Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@@H:5]1[CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[C@@H:8]([C:15]([O:17][CH3:18])=[O:16])[C:7]([CH3:19])=[CH:6]1)(=O)C.C1CCN2C(=NCCC2)CC1>Cl>[CH3:19][C:7]1[CH:6]=[CH:5][CH2:14][C:9]2([CH2:10][CH2:11][CH2:12][CH2:13]2)[C:8]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)[C@H]1C(C)=C[C@H](OC(C)=O)CC12CCCC2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1=C(C)C=CCC12CCCC2
Temperature: 40 °C
Reaction time: 7 h
Yield: 13 %

Procedure:
A part of the crude trans-methyl 9-acetoxy-7-methylspiro[4.5]dec-7-ene-6-carboxylate obtained (2.4 g) was dissolved in DBU (13 g, 85.6 mmol) and stirred for 21 h at 20° C. and for 7 h at 40° C. The reaction mixture was poured into cold 2N aqueous HCl (60 ml), and extracted twice with cyclohexane (50 ml). The combined organic phases were washed with water (50 ml), with a saturated aqueous solution of NaCl (50 ml), dried (MgSO4), and concentrated. FC (500 g SiO2, pentane/Et2O 100:1) of the crude product (1.47 g) gave methyl 7-methylspiro[4.5]deca-6,8-diene-6-carboxylate (0.77 g, 13% estimated overall yield). Boiling point: 100° C. (0.08 mbar).
Reaction SMILES: Cl.[CH:2]12[O:10][CH:6]([CH2:7][NH:8][CH2:9]1)[CH2:5][N:4]([CH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH2:3]2.[C:20]([O:24][C:25](=[O:31])[NH:26][CH2:27][CH2:28][CH2:29]Br)([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:20]([O:24][C:25](=[O:31])[NH:26][CH2:27][CH2:28][CH2:29][N:8]1[CH2:9][CH:2]2[O:10][CH:6]([CH2:5][N:4]([CH2:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:3]2)[CH2:7]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: N#Cc1ccc(CN2CC3CNCC(C2)O3)cc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 110.2 %

Procedure:
A suspension of 4-(9-Oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl-methyl)-benzonitrile hydrochloride (6.8 g, 0.021 mol; from step (ii) above), (3-Bromopropyl)-carbamic acid tert-butyl ester (3.93 g, 0.017 mol) and dry K2CO3 (8.24 g, 0.059 mol) in 27 ml of dry acetonitrile was stirred at 60° C. overnight under N2 atmosphere. The reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure to give (7.5 g) of the sub-title compound as pale a liquid.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[OH-].[Na+].[CH3:23]OS([O-])(=O)=O>C(O)C.O>[CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@@H:14]1[CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([O:20][CH3:23])[CH:8]=[CH:7][C:6]=3[C@H:5]1[CH2:4][CH2:3]2
Reactant: COS(=O)(=O)[O-]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
To a solution of estradiol (10.0 g, 36.7 mmol) in ethanol (100 ml) at reflux was added NaOH (100 mmol) in water (10 ml) followed by the dropwise addition of methylsulfate (Me2SO4) (100 mmol). Neutralization with 10% HCl, subsequent concentration of the mixture followed by filtration through silica gel with ethyl ether, afforded 3-methoxyestradiol as white needles. Dissolving metal reduction of 3-methoxyestradiol was carried out via the methods described by Wilds and affording the known dihydroestradiene derivative as a white solid. (See Feiser, L. F., Feiser, M. “Reagents for Organic Synthesis”, John Wiley and Sons, Inc., New York, 1967, pp. v, 583-4, 622-3.)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[Li+].[OH-].Cl>C1COCC1.O>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncc(Br)nc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
(Step 6-ii) To a solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (1 g, 4.33 mmol) in 10 mL THF was added a solution of LiOH (540 mg, 12.86 mmol) in 20 mL of water. The mixture was stirred at room temperature for 4 hours and acidified with 6M HCl to a pH of 2. The yellow precipitate was collected by filtration and washed with water. After drying in vacuo, the product, 3-amino-6-bromopyrazine-2-carboxylic acid (600 mg, 2.75 mmol, 64% yield), can be used directly in the next reaction without further purification.
Reaction SMILES: [CH3:1][NH2:2].CO.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]([O:24]CC)=O)=[N:20][N:21]=3)[N:18]=2)=[CH:9][CH:8]=1.ClCCl.B(Br)(Br)Br>O.C(Cl)(Cl)Cl.CO>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]([NH:2][CH3:1])=[O:24])=[N:20][N:21]=3)[N:18]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1nnc2ccc(-c3ccc(OC)cc3)nn12
Reactant: CN
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CNC(=O)c1nnc2ccc(-c3ccc(O)cc3)nn12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Methylamine/methanol solution (3 ml) was added to a methanol solution of 307 mg (0.97 mmol) of ethyl 6-(4-methoxyphenyl)[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate, and stirred at room temperature for 14 hours. The reaction liquid was concentrated under reduced pressure, and 2 ml (2.00 mol) of a dichloromethane solution of 1 M boron tribromide was added to a chloroform solution (4 ml) of the resulting residue, and stirred overnight at room temperature. Water was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 65 mg of a crude product of 6-(4-hydroxyphenyl)-N-methyl[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:13]([Mg]Br)=[CH2:14].Cl>O1CCCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]([OH:8])[CH:13]=[CH2:14])[CH:9]=1
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(O)c1cc(O)ccc1[N+](=O)[O-]
Temperature: -78 °C
Yield: 73 %

Procedure:
5-Hydroxy-2-nitrobenzaldehyde (6.0 g) is dissolved in dry tetrahyrofuran (90 ml) and thereto is added dropwise vinylmagnesium bromide (2.3 equivalents) with stirring at −78° C. The temperature of the reaction mixture is raised gradually. After completion of the reaction, 1N HCl is added to the reaction mixture, and the mixture is extracted with ethyl acetate, and the organic layer is separated, washed with an aqueous saturated saline solution, dried over sodium sulfate, and then distilled off the solvent. The residue is purified with a silica column chromatography to give 1-(5′-hydroxy-2′-nitrophenyl)-2-propen-1-ol (5.09 g) as yellowish brown powders.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=O.C(O)C.[BH4-].[Na+]>ClCCl.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:1][CH2:10][C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)[N:3]=1
Reactant: O=Cc1c[nH]cn1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Solvent: ClCCl
Product: Clc1cc(Cl)nc(NCc2c[nH]cn2)n1
Temperature: 40 °C
Reaction time: 7 h
Yield: 2.3 %

Procedure:
To a solution of 2-amino-4,6-dichloropyrimidine (1.00 g, 7.72 mmol) in dichloromethane (8 ml) were added 4-formylimidazole (0.74 g, 7.72 mmol) and tetraisopropyl orthotitanate (2.86 ml, 9.65 mmol). After stirring the mixture at 40° C. overnight ethanol (8 ml) and sodium borohydride (0.38 g, 10.0 mmol) were added. The reaction mixture was stirred 40° C. for 7 hours. Then mixture was concentrated in vacuo and the residue was purified by flash chromatography (methanol/dichloromethane gradient) to yield white crystals (43 mg, 26%); MS (EI): 247.1 (37Cl M+.), 245.1 (37Cl35Cl M+.), 243.1 (35Cl M+.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[Br:15]Br.C(=O)([O-])[O-].[Na+].[Na+]>Br.C(O)(=O)C.O.CCOC(C)=O>[Br:15][CH:10]([CH3:11])[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:13])([F:14])[F:1])=[CH:8][CH:7]=1)=[O:12]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(C(F)(F)F)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(Br)C(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 48 h
Yield: 106.4 %

Procedure:
Dissolve p-trifluoromethylpropiophenone (5.130 g, 25.120 mmol) in hydrogen bromide (30.00 mL) and acetic acid (20 mL). Add bromine (1.23 mL, 23.864 mmol) in acetic acid (25 mL) drop-wise over 30 minutes. Stir the reaction mixture for 48 hours, and dilute the reaction mixture with water (1 L) and EtOAc (250 mL). Add solid sodium carbonate portion-wise to adjust the pH to ˜7 allowing the gas evolution to cease between additions. Extract the resulting mixture with EtOAc (2×250 mL). Dry the organic extracts over Na2SO4. Filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give the title compound as a clear oil (7.140 g, 100% crude yield). 1H NMR (399.83 MHz, d6-DMSO) δ 8.20 (dd, J=0.7, 8.8 Hz, 2H), 7.92-7.90 (m, 2H), 5.85 (q, J=6.5 Hz, 1H), 1.78 (d, J=6.5 Hz, 3H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[N:18]=[CH:19][CH:20]=[C:21]4[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:22]=34)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[N:18]=[CH:19][CH:20]=[C:21]4[CH:25]=[CH:24][NH:23][C:22]=34)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nccc4ccn(COCC[Si](C)(C)C)c34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nccc4cc[nH]c34)nc12
Reaction time: 15 h
Yield: 15 %

Procedure:
To a stirred solution of N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.13 g, 219 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0 to 4% of a solution of methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(1H-pyrrolo[2,3-c]pyridin-7-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (11 mg, 15%). MS: (M+H)+=335; 1H NMR (DMSO-d6) δ: 9.25 (s, 1H), 8.43 (d, J=3.0 Hz, 1H), 8.28 (d, J=5.3 Hz, 1H), 7.96 (s, 1H), 7.65-7.69 (m, 2H), 6.65 (dd, J=2.9, 1.9 Hz, 1H), 1.46 (s, 8H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=O)C.CC(C[AlH]CC(C)C)C.CO.[Cl-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:10]1[C:9]2([CH2:14][CH2:15][CH:6]([CH:4]=[O:3])[CH2:7][CH2:8]2)[O:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=CC1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (5.4 g, 25.2 mmol, prepared as in STEP A above) in anhydrous toluene (25 mL) was cooled to −78° C. under an argon atmosphere. To the resulting solution was added a solution of DIBAL-H (26 mL, 1N DIBAL-H in toluene, 26 mmol) in toluene while ensuring the inside temperature was kept between −60 to −70° C. Methanol (25 mL) was added slowly and the resulting mixture was allowed to warm to room temperature, then treated with aqueous sodium chloride (20 mL). The resulting mixture was passed through a silica gel plug (100 g) using ethyl acetate. The resulting eluent was concentrated to yield 1,4-dioxa-spiro[4.5]decane-8-carbaldehyde.
Reaction SMILES: Cl.[C:2]1([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[N:22]=[C:21]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([NH2:32])=[N:28][NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[C:19](S(C)(=O)=O)[N:18]=1>CN1C(=O)CCC1.CCN(C(C)C)C(C)C>[NH2:16][C:17]1[N:18]=[C:19]([N:13]2[CH2:14][CH2:15][CH:11]([C:9]([NH:8][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:12]2)[CH:20]=[C:21]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([NH2:32])=[N:28][NH:29]3)=[CH:25][CH:24]=2)[N:22]=1
Reactant: O=C(Nc1ccccc1)C1CCNC1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC(C(=O)Nc3ccccc3)C2)n1
Temperature: 160 °C
Yield: 7.5 %

Procedure:
A mixture of N-phenyl-3-pyrrolidinecarboxamide hydrochloride (500 mg, 2.21 mmol), 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (500 mg, 1.6 mmol) in NMP (3 mL) and Hunig's base (1.5 mL) was heated at 160° C. for 1 hour under microwave conditions. The reaction mixture was concentrated and purified by SiO2 chromatography (eluent: 4.5:4.5:1 EtOAc:THF:NH4OH) to afford the title compound (50 mg) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 2.05 (m, 2H), 3.30 (m, 1H), 3.4-3.7 (m, 4H), 5.36 (s, 2H), 6.03 (s, 2H), 6.31 (s, 1H), 7.03 (m, 1H), 7.31 (m, 2H), 7.57-7.74 (m, 4H), 7.94 (s, 1H), 10.10 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=2)[N:4]=1.[CH2:18](O)[CH3:19]>>[CH3:17][S:14]([NH:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([CH2:2][N:4]([CH2:3][CH2:2][C:19]1[CH:18]=[CH:9][C:8]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:7][CH:6]=1)[CH3:5])[CH:12]=[CH:11]2)(=[O:16])=[O:15]
Reactant: CCO
Reactant: CS(=O)(=O)Nc1ccc2nc(CCl)ccc2c1
Product: CN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1ccc2cc(NS(C)(=O)=O)ccc2n1

Procedure:
4-[2-(Methylamino)ethyl]methanesulphonanilide (0.228 g, 1 mmol--see Preparation 14(B)) and 2-chloromethyl-6-methanesulphonamidoquinoline (0.135 g, 0.5 mmol--see Preparation 12(D)) were heated in ethanol solution (5 ml) at reflux for 4 hours. The solvent was then evaporated in vacuo and the residue dissolved in methylene chloride, washed with water, dried (MgSO4), filtered and evaporated in vacuo. The resulting gum was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 1%). The product-containing fractions were combined and evaporated in vacuo to give a foam which crystallised from ethanol, yield of the title compound 0.45 g, m.p. 165°-166°, confirmed spectroscopically to be identical to the product of Example 5.
Reaction SMILES: OS(C(F)(F)F)(=O)=O.[C:9](=[NH:32])([O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[CH:16][CH:15]=1)[NH2:10].[C:33]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH:42]([CH:48]=O)[C:43](OCC)=[O:44])=[CH:37][CH:36]=1)#[N:34].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][O:11][C:9]3[NH:10][CH:48]=[C:42]([CH2:41][C:38]4[CH:37]=[CH:36][C:35]([C:33]#[N:34])=[CH:40][CH:39]=4)[C:43](=[O:44])[N:32]=3)=[CH:19][CH:18]=2)=[CH:22][C:23]=1[C:28]([F:31])([F:30])[F:29]
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CCOC(=O)C(C=O)Cc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cc1
Temperature: 160 °C
Yield: 30.6 %

Procedure:
The mixture of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate triflate (120 mg, 0.236 mmol), ethyl 3-(4-cyanophenyl)-2-formylpropanoate (137 mg, 0.591 mmol) and K2CO3 (98 mg, 0.709 mmol) in DMA (5 mL) was heated with a microwave reactor at 160° C. for 1 hour. Purification via MDAP then afforded the title compound as a pale yellow solid (38 mg, 29.0% yield). LCMS: rt=3.90 min, [M+H+]=526.2
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[O:19][N:18]=[C:17]([CH3:20])[N:16]=3)[N:4]2[N:3]=1.[CH3:21][N:22]([CH3:32])[CH2:23][CH2:24][N:25]1[C:29]([CH2:30][OH:31])=[N:28][CH:27]=[N:26]1>>[CH3:21][N:22]([CH3:32])[CH2:23][CH2:24][N:25]1[C:29]([CH2:30][O:31][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3=[N:12][N:13]=[C:14]([C:15]4[O:19][N:18]=[C:17]([CH3:20])[N:16]=4)[N:4]3[N:3]=2)=[N:28][CH:27]=[N:26]1
Reactant: CN(C)CCn1ncnc1CO
Reactant: Cc1noc(-c2nnc3c4ccccc4c(Cl)nn23)n1
Product: Cc1noc(-c2nnc3c4ccccc4c(OCc4ncnn4CCN(C)C)nn23)n1

Procedure:
The reaction was carried out using the procedure described in Example 1, Step 4 using 6-chloro-3-(3-methyl[1,2,4]oxadiazol-5-yl)-[1,2,4]triazolo[3,4-α]phthalazine (WO-A-9850385) (125 mg, 0.44 mmol) and [2-(2-dimethylaminoethyl)-2H-[1,2,4]triazol-3-yl]methanol (Example 4, Step 2) (74 mg, 0.44 mmol). Crude residue was purified on silica, eluting product with 3% MeOH/DCM, followed by trituration with DCM and isohexane. The title compound was isolated by filtration to give a white solid (50 mg, 27%).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=1[C:22]([F:25])([F:24])[F:23].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)=[CH:15][C:14]=1[C:22]([F:23])([F:24])[F:25]
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(F)c(C(F)(F)F)c2)o1
Yield: 83.4 %

Procedure:
To a solution of ethyl 5-bromofuran-2-carboxylate (150 mg, 0.69 mmol) in DME (5 mL) were added 4-fluoro-3-(trifluoromethyl)phenylboronic acid (171 mg, 0.82 mmol), 2M Na2CO3 (1.03 mL, 2.06 mol), and catalytic amounts of Pd(Ph3)4 (158 mg, 0.14 mmol). The reaction mixture was refluxed for 5 h, diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (EtOAc/n-Hex=1:5) to give title compound (174 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17]([C:18]3[C:19](O)=[N:20][CH:21]=[N:22][CH:23]=3)=[C:12]2[O:11][N:10]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17]([C:18]3[C:19]([Cl:27])=[N:20][CH:21]=[N:22][CH:23]=3)=[C:12]2[O:11][N:10]=1
Reactant: Oc1ncncc1-c1ccnc2c(-c3ccc(F)cc3Cl)noc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2noc3c(-c4cncnc4Cl)ccnc23)c(Cl)c1
Temperature: 90 °C
Yield: 97.8 %

Procedure:
A suspension of 5-(3-(2-chloro-4-fluorophenyl)isoxazolo[4,5-b]pyridin-7-yl)pyrimidin-4-ol (5.0 mg, 0.015 mmol) in phosphorus oxychloride (100 μl, 1.073 mmol) was heated at 90° C. for 1 h, then allowed to cool to room temperature. The solvent was evaporated to give the title compound (5.3 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:27])[C:5]2[C:10]([C:11]#[C:12][CH2:13][CH2:14][OH:15])=[CH:9][N:8]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)[C:6]=2[N:7]=1.[H-].[Na+].Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(N(C)C)=O>[C:31](=[O:32])([O:33][CH2:34][CH3:35])[O:15][CH2:14][CH2:13][C:12]#[C:11][C:10]1[C:5]2[C:4]([Cl:27])=[N:3][C:2]([NH2:1])=[N:7][C:6]=2[N:8]([CH2:16][C:17]2[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=2)[CH:9]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCCO)c3c(Cl)nc(N)nc32)c1C
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)OCCC#Cc1cn(Cc2ncc(C)c(OC)c2C)c2nc(N)nc(Cl)c12

Procedure:
A solution of 4-[2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-but-3-yn-1-ol (see example 2) (1.53 g) and NaH (95%, 0.38 g) in anhydrous DMA (25 mL) was treated with ethyl chloroformate (1.5 mL) at 0-23° C. for 0.5 h. Work-up and preparative HPLC gave the title compound. HPLC Rt=5.65 min.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])[CH:2]=[CH2:3].[OH-].[K+]>CO.CCOC(C)=O>[CH2:1]([O:4][C:5]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(OC)ccc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCOc1cc(OC)ccc1C(=O)O
Reaction time: 12 h

Procedure:
To a solution of 2 (2.5 g, 11 mmol) in aqueous methanol (30 mL) was added KOH (1 eq, 630 mg). Reaction was heated to 50° C. for 12 hours before the addition of more KOH (630 mg). After 12 hours, the mixture was cooled, diluted with EtOAc and washed with 1M HCl. Aqueous layer was extracted with EtOAc (3×). Combined organic layers, dried over Na2SO4, and concentrated. Product was isolated as an off white solid and used without further purification.
Reaction SMILES: S(OC)(OC)(=O)=O.[F:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=O)=[CH:11][CH:10]=1.C[O-].[Na+].[Na].[N+:26]([CH3:29])([O-:28])=[O:27]>O.CO>[F:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[CH:29][N+:26]([O-:28])=[O:27])=[CH:11][CH:10]=1
Reactant: C[N+](=O)[O-]
Reactant: O=C1CCCN1Cc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: COS(=O)(=O)OC
Product: O=[N+]([O-])C=C1CCCN1Cc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
26.1 g (0.207 mol) of dimethyl sulphate are added to 40 g (0.207 mol) of 1-p-fluorobenzyl-pyrrolidin-2-one and the mixture is heated to 60° for 4 hours. It is then cooled and a solution of sodium methylate prepared from 4.75 g (0.207 gram atom) of sodium and 100 ml of methanol is introduced slowly, at 0°. When the addition is complete, the mixture is stirred for 30 minutes at 50° C. and again cooled to 0°, and 18.9 g (0.31 mol) of nitromethane are added dropwise whilst continuing the stirring. The reaction mixture is left at ambient temperature for 12 hours and is then heated to 50° for 2 hours. It is cooled, and poured into 500 ml of water, which are then extracted with chloroform. The organic layer is now separated off, washed with water and dried over magnesium sulphate, and the solvent is driven off. The residual product is washed with ether and recrystallised from ethanol. 27 g (55.2% yield) of 1-p-fluorobenzyl-2-nitromethylene-pyrrolidine are thus collected in the form of light yellow crystals melting at 108.5°-109°.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH:16]([C:18]2([CH3:21])[CH2:20][CH2:19]2)[CH3:17])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH:16]([C:18]2([CH3:21])[CH2:20][CH2:19]2)[CH3:17])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC(Oc1cc(Cl)ncn1)C1(C)CC1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OC(C)C2(C)CC2)ncn1
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.03 g of sodium hydride (60% in oil), to which 0.3 ml of a solution containing 0.05 g of 2-butyn-1-ol in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.3 ml of a solution containing 0.10 g of 4-chloro-6-[1-(1-methylcyclopropyl)ethyloxy]pyrimidine in tetrahydrofuran, followed by stirring at room temperature for 3 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.09 g of 4-(2-butynyloxy)-6-[1-(1-methylcyclopropyl)ethyloxy]pyrimidine (the present compound (8)).