(C)N(C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1c(C(C)(C)C)cc(C#N)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
2-Methoxyethoxymethyl chloride (4.1 g, 0.032 mole) is added dropwise to a 0° C. mixture of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzonitrile (Louis A. Cohen, Journal of Organic Chemistry 22, 1333, 1957) (5.0 g, 0.022 mole) and diisopropylaminomethane (4.2 g, 0.032 mole) in methylene chloride (50 ml). The mixture is allowed to warm to room temperature and stir 18 hours. The solution is diluted with methylene chloride (25 ml) and washed with water (25 ml), cold 2M HCl (20 ml), saturated aqueous NaCl, and dried over MgSO4. Filtered and concentrated in vacuo to obtain 6.7 g (6.9 g theor., 97%) of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzonitrile as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@@H:17]([F:19])[CH2:16][C@H:12]1[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(=O)(O)[O-].[NH4+]>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@@H:17]([F:19])[CH2:16][C@H:12]1[C:13]([NH2:20])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: O=C(O)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A stirred solution of (4S)-1-[(Benzyloxy)carbonyl]-4-fluoro-L-proline in dioxane was treated with pyridine (0.7 eq.) and Boc2O (1.3 eq.), then ammonium bicarbonate (1.26 eq.) was added and the mixture was stirred at room temperature for 15 hours. Dioxane was concentrated and the residue was taken up in ethyl acetate, washed with 1 N HCl and brine, dried over Na2SO4 to give, after filtration and concentration, title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([F:19])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([F:19])[CH:13]=2)=[N:28][OH:29])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1cc(F)ncc1Cl)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(CC(=NO)c1cc(F)ncc1Cl)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromo-phenyl)-1-(5-chloro-2-fluoro-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (1.6:1) as a white foam, MS (ESI−): m/z=445.0124 ([M−H]−, 1Br).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]2[C:12]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=3)=[O:14])=[CH:11][N:10]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:6]=2[N:7]=[CH:8][N:9]=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>C1COCC1>[C:31]1([O:30][C:28](=[O:29])[NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:13]([C:12]3[C:5]4[C:4]([NH2:3])=[N:9][CH:8]=[N:7][C:6]=4[N:10]([CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26]4)[CH:11]=3)=[O:14])[CH:16]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Oc3ccccc3)c1)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
NaH (0.21 g, 5.1 mmol) was added to a solution of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone (1.5 g, 4.7 mmol) in THF. (35 mL). After stirring for 1 h at room temperature, phenyl chloroformate (0.82 g, 5.4 mmol) was added. The resulting reaction mixture was stirred for an additional 3.5 h, quenched with water (15 mL), and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with saturated sodium bicarbonate (20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude reaction mixture was triturated (CH2Cl2) and filtered to afford the title compound as a white solid (1.78 g, 87%). MS: 442.3 (MH+); HPLC Rf: 2.5 min. (HPLC method 2).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([CH2:7][CH2:8][OH:9])[N:6]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[H-].[Na+].O>CN(C)C=O>[CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([CH2:7][CH2:8][O:9][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[N:6]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1nc(CCO)c(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(CCOc2ccc([N+](=O)[O-])cc2)c(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
2-(2,5-Dimethyl-4-oxazolyl)ethanol (17.0 g) and 4-fluoronitrobenzene (17.0 g) were dissolved in N,N-dimethylformamide (150 ml), and 60% sodium hydride in oil (6.0 g) was added dropwise to the solution under vigorous stirring. After stirring at room temperature for 1 hour, the reaction mixture was poured into water (1 l) and the crystals which separated out were collected by filtration and recrystallized from ethyl acetate-hexane to give 4-[2-(2,5-dimethyl-4-oxazolyl)ethoxy]nitrobenzene (27.5 g. 87.0%). Colorless columns, m.p. 97°-98° C. Elemental analysis for C13H14N2O4, Calcd.: C, 59.94; H, 5.38; N, 10.68. Found: C, 59.72; H, 5.44; N, 10.63.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][N:16]([CH3:19])[C:17]#[N:18].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>C1C(O)=CC=CC=1C.CO>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[C:4]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:2][C:17]([N:16]([CH3:19])[CH3:15])=[NH:18]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CN(C)C#N
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: Cc1cccc(O)c1
Solvent: CO
Product: CN(C)C(=N)Nc1ccccc1-c1ccccc1

Procedure:
A mixture of 2-aminobiphenyl hydrochloride (9.2 g) and N,N-dimethylcyanamide (4.8 g) in m-cresol (30 ml) was heated at 90°-95° C. for 10 hours to yield an oil which was dissolved in methanol (60 ml) and treated with fumaric acid (4.5 g) to give N-(2-biphenylyl)-N',N'-dimethylguanidine fumarate (m.p. 175°-176° C.) which was recrystallised from a 2:3 mixture of methanol and ether.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:20]([C:31]([OH:33])=[O:32])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:34][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[CH3:34][O:32][C:31]([CH:20]1[CH2:19][N:18]([C:16]([O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:17])[CH2:23][CH2:22][N:21]1[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[O:33]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1C(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperazine-1,2,4-tricarboxylic acid 1-tert-butyl ester 4-(9H-fluoren-9-ylmethyl)ester (2.21 mmol) in toluene: methanol (9:1) was added equimolar trimethylsilyldiazomethane (2.0 M in hexanes) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and purified using gradient elution from hexane/ethyl acetate (5%) to hexane/ethyl acetate (30%). ESI-MS m/z: 467 (M+1), UV retention time: 3.04 min.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]([O-:9])=[O:8].[Na+].[CH2:11](I)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:11][CH3:12])=[O:8]
Reactant: CCI
Reactant: O=C([O-])C1CCC=CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC=CO1
Temperature: 25 °C
Yield: 87 %

Procedure:
A mixture of sodium 3,4-dihydro-2H-pyran-2-carboxylate (150.0 g, 10 mol), ethyl iodide (192.3 g, 1.2 mol), sodium carbonate (10 g), and dimethylformamide (500 ml) was heated at 105°-110° C. for 5 hours. The reaction mixture was cooled to room temperature and water (450 ml) was added to dissolve inorganic sales. The mixture was extracted with four 200 ml portions of benzene. The combined organic layers were washed with four 200 ml portions of water and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent was removed by rotary evaporation. The oily residue was distilled under reduced pressure giving a yield of 87% of product having a bp of 75°-80° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].ClN([C:25]1[C:34]2[C:29](=[CH:30][C:31](O)=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][N:26]=1)C1C=CC=CC=1F.N1C=CC=CC=1>C(Cl)Cl>[CH3:36][O:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][C:31]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[N:28]=[CH:27][N:26]=[CH:25]2
Reactant: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2cncnc2cc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
Trifluoromethanesulphonic anhydride (0.55 ml, 3.3 mmol) was added to a stirred suspension of 4-(chloro-2-fluoroanilino)7-hydroxy-6-methoxyquinazoline (959 mg, 3 mmol), (prepared as described for the starting material in Example 2), in methylene chloride (2.2 ml) and pyridine (2.2 ml) under argon at 0° C. Thee reaction mixture was stirred for 1 hour at 0° C. allowed to warm to ambient temperature and stirred for a further 1.5 hours. The volatiles were removed by evaporation, the residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether/petroleum ether to give 444-chloro-2-fluoroanilino)6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline (270 mg, 60%) as a beige solid.