Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(CCN2CCC(N3C4C(=CC=C([Br:23])C=4)CC3)CC2)=CC=1.[CH3:26][N:27]([CH3:36])[C:28]1[CH:33]=[CH:32][C:31](C=O)=[CH:30][N:29]=1>>[Br:23][C:31]1[CH:32]=[CH:33][C:28]([N:27]([CH3:36])[CH3:26])=[N:29][CH:30]=1
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Reactant: CN(C)c1ccc(C=O)cn1
Product: CN(C)c1ccc(Br)cn1
Yield: 150.9 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.5 g) and 2-dimethylamino-5-formylpyridine (0.345 g) were treated as in Example 130 to give the title compound (0.376 g) as a colorless oil (yield: 65.3%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][NH:3]1.C(N(CC)CC)C.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:20]([N:3]1[CH2:4][CH:2]1[CH3:1])([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: CC1CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CN1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
2-Methyl aziridine is dissolved in CH2Cl2 and triethylamine under argon at 0° C. Benzylchloroformate is added and the contents of the flask are at room temperature overnight. The mixture is poured into 10% citric acid and is extracted with CHCl3. The organic layer is washed with dilute aqueous NaHCO3 and dried over MgSO4. The solution is evaporated to yield N-Cbz-2-methyl aziridine.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])=[O:4].[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>CN(C)C=O>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH2:2][C:3]([NH:5][C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8]([OH:10])=[O:9])=[O:4])=[CH:18][CH:17]=1
Reactant: O=C(CCl)Nc1ccccc1C(=O)O
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(F)cc1)Nc1ccccc1C(=O)O
Temperature: 0 °C
Yield: 104.1 %

Procedure:
N(chloroacetyl)anthranilic acid 4.0 g (8 mmol) and p-fluoroaniline 5.3 ml (56 mmol) were dissolved in 4 ml of dimethylformamide and heated at 80° to 90° C. for 4 hours. The reaction solution was poured into ice water and deposited crystals were collected by filtration. These crystals were washed with ether and recrystallized from ethanol to obtain N-[(4-fluorophenylamino)acetyl]anthranilic acid (melting point: 217° to 219° C.) 2.4 g (yield: 46%).
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[K+].[CH2:26]([O:31][CH:32]([CH3:49])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:27][CH2:28][CH2:29][CH3:30].Cl>O.CN(C)C=O>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH:32]([O:31][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:49])=[CH:21][CH:22]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCOC(C)CCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCc1cnc(-c2ccc(OCCCCCC(C)OCCCCC)cc2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
Separately, 3.12 g of 5-n-decyl-2-(4-hydroxyphenyl)pyrimidine and 0.53 g of potassium hydroxide were added to 14 ml of dimethylformamide, and the mixture was stirred for 3 hours at 100° C. To the mixture was added the above-prepared 2.98 g of 6-pentyloxyheptyl-p-toluenesulfonate followed by 5 hours of stirring under heating at 100° C. After the reaction, the reaction mixture was poured into 200 ml of cold water and acidified to about pH 3 with 6N-hydrochloric acid and extracted with benzene, followed by washing with water, drying with anhydrous magnesium sulfate and distilling-off of the solvent, to obtain 4.71 g of crude product. The product was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/2) and recrystallized from hexane to obtain 1.56 g of 5-n-decyl-2-[4-(6-pentyloxyheptyloxy)phenyl]pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)=[O:20])([CH3:17])([CH3:16])[CH3:15].O>CN(C)C=O>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]1=[O:1])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Oc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCCn1c(=O)ccc2ccccc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxyquinoline (640 mg) was added to a suspension of 600% sodium hydride (205 mg) in N,N-dimethylformamide (15 ml) and the mixture was stirred at 60° C. for 30 minutes. After cooling in ice a solution of N-(tert-butoxycarbonyl)-6-bromo-hexylamine (1.25 g) (Helv. Chim. Acta 76 891 (1993)) in N,N-dimethylformamide (10 ml) was added dropwise and stirring was continued overnight at room temperature. Ice and water were added and the mixture was extracted three times with ethyl acetate. The organic phases were washed with saturated sodium chloride, dried and evaporated to leave a yellow oil which after purification by chromatography on silica gel with ethyl acetate as eluent gave the desired compound as a colourless oil.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[CH:9][N:8]=[C:7]3[N:11]([CH3:21])[N:12]=[C:13]([C:14]4[CH:15]=[N:16][N:17]([CH3:20])[C:18]=4Br)[C:6]=23)[CH2:4][CH2:3][CH2:2]1.[CH:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C.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>[N:1]1([C:5]2[N:10]=[CH:9][N:8]=[C:7]3[N:11]([CH3:21])[N:12]=[C:13]([C:14]4[CH:15]=[N:16][N:17]([CH3:20])[C:18]=4[C:27]4[CH:28]=[CH:29][C:24]([CH:22]=[O:23])=[CH:25][CH:26]=4)[C:6]=23)[CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cn1ncc(-c2nn(C)c3ncnc(N4CCC4)c23)c1Br
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: CCO
Product: Cn1ncc(-c2nn(C)c3ncnc(N4CCC4)c23)c1-c1ccc(C=O)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
4-(Azetidin-1-yl)-3-(5-bromo-1-methyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (C28) (345 mg, 0.991 mmol), (4-formylphenyl)boronic acid (163 mg, 1.09 mmol), tetrakis(triphenylphosphine)palladium(0) (11.6 mg, 0.0100 mmol), and sodium carbonate (210 mg, 1.98 mmol) were combined in ethanol (10 mL). Water (2 mL) was added, and the reaction mixture was allowed to stir for 18 hours at 100° C. The reaction mixture was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel chromatography [Gradient: 0% to 100% (90:5:5 ethyl acetate/methanol/triethylamine) in heptane]. The product was obtained as a mixture with some impurities, and was used in the next step without additional purification. Yield: 270 mg, 0.723 mmol, 73%. APCI m/z 374.0 (M+1). 1H NMR (400 MHz, CD3OD), product peaks only: δ 2.25-2.34 (m, 2H), 3.8-4.0 (br m, 4H), 3.95 (s, 3H), 3.96 (s, 3H), 7.61 (br d, J=8.2 Hz, 2H), 7.76 (s, 1H), 7.92 (br d, J=8.4 Hz, 2H), 8.16 (s, 1H), 9.97 (s, 1H).
Reaction SMILES: [N:1]1([S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14](F)(=[O:16])=[O:15])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH3:18]>C1COCC1>[N:1]1([S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH2:18])(=[O:16])=[O:15])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: O=S(=O)(F)c1ccccc1S(=O)(=O)N1CCC1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1S(=O)(=O)N1CCC1

Procedure:
In a 1-l flask was placed 9.8 g. of 2-(azetidin-1-ylsulfonyl)benzenesulfonyl fluoride and 500 ml of THF. Then 9 ml of ammonia was added and the mixture was refluxed for two days. Four 25 ml portions of liquid ammonia were then added to the refluxing solution over a 48 hour period. The reaction mixture was concentrated and the residue chromatographed on silica gel (dichloroethane). The desired product was collected to give 4.9 g of a solid m.p. 121°-123° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[Cl:17][C:18]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCl>[Cl:17][C:18]1[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([N:7]1[CH2:8][CH2:9][N:4]2[CH:3]=[CH:2][N:1]=[C:5]2[CH2:6]1)=[O:21]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: c1cn2c(n1)CNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2ccnc2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.4 %

Procedure:
5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazine (0.099 g, 0.804 mmol) was suspended in dichloromethane (DCM) (8 ml). Triethylamine (0.123 mL, 0.884 mmol) and 2-chloro-3-(trifluoromethyl)benzoyl chloride (0.195 g, 0.804 mmol) were added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo, the residue dissolved in 1:1 DMSO/MeOH and purified by mass-directed automated preparative HPLC. Product fractions were concentrated in vacuo to yield an orange gum. This was partitioned between DCM (10 ml) and saturated aqueous sodium bicarbonate (4 ml) and the organic layer separated. This was concentrated in vacuo to yield 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.131 g, 0.397 mmol, 49.4% yield) as a yellow gum.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[C:5]=1[NH2:24].CC(C)([O-])C.[K+].O>CN1C(=O)CCC1>[C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:17][C:12]([C:11]2[NH:24][C:5]3[C:6]([CH:10]=2)=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:2])=[O:25])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cccc(C#Cc2ccc(-c3ccccc3)cc2)c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)c1cccc2cc(-c3ccc(-c4ccccc4)cc3)[nH]c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.9 %

Procedure:
To a cold solution of 2-amino-3-biphenyl-4-ylethynyl-benzoic acid methyl ester (300 mg, 0.91 mmol) in NMP (5 mL) was added dropwise a solution of potassium t-butoxide (205 mg, 1.83 mmol) in NMP (5 mL). This reaction mixture was allowed to stir at room temperature for 5 h. After the reaction is completed it was poured into water and pH was adjusted to 2. The resulting precipitate was collected by filtration and was washed with water. Finally it was dried in a vacuum oven to get the 145 mg of 2-biphenyl-4-yl-1H-indole-7-carboxylic acid as a pale yellow coloured solid.
Reaction SMILES: [Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH2:11])[N:7]=[CH:8][C:9]([I:10])=[C:4]2[CH:3]=1.I[CH2:14][CH3:15]>>[Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH:11][CH2:14][CH3:15])[N:7]=[CH:8][C:9]([I:10])=[C:4]2[CH:3]=1
Reactant: CCI
Reactant: Nc1ncc(I)c2cc(Cl)oc12
Product: CCNc1ncc(I)c2cc(Cl)oc12
Yield: 45 %

Procedure:
The title compound was prepared in 45% yield from 2-chloro-4-iodo-furo[2,3-c]pyridin-7-ylamine and iodoethane by a procedure analogous to Intermediate 7. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1 H), 6.47 (s, 1 H), 4.71 (br. s., 1 H), 3.59 (qd, J=5.6, 7.2 Hz, 2 H), 1.31 (t, J=7.2 Hz, 3 H); MS (ESI): 322.96, 324.96 [M+H]+; HPLC tR=3.75 min (ZQ3: polar—4 min).
Reaction SMILES: [CH3:1][C@@H:2]1[O:8][C:7](=[O:9])[CH2:6][C@@H:5]2[C@H:3]1[O:4]2.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[O:9]=[CH:7][CH2:6][C@H:5]1[O:4][C@H:3]1[C@H:2]([CH3:1])[OH:8]
Reactant: C[C@@H]1OC(=O)C[C@H]2O[C@@H]12
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: C[C@H](O)[C@@H]1O[C@@H]1CC=O
Reaction time: 2 h

Procedure:
To a solution of 2.58 g (20 mmol) of (1S, 2S, 6R)-2-methyl-3,7-dioxabicyclo[4.1.0]-heptan-4-one in 300 ml of anhydrous toluene cooled to -75° was added under argon 14 ml (24.5 mmol) of a 1.75 M solution of DIBAL-H in toluene. The reaction mixture was stirred at -75° for 2 hr and then quickly poured onto a slurry of 260 g of silica gel (Silica Gel 60 Merck) in toluene and allowed to filter. The slurry was washed with 3 L of methylene chloride-methanol (9:1). The combined filtrate and washings were evaporated to dryness under reduced pressure. The residual oil was distilled with a Kugelrohr distillation apparatus to afford 3,4-anhydro-2,6-dideoxy-L-ribo-hexose: bp 90° (oven temperature) (0.1 mm); [α]25D +25.16° (c 1.013, MeOH).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].[CH2:18]([CH:23]1[CH2:29][CH:28]2[NH:30][CH:25]([CH2:26][CH2:27]2)[CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22]>CCN(CC)CC>[CH2:18]([CH:23]1[CH2:24][CH:25]2[N:30]([CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]3[C:10]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:16])[CH:28]([CH2:27][CH2:26]2)[CH2:29]1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC1CC2CCC(C1)N2
Reactant: Cc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Solvent: CCN(CC)CC
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(C)cc21
Yield: 69.3 %

Procedure:
Crude (S)-4-(3-Iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one (0.15 g), Et3N (0.5 mL) and 3-pentyl-8-azabicyclo[3.2.1]octane (95 mg, 5.2 mmol) were reacted according to GP17. Flash CC (SiO2; CH2Cl2/I-PrOH 92:8) gave the title compound (0.12 g, 68%). 1H NMR (CD3OD) δ 7.06 (s, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.81 (brd, J=8.0 Hz, 1H), 4.52 (ABq, J=14.8, 27.2 Hz, 2H), 4.06 (dd, J=5.6, 14.2 Hz, 1H), 4.96 (dd, J=8.8, 14.2 Hz, 1H), 3.16-3.02 (m, 2H), 2.34-2.07 (m, 7H), 2.31 (s, 3H), 2.04-1.81 (m, 3H), 1.70-1.55 (m, 3H), 1.46-1.21 (m, 10H), 0.92-0.85 (m, 6H); 13C NMR (CD3OD) δ 167.2, 145.1, 133.6, 129.4, 125.5, 117.7, 117.5, 68.7, 61.6, 60.2, 58.6, 46.1, 39.6, 37.2, 36.9, 33.1, 32.4, 29.6, 29.5, 28.5, 27.8, 23.7, 21.18, 17.0, 14.4.
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[CH:23]=[C:24]([OH:29])[CH:25]=[C:26]([CH3:28])[CH:27]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:38]O>>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[CH:23]=[C:24]([CH:25]=[C:26]([CH3:28])[CH:27]=2)[O:29][CH2:38][C:37]([O:41][CH2:42][CH3:43])=[O:40])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: Cc1cc(O)cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1
Reactant: CCOC(=O)CO
Product: CCOC(=O)COc1cc(C)cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 89E and ethyl glycolate were processed as described in Example 62A to provide the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][C:31]([NH:37][CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[C:30]([S:51][CH2:52][CH2:53]O)[CH:29]=1>O1CCCC1.C(OCC)(=O)C>[F:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][C:31]([NH:37][CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[C:30]([S:51][CH2:52][CH2:53][I:25])[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])c(F)cc2SCCO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])c(F)cc2SCCI)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.6 %

Procedure:
To a stirred solution of triphenylphosphine (668 mg, 2.55 mmol) and imidazole (0.693 mL, 5.09 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. was added iodine (732 mg, 2.88 mmol). The resulting mixture was stirred at 0° C. for 5 minutes. To this mixture was then added tert-butyl 4-(4-fluoro-2-(2-hydroxyethylthio)-5-nitrophenylamino)piperidine-1-carboxylate (705 mg, 1.697 mmol) as a solution in tetrahydrofuran (5 mL), and the resulting mixture was stirred at room temperature for 20 minutes. The mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate, water, saturated sodium thiosulfate, and brine. The organic phase was dried, filtered, concentrated, and then chromatographed in 1:9 ethyl acetate:hexanes to afford the desired product (398 mg, 44.6%). 1H NMR (DMSO-d6) δ 7.53 (d, J=11.7 Hz, 1H), 7.27 (d, J=6.6 Hz, 1H), 5.10 (d, J=8.1 Hz, 1H), 3.96-3.85 (m, 2H), 3.64-3.52 (m, 1H), 3.50-3.41 (m, 2H), 3.39-3.32 (m, 2H), 2.99-2.81 (m, 2H), 1.91-1.81 (m, 2H), 1.48-1.32 (m, 11H); ESI-MS (m.z, %): 470 (100), 426 (81).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([C:13]3[N:17]4[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl.[NH2:26][O:27][CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][O:27]/[N:26]=[C:22](/[C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([CH:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[N:3]=[CH:4]4)[CH3:12])=[CH:14][N:15]=2)[N:18]=1)\[CH3:23]
Reactant: NOCCO
Reactant: CC(=O)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Agent: Cl
Product: C/C(=N\OCCO)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Yield: 18.3 %

Procedure:
The title compound (9.0 mg, 17%, 88% purity) was synthesized from 1-(3-(1-(1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (40.0 mg, 0.13 mmol) and 2-(aminooxy)ethanol hydrochloride (19.31 mg, 0.25 mmol) using the same procedure as described in the synthesis of example 13. 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.94 (d, 1H), 7.85 (s, 1H), 7.79 (s, 1H), 7.66 (s, 1H), 7.85 (d, 1H), 7.52 (d, 1H), 7.37 (dd, 1H), 4.72 (t, 2H), 4.21 (t, 2H), 3.97 (s, 3H), 3.66 (q, 1H), 2.20 (s, 3H), 1.78 (d, 3H). LCMS (method A): [MH]+=379, tR=5.25 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[CH2:29][CH2:28]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(OC(C)(C)C)=O)=[C:13]([O:25][CH3:26])[CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[O:34])[CH2:29][CH2:28]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:25][CH3:26])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
To a mixture of benzyl 4-(4-amino-3-{4-[(tert-butoxycarbonyl)amino]-3-methoxyphenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (7.68 g, 0.0134 mol) in dichloromethane (10 mL) was added a 25% solution of trifluoroacetic acid in dichloromethane at 0° C. The mixture was stirred under an atmosphere of nitrogen at room temperature for 18 hours. The solvents were removed under reduced pressure. The residue was cooled to 0° C. and basified with an aqueous 5 N solution of sodium hydroxide. The aqueous layer was extracted with dichloromethane (3×150 mL). The combined organic layer was washed with water and brine, and dried over magnesium sulfate. The solvents were removed under reduced pressure to give benzyl 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (6.02 g, 0.0127 mol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC>C1COCC1>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:21])[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:7]2[OH:9]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of methyl 5-bromo-2-(2-phenylacetamido)benzoate (7.71 g, 22.1 mmol, Intermediate 1, step a) in THF (50 mL) at −78° C. was added 1.0 M lithium bis(trimethylsilyl)amide in hexane (48.7 mL, 48.7 mmol) slowly, and the color changed from clear to clear red. The mixture was stirred at −78° C. to room temperature for 4 hours, during which time the color changed to cloudy yellow. The reaction was quenched with water, and acidified with 37% HCl until pH ˜5. The precipitated solid was filtered, washed with water and Et2O, and air dried to give the title compound. More solid was precipitated from the filtrate after standing overnight. The solid was collected by filtering, washing with water and Et2O, and air drying to afford more title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[N+](=[CH2:18])=[N-]>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:18])=[O:13]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)CCCC(=O)c1ccccc1Br
Solvent: CCOCC
Product: COC(=O)CCCC(=O)c1ccccc1Br
Yield: 97 %

Procedure:
To 0.54g (2.0 mmol) of the product of Example 2 dissolved in ether was added an ethereal solution of excess diazomethane at 0°C. to produce a 97% yield of the ester as a yellow oil. The ester was used without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](Cl)([Cl:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:1]1([O:7][C:8]([Cl:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cl
Reactant: Oc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(Cl)Oc1ccccc1
Yield: 90.6 %

Procedure:
The distillation residue is re-used with 500 g of phenol and 540 g of phosgene, without the use of fresh triphenylphosphine. After a phosgenation time of 10 hours, 754 g of distilled chloroformic acid phenyl ester are obtained (purity 99.8%; yield 90.4% of the theoretical yield).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[O-].[Na+].CO.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33]Cl.O>CO>[C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: ClCc1ccccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccn2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.9 %

Procedure:
To a solution of N-Boc-tyrosine (281 mg, 1.0 mmol) in methanol (0.5 mL) were added 28% sodium methoxide-methanol solution (0.8 mL, 4.0 mmol) and 2-picolyl chloride hydrochloride (230 mg, 1.4 mmol), and the mixture was stirred at 25° C. for 24 hr. Then, water (3 mL) was added make the system homogeneous, which system was then analyzed by HPLC. As a result, the objective N-Boc-(O-2-picolyl)tyrosine (346 mg, conversion yield 93%) was confirmed.