Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[CH:13][CH:14]=2)[C:9]1=[O:18]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2ccc(Cl)cc2C1=O
Solvent: CO
Solvent: ClCCl
Product: O=CCC1Cc2ccc(Cl)cc2C1=O
Reaction time: 0.75 h
Yield: 85 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 45 minutes while stirring through a solution, cooled to -70°, of 10.3 g of (RS)-2-(2-buten-1-yl)-6-chloro-1-indanone in 200 ml of anhydrous dichloro-methane and 100 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 5.13 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 60 ml of dichoromethane and, after the addition of 15 ml of water and 15 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate, concentrated in a vacuum and the crude product obtained was recrystallized from ethyl acetate/hexane. 8.29 g (85%) of (RS)-2-(2-oxoethyl)-6-chloro-1-indanone were obtained as a white solid with m.p. 80°.
Reaction SMILES: [O:1]1[C@H:3]2[C@H:4]([OH:29])[CH2:5][C:6]3[C@:26]([CH3:27])([C@@H:2]12)[C@@H:25]1[C:9]([C@H:10]2[C@:22]([CH3:28])([CH2:23][CH2:24]1)[C@@H:13]([C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:11]2)=[CH:8][CH:7]=3.[CH2:30]([OH:34])[CH2:31][CH2:32][OH:33].CC(C)([O-])C.[K+]>O>[OH:33][CH2:32][CH2:31][CH2:30][O:34][C@H:3]1[C@H:2]([OH:1])[C@@:26]2([CH3:27])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5][C@H:4]1[OH:29]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reactant: OCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H](OCCCO)[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 69.9 %

Procedure:
A mixture of 275 mg (6.9×10-4 mol) of 1α,2α-epoxy-3β-hydroxy-5,7-cholestadiene, 4 ml (5.5×10-2 mol) of 1,3-propanediol, and 258 mg (2.1×10-3 mol) of potassium t-butoxide was stirred in an argon atmosphere at 110° C. (bath temperature) for 4.5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted twice with diethyl ether and washed three times with water. Sodium chloride was added to the aqueous layer, and the mixture was extracted twice with ethyl acetate and washed once with a saturated aqueous sodium chloride solution. After drying the combined organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by flash column chromatography (silica gel:dichloro-methane:ethanol=10:1) to obtain 229 mg (70% yield) of the titled compound as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([OH:18])=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([CH:14]=[CH:15][C:16]([NH:19][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[O:18])=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: Nc1nccs1
Reactant: O=C(O)C=Cc1cnc(-c2ccc(F)cc2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(C=Cc1cnc(-c2ccc(F)cc2)nc1)Nc1nccs1

Procedure:
The compound was prepared as described in Example 116(d) from 39 mg (0.16 mmol) of 3-[2-(4-fluoro-phenyl)-pyrimidin-5-yl]-acrylic acid, 32 mg (0.32 mmol) of 2-aminothiazole, 267 mg (0.68 mmol) of HATU and 65 mg (0.64 mmol) of triethylamine. Yield: 4 mg.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=[O:12])[CH:4]=[CH:3][CH:2]=1>C(O)C.O=[Pt]=O>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=[O:12])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2cccnc12
Agent: O=[Pt]=O
Solvent: CCO
Product: O=C(O)c1cccc2c1NCCC2
Yield: 92 %

Procedure:
A solution of quinoline-8-carboxylic acid (85 mg) in ethanol (15 ml) was hydrogenated over PtO2 (250 mg) at 50 psi and room temperature for 2 hours. The catalyst was removed by filtration through keiselguhr and the filtrate concentrated in vacuo to afford the title compound (80 mg).
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:28]=1)[CH2:3][N:4]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])CC1C=CC=CC=1.C(O)C>CO.[H][H].[Pd]>[OH:1][CH:2]([C:23]1[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([S:29]([NH2:32])(=[O:30])=[O:31])[CH:28]=1)[CH2:3][NH:4][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]
Reactant: [H][H]
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)c1ccc(C)c(S(N)(=O)=O)c1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: COc1ccccc1OCCNCC(O)c1ccc(C)c(S(N)(=O)=O)c1
Reaction time: 8 h

Procedure:
In 200 ml of methanol was dissolved 20 g of 5-{1-hydroxy-2-[N-benzyl-2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamide. After adding thereto 20 ml of ethanol containing about 10% hydrogen chloride and 1 g of 10% palladium charcoal, the mixture was shaked in hydrogen gas stream. When the absorption of hydrogen stopped, the catalyst was filtered away and the filtrate was distilled off under reduced pressure. The residue was dissolved in 100 ml of ethanol while it was hot and the solution was allowed to stand overnight in ice chamber, whereby 12.8 g of the α-type crystals of 5-{1-hydroxy-2-[2-(2-methoxyphenoxy)ethylamino]-ethyl}-2-methylbenzenesulfonamide were obtained as the colorless crystals. The physical and chemical properties of the product were as follows:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10]C)[C:7]([O:12]C)=[CH:6][C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([OH:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(F)c(C=O)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)cc1F
Temperature: -30 °C
Reaction time: 5 h
Yield: 314.4 %

Procedure:
To a stirred suspension of 2-fluoro-4,5-dimethoxy-benzaldehyde (3.00 g, 16.3 mmol) in dichloromethane (100 mL) was added BBr3 (12.2 mL, 130 mmol) dropwise at −78° C. under nitrogen atmosphere. After addition, the mixture was warmed to −30° C. and stirred at this temperature for 5 h. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration and washed with dichloromethane to afford 2-fluoro-4,5-dihydroxy-benzaldehyde (8.0 g), which was used directly in the next step.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=O)=O)=CC=1>>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:32][CH:33]=1
Reactant: COc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Product: COc1ccc(CCN2CC[C@H](NC(=O)C34CC5CC(CC(C5)C3)C4)C2)cc1
Yield: 18.8 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.38 g) and 2-(4-methoxyphenyl)ethyl p-toluenesulfonate (0.56 g) were reacted under the same conditions as in Example 1 to give (S)-N-(1-(2-(4-methoxyphenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (0.11 g), melting point 81-83° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([Cl:39])=[CH:36][CH:37]=2)[N:32]=[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[C:30]=1[CH3:47]>CCOC(C)=O>[Cl:39][C:35]1[CH:34]=[C:33]2[C:38]([C:29]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:30]([CH3:47])[C:31]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[F:46])=[N:32]2)=[CH:37][CH:36]=1
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2cc(Cl)ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2F)nc2cc(Cl)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under a N2 atmosphere, 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (0.18 g, 0.65 mmol) was dissolved in DMF (2.00 mL, 26 mmol) and sodium hydride (0.017 g, 0.72 mmol) was added. The reaction was allowed to stir for 15 minutes at rt. 4,7-Dichloro-2-(2-fluorophenyl)-3-methylquinoline (0.100 g, 0.33 mmol) was added and the reaction was heated to 140° C. for 5 h. The reaction was diluted with EtOAc and washed with 2% sodium bicarbonate then brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude solid was purified by flash column chromatography eluting with 40% to 60% EtOAc in hexane, followed by further purification by preparative reverse phase HPLC to afford 1-(7-chloro-2-(2-fluorophenyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. Mass Spectrum (ESI) m/e=544.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (1H, d, J=2.3 Hz), 7.90 (1H, d, J=9.0 Hz), 7.54-7.65 (3H, m), 7.35-7.42 (2H, m), 7.11 (1H, d, J=8.2 Hz), 6.30 (1H, dd, J=8.2, 2.3 Hz), 5.57 (1H, d, J=2.3 Hz), 4.06 (1H, d, J=9.4 Hz), 3.80-3.92 (3H, m), 3.56-3.63 (4H, m), 3.40-3.54 (2H, m), 2.83-2.89 (4H, m), 2.06 (3H, d, J=1.6 Hz), 1.88-2.03 (2H, m), 1.81-1.87 (1H, m), 1.66 (1H, dt, J=13.4, 1.1 Hz)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][C:26]=1[OH:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][C:26]=1[O:34][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Oc1cc2cc[nH]c2cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3F)ncnc2cc1OCCCN1CCOCC1
Temperature: 90 °C
Yield: 37.4 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (110 mg, 0.325 mmol), (prepared as described for the starting material in Example 1), and 6-fluoro-5-hydroxyindole (59 mg, 0.39 mmol), (prepared as described for the starting material in Example 242), in DMF (1.8 ml) containing potassium carbonate (67 mg, 0.487 mmol) was heated at 90° C. for 2 hours. After cooling, water was added. The solid was separated and triturated with methanol. Water was added and the solid was filtered, washed with water and dried under vacuum to give 4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (55 mg, 41%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](Br)[CH:9]=1)(=O)C.[CH3:27][C:28]1[C:32](B(O)O)=[C:31]([CH3:36])[O:30][N:29]=1>>[O:7]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:32]2[C:28]([CH3:27])=[N:29][O:30][C:31]=2[CH3:36])[CH:9]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccnc(Br)c1
Product: Cc1noc(C)c1-c1cc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)ccn1

Procedure:
By carrying out the operation analogously to example 239, starting from 2-bromo-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VII, and 3,5-dimethyl-4-isoxazoleboronic acid, the desired product is obtained in the form of white crystals (yield=25%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6](Br)[C:7](=O)[CH3:8])[CH3:2].C(N(CC)CC)C.[C:19]([SiH2:23][O:24][C:25]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1)([CH3:22])([CH3:21])[CH3:20]>C(O)(C)C>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:30]2[CH:31]=[C:26]([C:25]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[O:24][SiH2:23][C:19]([CH3:22])([CH3:20])[CH3:21])[CH:27]=[CH:28][C:29]2=[N:32][C:7]=1[CH3:8])[CH3:2]
Reactant: CCOC(=O)CC(Br)C(C)=O
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1ccc(N)nc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOC(=O)Cc1c(C)nc2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn12
Yield: 55 %

Procedure:
3-Bromo-4-oxo-pentanoic acid ethyl ester (1.77 g, 7.86 mmol, 2.0 equiv) and triethylamine (1.10 ml, 7.86 mmol, 2.0 equiv) are added to a solution of 5-(tert-butyl-diphenyl-silanyloxymethyl)-pyridin-2-ylamine in iso-propanol (10 ml). The reaction mixture is heated to reflux for 5 hours. After cooling, volatiles are removed in vacuo. The residue is taken up with water and EtOAc. The aqueous phase is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (hexane/AcOEt 1:1 to 1:4) affords the title compound (1.10 g, 55%). MS (ES+): 487 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].F[C:14]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=1[C:16]#[N:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=2[C:16]#[N:17])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 130 °C
Yield: 95.9 %

Procedure:
A mixture of 4-chloro-3-(trifluoromethyl)phenol (1 g, 5.09 mmol), 2-fluoro-5-formylbenzonitrile (0.759 g, 5.09 mmol) and K2CO3 (0.844 g, 6.11 mmol) in DMF (10 mL) was heated with a microwave condition at 130° C. for 4 h. The solution was diluted with EA and washed with water twice, dried over Na2SO4 and concentrated in vacuo to afford the title compound (1.59 g, 96% yield) as a yellow solid. LCMS: rt=3.54 min, [M+H+]=326
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[N+:10]([O-])([O-])=O.[NH4+].N>C(O)C>[NH2:10]/[C:3](/[C:2]([CH3:9])([CH3:8])[CH3:1])=[CH:4]\[C:5]#[N:6]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)/C(N)=C/C#N
Temperature: 25 °C

Procedure:
To a solution of 4,4-dimethyl-3-oxo-pentanenitrile (22 g, 175.76 mmol) in 250 mL of ethanol is added ammonium nitrate (21 g; 263.64 mmol). The mixture is stirred under reflux overnight while ammonia gas is bubbled through the solution. The mixture is cooled to room temperature and diluted with 100 mL of water. The mixture is concentrated under reduced pressure to remove most of the ethanol. Aqueous sodium hydroxide (140 mL, 0.3N) is added and the mixture is extracted with ether (2×200 mL). The combined organic layers are washed with 50 mL of water, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford title compound. Assumed quantitative yield and used crude in subsequent reaction. ESI m/z 125=MH+
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:30]([O:34][C:35]([NH:37][CH2:38][C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:30]([O:34][C:35]([NH:37][CH2:38][C:39]([O:29][CH:26]1[CH2:27][CH2:28][CH:24]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9]2)[CH2:25]1)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(O)C1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)OC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentanol (50 mg, 0.129 mmol) and N-tert-butoxycarbonyl glycine (34 mg, 0.194 mmol) was mixed in N,N-dimethylformamide (1 ml). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31 mg, 0.155 mmol) and 4-dimethylamino pyridine (16 mg, 0.129 mmol) was added. The resulting mixture was stirred under nitrogen at ambient temperature for 24 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4), filtered and evaporated. The solid was purified by flash column chromatography on silica using ethyl acetate as the mobile phase to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl 2-[(tert-butoxycarbonyl)amino]acetate. The structure was confirmed by 1H NMR.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]([CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=[CH:14][CH2:15][CH2:16][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:9]1[C:28]([CH3:29])([CH3:30])[CH:27]1[CH2:26][CH2:25][C:13]([CH3:12])=[CH:14][CH2:15][CH2:16][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(=O)CCC=C(C)CCC=C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCC=C(C)CCC1OC1(C)C
Temperature: -50 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of 2.59 g of m-chloroperbenzoic acid in 50 ml of methylene chloride was added to a solution of 3.6 g of the product of Step A in 50 ml of methylene chloride cooled to -50° C. and the mixture was held at -5° C. for 1 hour and was then poured into a saturated aqueous sodium bicarbonate solution. The organic phase was decanted and the aqueous phase was extracted with methylene chloride. The organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed over silica and was eluted with a 7-3 benzene-ethyl acetate mixture to obtain 2.2 g of ethyl 10-epoxy-7,11-dimethyl-3-oxo- 6-dodecenoate in the form of a pale yellow oil with a refractive index of nD22 = 1.4662.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)[CH:3]=1.[NH3:21]>CO.C(Cl)Cl>[O:18]1[C:14]2([CH2:19][CH2:20][CH:11]([C:4]3[CH:3]=[C:2]([NH2:21])[N:7]4[N:8]=[CH:9][CH:10]=[C:6]4[N:5]=3)[CH2:12][CH2:13]2)[O:15][CH2:16][CH2:17]1
Reactant: Clc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: Nc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Temperature: 100 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
7-chloro-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidine (5.58 mmol, 1.64 g) is charged to 10-20 mL microwave vessel. To this vessel is added 10 mL ˜7N NH3 in methanol. The vessel was sealed and heated at 100° C. for 18 hours. After 18 hours, the reaction mixture was cooled to room temperature and diluted with 100 mL DCM. The resulting solution is washed with saturated NaHCO3(aq) and extracted with DCM twice more. The combined organics were dried over Na2SO4 and the solvent removed in vacuo to yield 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-amine (1.52 g, 99% yield) as pale orange solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:15]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)nc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(Br)nc1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A solution of 6-bromo-3-pyridinecarboxaldehyde (3.06 g, 15.63 mmol) and (carbethoxymethylene)triphenylphosphorane (6.60 g, 17.97 mmol) in toluene (45 mL) was heated at reflux overnight and then cooled to room temperature. After solvent removal at reduced pressure, the residue was chromatographed (16% EtOAc/hexane) to give 3.9 g (97%) of ethyl(E)-3-(6-bromo-3-pyridinyl)-2-propenoate as a pale-yellow solid. Recrystallization from hexane yielded 3.5 g (87%) of pure E-isomer as a white solid, mp 79-80° C. By comparison, the material prepared by the literature method (van den Heuvel, M., et al., J. Org. Chem., 2004, 69, 250-262) had a melting point of 83.6-84.1° C. IR 2979, 1709, 1462, 1179 cm−1; 1H NMR (CDCl3) δ 1.36 (t, J=7.2 Hz, 3H, OCH2CH3), 4.31 (q, J=7.2 Hz, 2H, OCH2CH3), 6.53 (d, J=16.2 Hz, 1H, CH═CHCO), 7.55 (d, J=8.1 Hz, 1H, 5-ArH), 7.68 (d, J=16.2 Hz, 1H, CH═CHCO), 7.72 (dd, J=2.1 Hz, 8.1 Hz, 1H, 4-ArH), 8.52 ppm (d, J=2.1 Hz, 1H, 2-ArH).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)C.O.[NH2:20][NH2:21]>C(O)C>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:6]2[CH2:5][C:4](=[O:3])[NH:21][N:20]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(C2=NNC(=O)C2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a solution of ethyl-3,4-dimethoxybenzoylacetate (1 g, 4 mmol), (Heterocycles 1979, 13, 239), in ethanol (5 ml) containing hydrazine hydrate (192 μl, 4 mmol) was stirred for 30 minutes at ambient temperature followed by 40 minutes being heated at reflux. After cooling at ambient temperature, the mixture was concentrated to half the volume and ether (10 ml) was added. After trituration, the solid was collected by filtration, washed with ether and dried under vacuum to give 3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (521 mg, 60%).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(OCC)C>[C:28]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:33]=[CH:32][C:31]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][O:3][C:2]=2[CH3:1])=[CH:30][CH:29]=1
Reactant: Cc1occc1CO
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Cc1occc1COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A solution of (2-methyl-furan-3-yl)-methanol (1)(5.0 g) in diethyl ether (75 mL) was cooled to 0° C. with stirring and treated with triphenylphosphine (12.85 g) and biphenyl-4-ol (7.59 g). The resulting solution was then treated drop-wise with diisopropylazodicarboxylate (9.75 mL). After stirring for 10 minutes at 0° C. the reaction mixture was allowed to warm to room temperature and then stirred for a further 3 hours. The reaction mixture was then filtered and concentrated in vacuo. The residue was purified by flash chromatography, eluting with diethyl ether/petroleum ether (1:19 by volume), to give compound 44 as a white solid (7.0 g). LC/MS System A: Rt=4.38 mins.