Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:9]([C:14]([O:16]C2C(F)=C(F)C(F)=C(F)C=2F)=O)=[N:10][CH:11]=[CH:12][CH:13]=1.[F:28][C:29]([F:42])([F:41])[O:30][C:31]1[CH:32]=[C:33]([CH2:37][C:38](Cl)=[O:39])[CH:34]=[CH:35][CH:36]=1>C(#N)C.O>[OH:16][C:14]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[O:7][C:38](=[O:39])[C:37]=1[C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:29]([F:28])([F:41])[F:42])[CH:32]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ncccc1O
Reactant: O=C(Cl)Cc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=c1oc2cccnc2c(O)c1-c1cccc(OC(F)(F)F)c1
Temperature: 22.5 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
3.5 g of K2CO3 were added to a solution of 0.64 g of pentafluorophenyl 3-hydroxy-pyridine-2-carboxylate (from step 1) and 0.5 g of (3-trifluoromethoxyphenyl)acetyl chloride in 150 ml of acetonitrile, and the mixture was stirred at 20-25° C. under an atmosphere of nitrogen for about 12 hours. After filtration, the solvent was removed from the filtrate and the residue obtained was taken up in water and, after acidification to pH<4, extracted with CH2Cl2. The organic phase was dried, then freed from the solvent. The residue gave, after preparative HPLC [column: Luna (2), from Phenomenex, 300*50 mm 10 μm; mobile phase: water (+0.0375% trifluoroacetic acid) and acetonitrile in mixing ratios of 80:20 and 50:50; flow rate 80 ml/min; detection at 220 and 254 nm), 20-25° C.], 300 mg of the title compound.
Reaction SMILES: [CH:1]1([O:32][P:33]([OH:36])([OH:35])=[O:34])[CH:6]([O:7][P:8]([OH:11])([OH:10])=[O:9])[CH:5]([O:12][P:13]([OH:16])([OH:15])=[O:14])[CH:4]([O:17][P:18]([OH:21])([OH:20])=[O:19])[CH:3]([O:22][P:23]([OH:26])([OH:25])=[O:24])[CH:2]1[O:27][P:28]([OH:31])([OH:30])=[O:29].Cl>C(O)C>[C@@H:3]1([O:22][P:23]([OH:26])([OH:25])=[O:24])[C@@H:4]([O:17][P:18]([OH:20])([OH:21])=[O:19])[C@H:5]([O:12][P:13]([OH:15])([OH:16])=[O:14])[C@@H:6]([O:7][P:8]([OH:11])([OH:10])=[O:9])[C@@H:1]([O:32][P:33]([OH:36])([OH:35])=[O:34])[C@H:2]1[O:27][P:28]([OH:30])([OH:31])=[O:29]
Reactant: O=P(O)(O)OC1C(OP(=O)(O)O)C(OP(=O)(O)O)C(OP(=O)(O)O)C(OP(=O)(O)O)C1OP(=O)(O)O
Agent: Cl
Solvent: CCO
Product: O=P(O)(O)O[C@H]1[C@H](OP(=O)(O)O)[C@@H](OP(=O)(O)O)[C@H](OP(=O)(O)O)[C@@H](OP(=O)(O)O)[C@H]1OP(=O)(O)O
Reaction time: 0.08 h

Procedure:
0.5 ml Ethanol was mixed with 1.4 ml assay buffer and 1 ml phytate solution in a 12 ml test tube. The mixture was equilibrated in a water bath at 37° C. for 5 min before the reaction was started by addition of 0.1 ml phytase solution. For the blank measurement 0.1 ml assay buffer was added instead of phytase solution. After 1 hour incubation at 37° C. the reaction was stopped by addition of 0.75 ml 2.5 M HCl. All incubations were performed in duplicate.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=2[CH:15]=1)[C:9]([O:11]C)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O>C1COCC1>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=2[CH:15]=1)[C:9]([OH:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC(C)(C)O2)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H](Cc1ccc2c(c1)OC(C)(C)O2)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of (S)-methyl 2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanoate (5000 mg, 14229 μmol) in 100 mL of THF at 0° C. was added lithium hydroxide (0.2 M, 28458 μl, 14229 μmol) over 10 minutes. After stirring at 0° C. for 1 hour the reaction was poured into a separatory funnel and 100 mL of water was added. The mixture was washed with 150 mL of ether, then acidified to pH 2-3- with 1 N HCl. Ethyl acetate was added, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organics were washed with water and then brine before being dried over sodium sulfate, filtered and concentrated to furnish (S)-2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanoic acid (4005 mg, 83% yield) as a colorless viscous oil.
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([N:11]2[CH:12]=[CH:13][C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])=[CH:10]2)(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.2 %

Procedure:
A mixture of 7.0 g (E)-3-[1-(4-bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester with 200 ml dichloromethane and 21.0 ml TFA is stirred at ambient temperature for 24 h. The dichloromethane and TFA is evaporated and the residue is coevaporated with toluene for 3 times. By this method 6.0 g of the title compound is obtained.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH2:17])[CH2:15][OH:16])=[CH:10][CH:9]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[Cl-].[NH4+]>O1CCCC1>[OH:16][CH2:15][C@@H:14]([NH:17][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:11]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N[C@H](CO)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN[C@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
Following the literature procedure (Panek, J., J. Org. Chem., 1998, 63, 2382), triethylamine (6.2 ml, 44.5 mmole) was added to a solution of (S)-phenylglycinol (5 g, 36.45 mmole) in anhydrous tetrahydrofuran (150 ml) under argon at 0° C. After stirring for 15 min, tert-butyl bromoacetate (5.9 ml, 39.96 mmole) was added slowly to this cooled solution. The resulting mixture was warmed to room temperature, and stirred for 15 h. Saturated ammonium chloride aqueous solution was added, and the aqueous layer was extracted with diethyl ether (3 times). The combined extracts were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The resulting solid was recrystallized from a diethyl ether/n-hexane mixture to give tert-butyl (S)-(2-Hydroxy-1-phenyl-ethylamino)-acetate as a white solid (3 g, 33%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH:10]([O:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1)([CH3:12])[CH3:11].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:16]2[CH:15]=[C:14]([O:13][CH:10]([CH3:12])[CH3:11])[NH:18][N:17]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Yield: 68.9 %

Procedure:
A solution of 2,4,5-trichloropyrimidine (533 mg, 2.93 mmol), 5-isopropoxy-1H-pyrazol-3-amine (413 mg, 2.93 mmol) and triethylamine (0.49 ml) in THF (5 ml) was stirred at room temperature for 10 hours. Solvent was removed and EtOAc was added. The solution was washed with water and dried over anhydrous sodium sulfate and was concentrated to give title compound as a white solid (582 mg, 69%). LC-MS, 246 (M-42); 1H NMR (CDCl3) δ 8.19 (s, 1H), 7.80 (s, 1H), 5.79 (s, 1H), 4.65 (m, 1H), 1.30 (d, 6H).
Reaction SMILES: Br[CH:2]1[CH2:4][CH2:3]1.[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])([O-:7])=[O:6]>>[CH:2]1([O:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N+:5]([O-:7])=[O:6])[CH2:4][CH2:3]1
Reactant: BrC1CC1
Reactant: O=[N+]([O-])c1ccccc1O
Product: O=[N+]([O-])c1ccccc1OC1CC1

Procedure:
In a similar manner as in Example 1, bromocyclopropane was reacted with o-nitrophenol to yield 2-cyclopropoxynitrobenzene; which was reduced to the corresponding aniline; reacted with N-methylolpyrrolidone to form the corresponding N-methylenepyrrolidonyl derivative; and acetylated with chloroacetyl chloride to form the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][C:8](=[O:16])[N:7]=[C:6]2[N:17]([NH2:23])C(OCC)=O.CN(C)[CH:27]=[O:28]>>[CH3:24][N:2]([CH3:1])[C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]2[NH:9][C:8](=[O:16])[N:7]3[C:27](=[O:28])[NH:23][N:17]=[C:6]3[C:5]=2[CH:4]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)N(N)c1nc(=O)[nH]c2cc([N+](=O)[O-])c(N(C)C)cc12
Product: CN(C)c1cc2c(cc1[N+](=O)[O-])[nH]c(=O)n1c(=O)[nH]nc21
Temperature: 25 °C
Yield: 65 %

Procedure:
350 mg (1.04 mmol) of ethyl (6-dimethylamino-7-nitro-2-oxo-1,2-dihydro-quinazolin-4-yl)-carbazate in 30 ml of dry dimethylformamide were heated at reflux for 3 hrs. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator. The residue was triturated with a small amount of acetone and the red precipitate was filtered off and dried in a vacuum. 195 mg (65%) of 9-dimethylamino-8-nitro-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione were obtained as a red powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:23]1[CH2:33][CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24]1>CC(C)=O>[CH2:29]([O:28][C:26](=[O:27])[CH:25]1[CH2:31][CH2:32][CH2:33][N:23]([CH2:2][CH2:3][CH:4]=[C:5]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:24]1)[CH3:30]
Reactant: BrCCC=C(c1ccccc1)c1ccco1
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CCCN(CCC=C(c2ccccc2)c2ccco2)C1
Temperature: 25 °C
Reaction time: 216 h
Yield: 47.7 %

Procedure:
1-Bromo-4-(2-furanyl)-4-phenylbut-3-ene (0.23 g, 0.83 mmol) was dissolved in anhydrous acetone (10 ml) and dried potassium carbonate (0.46 g, 3.32 mmol) was added, followed by ethyl nipecotate (0.16 g, 1 mmol). The suspension was stirred at room temperature for 9 days, filtered and evaporated to a residue. The residue was purified by column chromatography on silica gel (Merck Art 9385), eluting with heptane/tetrahydrofuran (7:3), to provide the title ester (140 mg, 47%) as an oil. T.l.c. rf=0.36 (SiO2, heptane/THF (7:3)).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:14]([NH:21][CH:22]2[CH2:27][CH2:26][C:25](=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:23]2)=[N:15][CH:16]=[N:17][C:18]=1[CH2:19][CH3:20]>ClCCl>[Cl:12][C:13]1[C:14]([NH:21][CH:22]2[CH2:27][CH2:26][C:25]3([O:9][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:23]2)=[N:15][CH:16]=[N:17][C:18]=1[CH2:19][CH3:20]
Reactant: CCCCCC=C1CCC(Nc2ncnc(CC)c2Cl)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCC1OC12CCC(Nc1ncnc(CC)c1Cl)CC2
Reaction time: 4 h

Procedure:
A solution of 4.0 g (0.02 mol) of m-chloroperbenzoic acid (85% strength) in 25 ml of dichloromethane was slowly added dropwise at 0° C. to a solution of 6.4 g (0.02 mol) of 5-chloro-6-ethyl-4-(4-hexylidenecyclohexylamino)pyrimidine (WO 95 07894) in 25 ml of dichloromethane. Stirring of the mixture was continued at room temperature for 4 hours. After the mixture had been allowed to stand overnight, it was extracted by stirring with aqueous sodium hydrogen carbonate solution, and the organic phase was dried and concentrated. The crude product was chromatographed on silica gel (petroleum ether/ethyl acetate 4:1). First, 1.8 g (265.6% of theory) of the isomer having the higher Rf value (0.62) were eluted (colorless crystals, m.p.: 41°-42° C.), followed by 1.2 g (18.2% of theory) of isomer mixture and 0.22 g (3.3% of theory) of the isomer having the lower Rf value (0.53) as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]([O:16][CH2:17][CH2:18][OH:19])=[N:10][C:11]([F:15])=[C:12]([Cl:14])[CH:13]=1.[Cl:20][C:21]([Cl:26])([CH3:25])[C:22](Cl)=[O:23]>C(#N)C>[Cl:20][C:21]([Cl:26])([CH3:25])[C:22]([O:19][CH2:18][CH2:17][O:16][C:9]1[C:8]([Cl:7])=[CH:13][C:12]([Cl:14])=[C:11]([F:15])[N:10]=1)=[O:23]
Reactant: OCCOc1nc(F)c(Cl)cc1Cl
Reactant: CC(Cl)(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Cl)(Cl)C(=O)OCCOc1nc(F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution was prepared by admixing 250 milliliters of acetonitrile, 55.3 grams (0.4 mole) of potassium carbonate, 42.5 grams (0.16 mole) of 2-(3,5-dichloro-6-fluoro-2-pyridyloxy)ethanol and 32.3 grams (0.2 mole) of 2,2-dichloropropionyl chloride. This mixture was stirred at room temperature for 4 days. The solids which formed were removed by filtration and the filtrate was concentrated under a reduced pressure. The residual material which remained was dissolved in hexane and washed with water. The hexane was removed under a reduced pressure to yield a pale-orange liquid having a refractive index of n/25D=1.5239. The product was confirmed to be 2-(3,5-dichloro-6-fluoro-2-pyridyloxy)ethyl 2,2-dichloro propionate by its infrared and nuclear magnetic resonance spectrums.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cn1cc(Br)cn1
Product: C[C@@H](c1ccc(-c2cnn(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1-methyl-1H-pyrazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI+): m/z=434 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[NH:17]1[CH2:19][CH2:18]1>CCOC(C)=O>[N:17]1([C:2]2[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[C:5]([NH2:7])=[O:6])[CH2:19][CH2:18]1
Reactant: NC(=O)c1c([N+](=O)[O-])ccc(Cl)c1[N+](=O)[O-]
Reactant: C1CN1
Solvent: CCOC(C)=O
Product: NC(=O)c1c([N+](=O)[O-])ccc(N2CC2)c1[N+](=O)[O-]
Temperature: -20 °C

Procedure:
A solution of 3-chloro-2,6-dinitrobenzamide (Palmer et al., J. Med. Chem., 1996, 29, 2518-2528) (0.50 g, 2.04 mmol) and aziridine (1.00 g, 0.023 mol) in EtOAc (80 mL) was stirred at room temperature for 18 h. After washing with water the solution was dried over Na2SO4 and concentrated under reduced pressure to ca. 20 mL. Petroleum ether was added until a slight cloudiness persisted and the solution was chilled at −20° C. to give 13: mp 206-210° C. (dec.); 1H NM [(CD3)2SO] δ8.26 (br s, 1H, CONH), 8.24 (d, J=9.0 Hz, 1H, H-5), 7.92 (br s, 1H, CONH), 7.44 (d, J=9.0 Hz, 1H, H-4), 2.35 (s, 4H, aziridine-H); 13C NMR δ162.67 (s), 150.63 (s), 141.82 (s), 139.32 (s), 128.17 (s), 127.77 (d), 123.31 (d), 28.41 (t). Anal. Calcd for C9H8N4O5; C, 42.86;H, 3.20; N, 22.22. Found: C, 42.97;H, 3.15; N, 22.32%.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>C(Cl)Cl>[CH3:11][S:12]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:14])=[O:13]
Reactant: OCCOc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccccc1

Procedure:
To a solution of 2-(phenoxy)ethanol (1.35 g, 9.78 mmoles) and triethytamine (2.04 ml, 14.7 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.91 ml, 12 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction solution was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to column chromatography [eluent:hexane/methyl (1:1)] to obtain crude 1-methanesulfonyloxy-2-(phenoxy)ethane as a pale yellow oily product.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([O:26]CC)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=2)[N:4]=1)[CH3:2].[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=2)[N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1ccn2c(C(=O)Nc3cccc4c3c(CC)nn4Cc3cccc(C)n3)cnc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)O)ccn34)c12
Temperature: 70 °C
Yield: 101.2 %

Procedure:
To ethyl 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridine-7-carboxylate (430 mg, 0.891 mmol; prepared as in Example 23) in THF/H2O (6 mL/1 mL) was added lithium hydroxide (21.3 mg, 0.891 mmol). The reaction mixture was sealed and heated to 70° C. for 2 hours. The mixture was cooled to ambient temperature and HCl (0.45 mL, 4M in dioxane) was added. The mixture was concentrated under reduced pressure to give crude product (410 mg, mixed with LiCl).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[CH2:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].C(=O)(O)[O-].[Na+].O1CCOCC1>O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[CH2:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)=[O:25]
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)OC1(C)C
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)c2c(N)ncnc21
Temperature: 120 °C

Procedure:
To a 25 mL pressure tube was charged 3-iodo-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70.9 mg, 0.234 mmol), 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (93 mg, 0.234 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9.55 mg, 0.012 mmol), and sodium bicarbonate (39.3 mg, 0.468 mmol) followed by dioxane (4 mL), and water (1 mL). The reaction was heated at 120° C. for 40 min in microwave reactor. LCMS showed incomplete conversion. The reaction was heated in microwave at 120° C. for another 1 hour. The reaction was cooled to room temperature, the mixture was transferred into a 100 mL erlenmeyer flask, rinsed by EtOAc, with the water layer and black greasy solid stayed in tube (total 100 mL of EtOAc was added to the mixture). The EtOAc solution was evaporated to dryness, and re-dissolved in CH2Cl2/MeOH (8 mL/2 mL). It was purified by flash column 25-100% EtOAc/hexane, then 0-10% MeOH/EtOAc, Analogix Si SF15-24g, to afford a brown solid. The brown solid was further purified by recrystallization from CH3CN to give the title compound as a brown solid. LC/MS (ES) m/z=449.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49 (d, J=6.82 Hz, 6H), 3.27-3.33 (m, 2H), 3.97 (s, 2H), 4.31 (t, J=8.46 Hz, 2H), 5.06 (t, J=6.82 Hz, 1H), 7.18-7.21 (m, 1H), 7.22-7.27 (m, 2H), 7.44 (d, J=8.08 Hz, 1H), 7.54 (s, 1H), 8.15 (d, J=8.34 Hz, 1H), 8.23 (s, 1H).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][OH:21]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:21][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7]
Reactant: COc1cccc(CO)c1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: COc1cccc(COc2cccc([N+](=O)[O-])c2C#N)c1
Yield: 83 %

Procedure:
Prepared as in Example 158c from 2,6-dinitrobenzonitrile and 3-methoxybenzylalcohol in 83% yield. 1H NMR (400 MHz, d-DMSO) δ 3.75 (s, 3H), 5.38 (s, 2H), 6.91 (d, J=8.0 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 7.07 (s, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.78 (d, J=8.8 Hz, 4H), 7.93-7.87 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)CCC.C1(C)C=CC=CC=1>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.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:33]4[S:34][CH:35]=[CH:36][CH:37]=4)=[CH:7][C:6]=3[C:5]2([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:14]=1
Reactant: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(-c3cccs3)cc21
Reaction time: 1 h

Procedure:
A mixture of 2,7-dibromo-9,9-dihexylfluorene (7) (8.0 g, 16 mmol), 2-tributylstannylthiophene (2.98 g, 8.0 mmol), tetrakis(triphenylphosphine)palladium (0) (200 mg, 1.73×10−4 mol) aqueous sodium carbonate (2M, 2 cm3), toluene (5 cm3) and ethanol (2 cm3) was heated under reflux for 24 h under argon. Toluene and ethanol were removed and hexane (10 cm3) and aqueous KI (2%, 10 cm3) added and the mixture stirred vigorously for 1 h. Diethyl ether (10 cm3) and dilute HCl(aq)(3M, 10 cm3) were added, the aqueous layer separated and washed with diethyl ether (2×10 cm3). The organic layers were combined, dried over anhydrous magnesium sulphate, filtered and concentrated to a dark brown oil which was purified by column chromatography [silica gel, hexane] to yield a pale jade coloured oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11]Br)=[CH:6][CH:5]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][N:15]=[N+:16]=[N-:17])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 4 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
4-(2-Bromo-acetyl)-benzoic acid methyl ester (15.5 mmol) was dissolved in ethanol (120 ml) and acetic acid (4.8 ml). Sodium azide (31 mmol) was added and the reaction stirred at 4° C. overnight. The ethanol was removed and the mixture diluted with ethyl acetate (100 ml). The organic layer was washed with saturated sodium hydrogen carbonate (2'50 ml) and dried (MgSO4). The solvent was removed in vacuo to give a yellow solid, which was re-crystallized from ethanol to give the title compound as a pale yellow solid (2.6 g). IR 2117 cm−1