Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH:5]=[N:4][CH:3]=[N:2]1.[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>ClCCl.C(O)CCC>[N:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]32[O:19][CH2:18][CH2:17][O:16]3)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: OCCO
Reactant: O=C1c2ccccc2CCC1n1cncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CCC(n1cncn1)C21OCCO1

Procedure:
A mixture of 10 g. 3,4-dihydro-2-(1H-1,2,4-triazol-1-yl)-1-(2H)-naphthalenone, 5.8 g. ethylene glycol and 11.5 g. p-toluenesulfonic acid was refluxed in a mixed solvent of 150 ml. toluene and 70 ml. n-butanol under a Dean-Stark [trademark] trap for 48 hours. The solvent was evaporated leaving a slurry which was taken up in dichloromethane and washed twice with 10% aqueous sodium hydroxide and once with water. The extract was dried in sodium sulfate, filtered and evaporated leaving an oily residue which crystallized on cooling to yield 1.5 g. of white crystals. These white crystals were 3',4'-dihydro-2'-(1H-1,2,4-triazole-1-yl)-spiro-[1,3-dioxolane-2,1'(2'H)-naphthalene. This compound had a melting point of 108° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]([F:24])([F:23])[CH:17]([F:22])[C:18]([F:21])([F:20])[F:19])=[O:13].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[Br-:1].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]([F:24])([F:23])[CH:17]([F:22])[C:18]([F:21])([F:20])[F:19])=[O:13]
Reactant: O=C(CCCCCCCCCCBr)OCC(F)(F)C(F)C(F)(F)F
Reactant: c1ccncc1
Solvent: CO
Product: O=C(CCCCCCCCCCc1ccccn1)OCC(F)(F)C(F)C(F)(F)F
Product: [Br-]

Procedure:
The process of producing the surfactant of claim 1 comprising (a) reacting at reflux 2,2,3,4,4,4-hexafluorobutanol and 11-bromoundecanoic acid in presence of methane sulfonic acid as a catalyst and benzene as a solvent to obtain 2,2,3,4,4,4-hexafluorobutyl 11-bromoundecylate and then (b) reacting at reflux 2,2,3,4,4,4-hexafluorobutyl 11-bromoundecylate with pyridine in presence of methanol as a solvent to obtain 2,2,3,4,4,4-hexafluorobutyl 11-pyridylundecylate bromide.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(C)(C)C.[Li]CCCC.[CH3:23][C@H:24]1[C@@H:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:27][C:26](=[O:35])[NH:25]1.C(OC(=O)C(C)(C)C)(=O)C(C)(C)C>C1COCC1.C(N(CC)CC)C>[C:1]1([CH2:7][C:8]([N:25]2[C@@H:24]([CH3:23])[C@@H:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:27][C:26]2=[O:35])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: O=C(O)Cc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1C(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A mechanically stirred solution of phenylacetic acid at -78° C. is treated with one part pivaloyl chloride then one part triethylamine. The mixture is stirred at -78° C. for 15 minutes, at 0° C. for 45 minutes, then recooled to -78° C. In a separate flask, one part 2.5M nBuLi is added to a solution of (4S,5R)-(-)-4-methyl-5-phenyl-2-oxazolidinone in THF at -78° C. The solution is stirred for 15 minutes then transferred to the flask containing pivalic anhydride via cannula. The mixture is stirred for 15 minutes at -78° C. and 9 hours at room temperature. The mixture is quenched with 2M KHSO4 and, after evaporation of the THF, is extracted 3 times with ethyl acetate. The combined ethyl acetate extracts are dried over MgSO4, filtered and concentrated to provide the crude title compound which is purified by column chromatography eluting with ethyl acetate-hexane.
Reaction SMILES: [N+:1]([O-:6])([N+:3]([O-:5])=[O:4])=[O:2].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[NH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:1]=[N:3][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N+:1]([O-:6])([N+:3]([O-:5])=[O:4])=[O:2].[N+:1]([C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][CH:10]=1)([O-:6])=[O:2]
Reactant: Nc1ccccc1
Agent: O=[N+]([O-])[N+](=O)[O-]
Solvent: c1ccccc1
Product: Nc1ccc([N+](=O)[O-])cc1
Product: c1ccc(N=NNc2ccccc2)cc1

Procedure:
Primary aromatic amines also have been diazotized in solvents by means of pure nitrogen tetroxide. O. N. Witt, Tagbl. Natf.-Vers. Baden-Baden 1879, 194 (Chem. Zentr. 1880, II, 226) reported obtaining benzenediazonium nitrate by the reaction of anhydrous pure nitrogen tetroxide with aniline in an anhydrous benzene solution; and B. Houston et al., J. Am. Chem. Soc. 47, 3011-3018 (1925), obtained a diazoaminobenzene derivative as well as the corresponding diazonium nitrate by the action of pure, anhydrous nitrogen tetroxide on o-, m-, and p-nitroaniline in an anhydrous benzene solution.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16]C(=O)C)[C:11]=1[F:20])[C:6](=O)[CH3:7])[CH3:2].F[C:23](F)(F)[CH2:24][OH:25].[CH3:28][S:29]([OH:32])(=[O:31])=[O:30].[CH2:33](O)[CH3:34]>CC(O)C.O>[CH3:28][S:29]([OH:32])(=[O:31])=[O:30].[F:20][C:11]1[C:12]([NH2:16])=[N:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:5]1[C:4](=[O:21])[O:3][C:1]2[CH:2]=[C:24]([OH:25])[CH:23]=[CH:34][C:33]=2[C:6]=1[CH3:7]
Reactant: CCO
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)C(Cc1ccnc(NC(C)=O)c1F)C(C)=O
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: Cc1c(Cc2ccnc(N)c2F)c(=O)oc2cc(O)ccc12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, the oily product of step 3 (15.0 g) was dissolved in 2,2,2-trifluoroethanol (33 mL) Resorcinol (5.3 g, 47.9 mmol) and methanesulfonic acid (11.7 mL, 181 mmol) were added thereto at 24° C., and the mixture was stirred at 90° C. for 4 hours. The mixture was cooled to room temperature and allowed to stand for 13 hours, ethanol (33 mL) and water (11 mL) were then added, and the mixture was stirred at 90° C. for 4.5 hours. It was cooled to 55° C., 2-propanol (105 mL) was added, and the mixture was cooled to room temperature and allowed to stand for 14 hours. The precipitated crystals were collected by filtration, washed twice with 2-propanol (33 mL), and dried under reduced pressure to obtain the title compound (8.2 g).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NN1CCCCC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NN2CCCCC2)[nH]n1
Yield: 65 %

Procedure:
As described for example 8b, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using 1-aminopiperidine instead of 4-aminomorpholine, to the title compound (78 mg, 65%), which was obtained as a white solid. MS: m/e=400.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([OH:10])=[CH:6][N:5]=2)[CH2:3][CH2:2]1.F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([O:10][C:12]3[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=3)=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cnc(C2CC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cnc(C3CC3)nc2)cc1
Yield: 99.5 %

Procedure:
2-Cyclopropylpyrimidin-5-ol (0.272 g, 2.0 mmol), 4-fluorobenzaldehyde (0.22 mL, 2.1 mmol) and potassium carbonate (0.414 g, 3.0 mmol) in dry DMF (2.0 mL) were heated to 120° C. in a sealed tube for 3 hours. The slurry was diluted with water and extracted twice with EtOAc. The combined organic phases were washed three times with water and brine, dried, filtered and concentrated to give a yellow oil. Purification by column chromatography using 20 g silica and a gradient of 0% to 50% EtOAc-heptanes as eluent gave 0.478 g (99% yield) of the subtitle compound as a colourless oil.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[P:6](Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[CH:1]([NH:4][P:6]([NH:4][CH:1]([CH3:3])[CH3:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: ClP(Cl)c1ccccc1
Solvent: CCOCC
Product: CC(C)NP(NC(C)C)c1ccccc1
Reaction time: 72 h
Yield: 33 %

Procedure:
To a stirred solution of isopropylamine (30 ml, 352 mmol) in diethyl ether (250 ml), dichlorophenylphosphine (9.63 ml, 71 mmol, dissolved in 50 ml diethylether) was added at 0° C. over a period of 30 min. After stirring for a total of 72 hrs the solution was filtered. The residue was washed with diethylether and the solvent was removed in vacuum. The remaining oil was distilled at 0.2 Torr/76-78° C. to give a colorless liquid with 33% yield (5.3 g). 31P{H} NMR: 49.0 ppm.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[C:17]3[C:12](=[C:13]([O:20][CH3:21])[C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[CH2:11][NH:10][CH2:9]2)=[CH:6][C:5]([O:22]C)=[C:4]([O:24]C)[CH:3]=1.B(Br)(Br)[Br:27].ClCCl.CO>ClCCl>[BrH:27].[F:1][C:2]1[C:7]([CH:8]2[C:17]3[C:12](=[C:13]([O:20][CH3:21])[C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[CH2:11][NH:10][CH2:9]2)=[CH:6][C:5]([OH:22])=[C:4]([OH:24])[CH:3]=1
Reactant: BrB(Br)Br
Reactant: COc1cc(F)c(C2CNCc3c2ccc(OC)c3OC)cc1OC
Solvent: ClCCl
Solvent: CO
Product: Br
Product: COc1ccc2c(c1OC)CNCC2c1cc(O)c(O)cc1F

Procedure:
0.90 g of 4-(6-fluoro-3,4-dimethoxyphenyl)-7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline was dissolved in 25 ml of dichloromethane; and to the mixture was added dropwise 1M boron tribromide-dichloromethane solution (27 ml) under an argon gas stream, at internal temperature of -30° to -60° C. under cooling while stirring. The mixture was stirred for 3 hours at room temperature and 7.0 ml of methanol was added to the mixture under cooling with dry ice-methanol bath, dropwise. The mixture was stirred for 30 minutes at room temperature, the crystals which separated out was collected, giving 0.75 g of 4-(6-fluoro-3,4-dihydroxyphenyl)-7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][OH:15])[CH2:12][CH:11]2[CH:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH:11]2[CH:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C(CO)CC2CC21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C(COS(C)(=O)=O)CC2CC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To an ice-cold solution of 3-Hydroxymethyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (2.52 grams, 11.83 mmol) in dry dichloromethane (10 mL) was added triethylamine (2.5 mL, 17.75 mmol) followed by methanesulfonyl chloride (1.0 mL, 13.01 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with dichloromethane. Organic layer was washed with saturated sodium bicarbonate solution followed brine, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure and the crude product was purified by flash column chromatography using 230-400 mesh silica gel to obtain title compound, 3.09 grams as gummy liquid. Yield: 90%.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][NH:28][CH2:29]4)=[CH:24][CH:23]=3)[N:19]=[C:18]([NH2:32])[N:17]=2)[CH2:12][CH2:11]1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][C:47](O)=[O:48])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[NH2:32][C:18]1[N:19]=[C:20]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28]([C:47](=[O:48])[CH2:46][CH:43]4[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:39])[CH2:41][CH2:42]4)[CH2:29]3)=[CH:24][CH:23]=2)[CH:21]=[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]2)[N:17]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCN(C(=O)OC(C)(C)C)CC3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
Triethylamine (40 uL, 0.29 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (25 mg, 0.058 mmol), [1-(tert-butoxycarbonyl)piperidin-4-yl]acetic acid (17 mg, 0.069 mmol) (AstaTech Cat. #66860), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (28 mg, 0.063 mmol) in N,N-dimethylformamide (0.8 mL). The mixture was stirred at r.t. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with MeOH in dichloromethane (0-10%) to afford the desired product (25 mg, 79%). Analytic LCMS (M+H)+: m/z=550.3.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:2]3[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:18][CH:19]=2)=[CH:25][CH:26]=1
Reactant: Cc1ccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: Nc1ncccc1Br
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: O
Solvent: COCCOC
Product: Cc1ccc(Oc2ccc(-c3cccnc3N)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 70.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (12.5 g) was added to a suspension of 3-bromopyridin-2-amine (31.2 g), 4,4,5,5-tetramethyl-2-[4-(4-methylphenoxy)phenyl]-1,3,2-dioxaborolane (72.8 g) and sodium carbonate (38.3 g) in 1,2-dimethoxyethane (500 mL) and water (250 mL) and the mixture was stirred at 100° C. under N2 for 16 hr. The mixture was diluted with water at room temperature and extracted with EtOAc-THF (3:1). The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give a crude product, which was washed with diisopropyl ether to give the title compound (35.2 g) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH3:11][C:12]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.O>CN(C=O)C.C(OCC)(=O)C>[Si:15]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([C:12]([CH3:14])([CH3:13])[CH3:11])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(O)c1

Procedure:
A solution of 3-(2-hydroxyethyl)phenol (7.55 g, 0.0546 mol), TBSCl (8.22 g, 0.0546 mol) and imidazole (3.71 g, 0.0546 mol) in DMF was stirred for 18 h at room temperature. Water (200 mL) and ethyl acetate (200 mL) were added; the organic layer was separated and washed with water (2×100 mL), dried over MgSO4, filtered and evaporated to dryness under reduced pressure to produce the desired product as a clear oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH3:15]CN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CO.C(Cl)Cl>[CH3:15][O:13][C:12](=[O:14])[CH2:11][O:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)COCCc1cccc(F)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)COCCc1cccc(F)c1
Yield: 92.6 %

Procedure:
A solution of [2-(3-fluoro-phenyl)-ethoxy]-acetic acid (1.20 g, 6.05 mmol), EDCl (1.28 g, 6.66 mmol), HOBt (0.90 g, 6.66 mmol) and DIPEA (1.56 ml, 9.08 mmol) in methanol (4 ml) was stirred at 0° C. for 2 hours. The reaction mixture was brought to dryness, the residue was dissolved in CH2Cl2 and was washed twice with 1M NaOH and brine. The organic layers were dried over MgSO4, filtered, the solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, EtOAc/heptane, 1:4) to yield the title compound (1.20 g, 5.6 mmol; 93%) as colorless liquid. MS: m/e=213.2 [M+H]+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][O:8][CH3:9])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:9][O:8][CH2:7][C:5]1[O:6][C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3][C:4]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: COCc1oc(Br)cc1C(=O)OC
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: O
Solvent: COCCOC
Product: COCc1oc(-c2ccccc2)cc1C(=O)OC
Yield: 87.5 %

Procedure:
A mixture of methyl 5-bromo-2-(methoxymethyl)-3-furancarboxylate (3.7 g), phenylboronic acid (2.2 g), tetrakis(triphenylphosphine)palladium(0) (0.9 g), 2N aqueous sodium carbonate solution (18 mL) and 1,2-dimethoxyethane (30 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give the title compound (3.2 g, 87%) as an oil.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:17]2[N:13]([C:14](=[O:30])[N:15]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[C:21]=3[CH3:29])[C@H:16]2[CH2:18][CH3:19])[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[K+].CO>C1COCC1.CCOC(C)=O>[CH2:18]([C@@H:16]1[N:15]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[C:21]=2[CH3:29])[C:14](=[O:30])[N:13]2[CH2:12][CH2:11][C@@H:10]([OH:9])[C@@H:17]12)[CH3:19]
Reactant: CC[C@H]1[C@@H]2[C@H](OC(=O)c3ccccc3)CCN2C(=O)N1c1ccc(C#N)c(Cl)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H]1[C@@H]2[C@H](O)CCN2C(=O)N1c1ccc(C#N)c(Cl)c1C
Yield: 89.6 %

Procedure:
Compound 87A (64 mg, 0.15 mmol) was dissolved in 1.5 mL of THF, treated with 1N KOH in anhydrous methanol (0.32 mL, 0.32 mmol) at rt for 2 h. Diluted the reaction mixture with 30 mL EtOAc, washed with saturated aqueous NaHCO3 solution (10 mL), brine (10 mL×2), dried over MgSO4, filtered and concentrated. The resulting mixture was purified by reverse phase HPLC (Phenomenex Luna 30×250 mm S5 C18, 30 min. gradient time, 25 mL/min, 30-100% B solvent, A=10% MeOH/water, B=90% MeOH/Water), provided the title compound (43 mg). Analytical HPLC retention time 2.947 min (purity 98%). Condition: YMC Combiscreen ODS-A C18 4.6×50 mm column, 4 min gradient, 4 mL/min flow, 0-100% B solvent, A=10% MeOH/water+0.1% H3PO4, B=90% MeOH/Water+0.1% H3PO4. MS (ES) m/z 320.24 [M+H]+, HRMS calcd for [M+H] 320.1166, found 320.1152.
Reaction SMILES: [CH2:1]([N:8]1[CH2:28][CH2:27][C:11]2[N:12]=[C:13](Cl)[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C@@H:19]([O:22][CH3:23])[C:18]([CH3:25])([CH3:24])[CH2:17]3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH3:48])[C:37]=2B2OC(C)(C)C(C)(C)O2)[N:32]([S:49]([C:52]2[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=2)(=[O:51])=[O:50])[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.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]([N:8]1[CH2:28][CH2:27][C:11]2[N:12]=[C:13]([C:37]3[C:36]([CH3:48])=[CH:35][CH:34]=[C:33]4[C:38]=3[C:30]([CH3:29])=[N:31][N:32]4[S:49]([C:52]3[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=3)(=[O:50])=[O:51])[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C@@H:19]([O:22][CH3:23])[C:18]([CH3:25])([CH3:24])[CH2:17]3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3c(B4OC(C)(C)C(C)(C)O4)c(C)ccc32)cc1
Reactant: CO[C@@H]1CCN(c2nc(Cl)nc3c2CN(Cc2ccccc2)CC3)CC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(Cc2ccccc2)CC3)CC1(C)C
Temperature: 100 °C

Procedure:
To a solution of (R)-6-benzyl-2-chloro-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (5.04 g, 12.6 mmol) in 1,4-dioxane (100 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indazole, Example 3, (6.16 g, 12.6 mmol), Pd(Ph3P)4 (2.18 g, 1.89 mmol) and a 2 M solution of sodium carbonate (18.9 mL, 37.7 mmol). The reaction mixture was heated at 100° C. under a nitrogen atmosphere for 16 h. The reaction mixture was then allowed to cool to rt and was diluted with EtOAc and water. The layers were mixed and then separated. The organic layer was washed with water and then brine. The separated organic layer was then dried over sodium sulfate, filtered and concentrated. The residue was then purified via FCC (0-70% EtOAc/heptane) to give the title compound. MS (ESI+) m/z 665.6 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)=O.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[N:16]1[C:3]([C:5]2[CH:6]=[CH:7][C:8]3[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=3[CH:15]=2)=[CH:2][N:18]2[CH:19]=[CH:20][CH:21]=[N:22][C:17]=12
Reactant: Cn1c(=O)sc2ccc(C(=O)CBr)cc21
Reactant: Nc1ncccn1
Product: Cn1c(=O)sc2ccc(-c3cn4cccnc4n3)cc21
Yield: 47.8 %

Procedure:
5-(Imidazo[1,2-a]pyrimidin-2-yl)-3-methyl-2-benzothiazolinone (2.7 g) was prepared in substantially the same manner as that of Example 30 from 5-(2-bromoacetyl)-3-methyl-2-benzothiazolinone (5.72 g) and 2-aminopyrimidine (5.7 g).