Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OO)(=[O:14])C>CC(C)=O>[C:1]([C:5]1[CH:10]=[C:9]([OH:14])[C:8](=[CH:7][CH:6]=1)[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CC(=O)OO
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(O)c(O)c1
Yield: 50 %

Procedure:
A five-neck flask having a volume of 500 ml and provided with a stirrer, a reflux condenser, a sampling tube, a test specimen inlet and a thermometer was charged with 75.1g (0.5 mol) of paratert.-butyl phenol and 20 ml of acetone as a solvent. The flask was placed in a constant temperture bath ketp at 60°C. Into the flask contents, 3.80g (0.05 mol) of peracetic acid in the form of about 35 weight% acetone solution was added through a micro-feeder over 12 minutes. Within 60 minutes after the start of the addition of peracid, the reaction solution was analyzed by gas chromatography. Consequently, it was found that the conversion of para-tert.-butyl phenol was 5.1%, that 4-tert.-butyl pyrocatechol was formed in a yield of 50% based on the converted butyl phenol and that the conversion of the peracetic acid was 95.2%.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Si:1]([O:8][CH2:9][CH2:10][NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][CH:23]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (2.00 g, 11.5 mmol) in dichloromethane (50 ml) was added ethyl 4-aminobenzoate (1.90 g, 11.5 mmol), and the mixture was stirred at room temperature for 1 hr. Sodium triacetoxyborohydride (3.41 g, 16.1 mmol) was added, and the mixture was stirred overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1-1:1, v/v) to give the title compound (3.52 g, 95%) as a colorless oil.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>C(Cl)Cl>[I:1][C:2]1[C:3]([CH3:8])=[N:4][N:5]([S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:9])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[C:6]=1[CH3:7]
Reactant: Cc1n[nH]c(C)c1I
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2nc(C)c(I)c2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
In a 50 ml reaction vessel under argon, a solution of crude 4-iodo-3,5-dimethyl-1H-pyrazole x52 (1.15 g, 5.2 mmol) in 25 ml of dry CH2Cl2 is added to 4-methylbenzenesulfonyl chloride (1.18 g, 6.2 mmol). Pyridine (0.42 ml, 5.2 mmol) is added and the mixture is stirred for 16 h at room temperature. The organic phase is washed with water, dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography on silicagel (CH2Cl2/hexane: 70/30 (v/v)) to afford 4-iodo-3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole x53 (1.44 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[F:12].[OH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[N:16]1[CH2:17][CH2:18][CH:14]([OH:13])[CH2:15]1
Reactant: OC1CCNC1
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: OC1CCN(c2cc(C(F)(F)F)ccc2F)C1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
A solution of 2-bromo-1-fluoro-4-(trifluoromethyl)benzene (4.6 g), 3-hydroxypyrrolidine (1.5 g), palladium(II) acetate (193 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.07 g) and cesium carbonate (16.8 g) in toluene (90 ml) was stirred under an argon gas atmosphere at 85° C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-65:35) to give the title compound (2.12 g, yield 49%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([CH2:29][CH3:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH:25]([CH2:29][CH3:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CCC1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 3-ethyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 417.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([NH:9]C(=O)C(C)(C)C)[C:3]=1[C:16]#[C:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.C1OCCOCCOCCOCCOCCOC1.CC([O-])(C)C.[K+].O>C(O)(C)(C)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][C:17]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:16][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2c(NC(=O)C(C)(C)C)ncc(F)c2Cl)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3c(Cl)c(F)cnc3[nH]2)CC1

Procedure:
A mixture of Example 255A (1000 mg, 2.283 mmol), 18-crown-6 (302 mg, 1.142 mmol), and potassium 2-methylpropan-2-olate (512 mg, 4.57 mmol) in 15 mL t-butanol was heated under microwave (Biotage) conditions at 135° C. for 35 minutes. Water was added and the mixture was extracted with dichloromethane. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was triturated with diethyl ether and filtered to afford the title compound. MS (ESI(+)) m/e 354 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:19])[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=3)[C:9]=2[CH:10]=1.[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC>C(COC)OC>[CH:20]([C:2]1[CH:3]=[C:4]([OH:19])[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=3)[C:9]=2[CH:10]=1)=[CH2:21]
Reactant: Oc1ccc(-n2ncc3c(O)cc(Br)cc32)cc1F
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Solvent: COCCOC
Product: C=Cc1cc(O)c2cnn(-c3ccc(O)c(F)c3)c2c1
Temperature: 90 °C
Yield: 33.7 %

Procedure:
To a solution of 6-bromo-1-(3-fluoro-4-hydroxyphenyl)-1H-indazol-4-ol (360 mg, 1.11 mmol) (E5) in dimethoxyethane (10 mL) was added dichlorobis(tris-o-tolylphosphine)palladium (44 mg, 0.056 mmol) and tributylvinyltin (0.65 mL, 2.22 mmol). The reaction mixture was heated at 90° C. under argon overnight. After cooling to room temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated and the crude product purified by silica gel chromatography eluting with 5-100% ethyl acetate in hexane. The product was further purified by MDAP to yield the title compound (E6) (101 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[F:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH2:21]>C(O)CCC.C(Cl)Cl>[F:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH:21][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Cc1ccc(F)c(N)c1
Reactant: Clc1ccnc(Cl)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(F)c(Nc2ccnc(Cl)n2)c1
Temperature: 100 °C
Yield: 21.5 %

Procedure:
2,4-Dichloropyrimidine (7.0 g, 47 mmol) was dissolved in n-butanol (5 ml), followed by addition of DIPEA (9.0 ml, 51.7 mmol), then 2-fluoro-5-methylaniline (5.3 ml, 47 mmol). The mixture was heated at 100° C. overnight, and then allowed to cool to ambient temperature. The mixture was evaporated to give an oil, which was taken up in DCM (250 ml) and washed with water (3×50 ml), brine (50 ml), dried over MgSO4 and evaporated to give an orange oil. This was purified by column chromatography eluting with EtOAc:isohexane (10:90) to give the title product as a white solid (2.40 g, 21%). NMR (300 MHz): 2.3 (s, 3H), 6.7 (d, 1H), 7.0 (m, 1H), 7.2 (m, 1H), 7.5 (d, 1H), 8.1 (d, 1H), 9.7 (s, 1H); m/z: (ES+) 237.9 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([OH:30])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[NH:29][C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:22]=12.O.[P:32]([O-:36])([O-:35])([OH:34])=[O:33].[K+].[K+].Cl>CC(C)=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([OH:30])[CH2:15][O:16][C:17]2[C:22]3[C:23]4[C:28]([NH:29][C:21]=3[CH:20]=[CH:19][CH:18]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH2:33].[OH:34][P:32]([OH:36])([OH:35])=[O:33]
Reactant: O=P([O-])([O-])O
Agent: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=P(O)(O)O
Temperature: 32.5 °C
Reaction time: 0.17 h

Procedure:
Carvedilol (15 gm, 0.0375M), water (240 ml, 13.33M) and dipotassium hydrogen orthophosphate (6.5 g, 0.0375M) were charged in to a reactor and stirred for 10 minutes at 30-35° C. Cooled the reaction mass to 5-10° C. The pH of the reaction mass was adjusted to 4.5-5 with hydrochloric acid. The temperature was raised to 50-55° C. Acetone (51 ml, 0.7M) was added and stirred at 50-55° C. for two hours. Reaction mass was cooled to 30-35° C. and stirred for 24 hours. The reaction mass was further cooled to 5-10° C. and maintained for 1 hour. Carvedilol dihydrogen phosphate monohydrate was filtered, washed with water, suck dried and dried under vacuum at 40-45° C. till constant weight to obtain carvedilol phosphate monohydrate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:6]([NH2:15])=[CH:5][CH:4]=1.[C:16]([N:23]1[CH2:31][CH2:30][CH2:29][C@@H:25]([C:26](O)=[O:27])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:15][C:26]([C@@H:25]2[CH2:29][CH2:30][CH2:31][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24]2)=[O:27])=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:8]=1
Reactant: COCCCNc1cc(OC)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: COCCCNc1cc(OC)ccc1NC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 155.8 %

Procedure:
5-Methoxy-N1-(3-methoxypropyl)benzene-1,2-diamine (42B) (1.81 mmol, 380 mg) in DMF (20 mL) was added (R)-(−)-N-Boc-nipecotic acid (2.35 mmol, 541 mg) and N-methylmorpholine (5.43 mmol, 0.60 mL). The reaction mixture was stirred at rt for 5 min and then added HATU (2.72 mmol, 1.03 g) and kept stirring at rt overnight. The reaction mixture was poured into H2O, extracted with EtOAc. The extract was washed with H2O, NaHCO3, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, EtOAc-hexane: 1:2) to afford (R)-tert-butyl 3-(4-methoxy-2-(3-methoxypropylamino)phenylcarbarnoyl)piperidine-1-carboxylate (42C) (2.82 mmol, 1.19 g, three-step yield: 80.6%). ESI-MS: m/z 422.5 (M+H)+.
Reaction SMILES: COC(C1C=CC=CC=1)=C(OC)C(O)=O.[CH3:16][O:17][C:18]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:19]=1[CH:20]=[CH:21][C:22]([OH:24])=[O:23].[H][H]>[Pd].C(O)C>[CH3:16][O:17][C:18]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:19]=1[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: [H][H]
Reactant: COc1ccc(OC)c(C=CC(=O)O)c1
Agent: [Pd]
Agent: COC(C(=O)O)=C(OC)c1ccccc1
Solvent: CCO
Product: COc1ccc(OC)c(CCC(=O)O)c1
Reaction time: 4 h
Yield: 405.1 %

Procedure:
Polymer VIII was prepared by reacting PEI with a lactone derivative of dimethoxycinnamic acid as described by Taylor (1962). The lactone was prepared using known procedures (Anliker et al. 1957; Westfahl et al. 1954; Fichter et al. 1927). 2,5-dimethoxycinnamic acid (Aldrich Chemical Company, 2.73 g, 3.1 mmole) was added to a mixture of 10% palladium on carbon catalyst (Aldrich Chemical Company, 0.54 g) in 100 mL 95% ethanol under 34 psi hydrogen gas. The mixture was shaken for 4 hours, converting the double bond into a single bond with saturated carbons. The catalyst was filtered off and the filtrate was evaporated to dryness to give 2.64 g of 2,5-dimethoxyhydrocinnamic acid (95% yield). This intermediate (2.20 g, 10.5 mmole) was refluxed in 48% aqueous HBr (15 mL, 132 mmole) for 2.5 hours. As the solution was cooled, white crystals appeared. The mixture was cooled further to 2° C., then the crystals were filtered off, washed with cold water, and dried in vacuo, yielding 1.40 g (81%), melting point 160°-161° C. (reported mp 162°-163° C.). 1H-NMR in D6-acetone confirmed the structure. IR spectra (KBr pellets) showed the lactone band at 1736 cm-1.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=2)[N:4]=1.[OH-].[Na+]>Br>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3](=[O:2])[CH:12]=[CH:11]3)[CH:14]=1
Reactant: COc1ccc2cc(-c3cccnc3)ccc2n1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: O=c1ccc2cc(-c3cccnc3)ccc2[nH]1

Procedure:
A stirred solution of 2-methoxy-6-(3-pyridyl) quinoline (1.83 g) in 48% aqueous hydrobromic acid (6 cm3) was heated at 100° C. for 1.5 hours. The mixture was then cooled in an ice bath, adjusted with 5M sodium hydroxide solution to pH 8, and continuously extracted with chloroform for 6 hours. The dried (MgSO4) organic extract was then evaporated to give a solid which was recrystallised from methanol-ethyl acetate to afford 6-(3-pyridyl)-2-[1H]-quinolone, m.p. 217°-218°, (0.62 g).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C1C=CC=CC=1.[Br:21][CH2:22][C:23](Br)=[O:24]>C(OC(C)C)(C)C.C(OCC)C>[Br:21][CH2:22][C:23]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)=[O:24]
Reactant: O=C(Br)CBr
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Solvent: CCOCC
Solvent: CC(C)OC(C)C
Solvent: CN(C)c1ccccc1
Product: O=C(CBr)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
To a mixture of p-nitrobenzyl alcohol (45 g) and N,N-dimethylaniline (37.2 ml) in a mixture of diisopropyl ether and diethyl ether (300 ml) was added dropwise bromoacetyl bromide (25 ml) at 30° to 35° C., and the reaction mixture was stirred at the same temperature for an hour. After the reaction mixture was poured into ice-water, the separated organic layer was washed with 5% aqueous sodium bicarbonate. The solution was evaporated under reduced pressure to give p-nitrobenzyl bromoacetate. To a solution of this residue in N,N-dimethylformamide (150 ml) was added N-hydroxyphthalimide 39.3 g) and triethylamine (50 ml), and the reaction mixture was stirred for an hour at room temperature. The resultant mixture was poured into ice-water, and the precipitates were collected by filtration and washed with water to give p-nitrobenzyl 2-phthalimidooxyacetate (69.26 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([O:30][N:31]=C(C)C)[CH:23]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl>CCO>[CH3:1][C:2]1[C:3]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:21][C:22]2[CH:29]=[CH:28][C:25]3[C:26]([NH2:27])=[N:31][O:30][C:24]=3[CH:23]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=NOc1cc(CN2[C@@H](c3ncccc3C)CCC[C@H]2c2ncccc2C)ccc1C#N
Agent: Cl
Solvent: CCO
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1Cc1ccc2c(N)noc2c1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of 4-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-2-isopropylideneaminooxy-benzonitrile (0.145 g, 0.320 mmol) in EtOH (4 mL) was added aqueous HCl (3 N, 4 mL), and the mixture was stirred and heated at reflux overnight. The mixture was then cooled to room temperature, EtOH was removed, and saturated aqueous NaHCO3 (20 mL) was added. The aqueous mixture was extracted with CH2Cl2 (4×40 mL), and the combined extract was dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified on silica gel column (100:5:2 CH2Cl2/CH3OH/NH4OH), affording 6-((2′S,6′R)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-2,2′;6′,2″-terpyridin-1′-ylmethyl)-1,2-benzisoxazol-3-ylamine as a white solid (0.082 g, 62%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16].O>O1CCCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])[CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1cc(N)no1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 5-methylisoxazole-3-amine (1.00 g, 10.2 mmol) and pyridine (0.998 ml, 12.2 mmol) in tetrahydrofuran (34 ml) was added 2,2,2-trichloroethyl chloroformate (1.69 ml, 12.2 mmol) with ice-cooling and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Hexane was poured to the residue and a solid was collected by filtration to obtain the desired product (2.55 g, 91.4%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[C:11]([F:18])[C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[S:25][C:24]([N:26]2[CH2:29][C:28]3([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:27]2)=[N:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:21]2[S:25][C:24]([N:26]3[CH2:29][C:28]4([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)[CH2:27]3)=[N:23][N:22]=2)=[C:11]([F:18])[C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(Br)s1)C2
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1F
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: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3ccc(OCc4ccccc4)c(F)c3F)s1)C2
Temperature: 100 °C
Yield: 36.3 %

Procedure:
Nitrogen was bubbled through a stirred solution of (4-(benzyloxy)-2,3-difluorophenyl)boronic acid (356 mg, 1.349 mmol) and tert-butyl 2-(5-bromo-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (343 mg, 0.881 mmol) in dioxane (8 mL). To this solution was added Pd(PPh3)4 (52 mg, 0.045 mmol) followed by a solution of Na2CO3 (286 mg, 2.7 mmol) in water (2 mL). The reaction mixture was sealed and heated at 100° C. for 1 hour under microwave irradiation. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (75 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to afford the crude product as a light orange/brown solid. The crude material was pre-absorbed onto silica gel and purified by flash chromatography using a 40 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a white solid (169 mg, 35% yield). LC-MS: Rt 1.62 min; MS m/z 529.4 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.82 (m, 1H), 7.46-7.51 (m, 2H), 7.36-7.45 (m, 3H), 7.24-7.32 (m, 1H), 5.30 (s, 2H), 3.89 (s, 4H), 3.24-3.31 (m, 4H), 1.66-1.78 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CO.C(Cl)Cl>C1(C)C=CC=CC=1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH:41][C:7]3[N:8]=[CH:9][C:4]4[C:3]([CH3:21])=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[C:5]=4[N:6]=3)=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Temperature: 25 °C
Yield: 38 %

Procedure:
A suspension of 6-bromo-8-cyclopentyl-2-methansulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (10.00 g, 0.027 mol, prepared as in Example 6 of WO 01/707041 which is incorporated here by reference) and 10.37 g (0.0373 mol) of 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester in toluene (100 mL) was heated under nitrogen in an oil bath for 7 hours. Thin layer chromatography (SiO2, 10% MeOH/DCM) indicated that both starting materials remained. The suspension was heated under reflux for a further 18 hours. The resulting suspension was cooled to room temperature and filtered to give 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.93 g, 38%). mp >250° C. MS (APCI); M++1: Calc'd, 584.2, Found, 584.2
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:37]C1C=C2C(=CC=1F)OC(C1C=CC=CC=1)=C(I)C2=O>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([F:37])=[C:24]([F:29])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2cc(F)c(F)cc12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(F)c(F)cc4c3=O)cc2)CCC1
Yield: 90 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 6,7-difluoro-3-iodo-2-phenyl-chromen-4-one was reacted to give the title compound as a pale yellow oil (91 mg, 90%). LCMS (Method B): RT=5.01 min, [M+Na]+=526.