Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:27][CH3:28])[CH2:22][S:23](O)(=[O:25])=[O:24])[C:11](=[O:29])[C@:10]([CH2:31][C:32]([O:34][CH3:35])=[O:33])([CH3:30])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[O:42]1[CH2:45][CH:44]([NH2:46])[CH2:43]1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:27][CH3:28])[CH2:22][S:23](=[O:24])(=[O:25])[NH:46][CH:44]3[CH2:45][O:42][CH2:43]3)[C:11](=[O:29])[C@:10]([CH2:31][C:32]([O:34][CH3:35])=[O:33])([CH3:30])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC1COC1
Reactant: CC[C@@H](CS(=O)(=O)O)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC[C@@H](CS(=O)(=O)NC1COC1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of (S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-methoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-1-yl)butane-1-sulfonic acid (189.8 mg, 0.35 mmol; Example 372, Step B) in dichloromethane (5.0 mL) was added oxalyl chloride (0.061 mL, 0.70 mmol), followed by DMF (2 drops). The reaction was stirred at room temperature for 3.5 hours, then concentrated in vacuo. The sulfonyl chloride intermediate was dissolved in dichloromethane (5.0 mL), then treated with 3-oxetanamine (50.0 mg, 0.684 mmol; Pharmablock R & D Co. Ltd., Nanjing, China) and N,N-diisopropylethylamine (0.122 mL, 0.699 mmol). After stirring at room temperature for 16 hours, the reaction was quenched with methanol (2.0 mL), then concentrated in vacuo. Purification of the residue by chromatography on silica gel (4 g SiO2, 0%-50% EtOAc in hexanes) provided the title compound as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.O=[C:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1>C(O)(=O)C.O>[CH3:2][O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:10][C:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][C:14]2=1
Reactant: COC(=O)C1CCC(=O)CC1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C1CCc2[nH]c3ccc(OC)cc3c2C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
(4-Methoxyphenyl)hydrazine hydrochloride (80.0 mg, 0.46 mmol) and methyl 4-oxocyclohexanecarboxylate (85.9 mg, 0.55 mmol) were dissolved in acetic acid (0.5 mL). The mixture was heated at 80° C. with stirring under nitrogen for 3 h, cooled, diluted with water (2 mL) and the resulting precipitate was collected by filtration, gently washed with water and dried in vacuo to yield the title compound (107 mg, 90%) as an off-white solid. C15H17NO3, Mr=259.30; 1H NMR (400 MHz, DMSO-d6) d: 1.81-1.91 (m, 1H), 2.15-2.19 (m, 1H), 2.66-2.84 (m, 4H), 2.90 (dd, J=4.6/14.2 Hz, 1H), 3.65 (s, 3H), 3.72 (s, 3H), 6.61 (dd, J=2.4/8.8 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 10.51 (s, 1H); LCMS (ESI) tR: 2.27 min (>99%, ELSD), m/z: 260.2 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pt]=O>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=Cc1cc(Cl)cc(Cl)c1
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 3-(3,5-dichlorophenyl)-acrylic acid tert butyl ester (4 g, 14 mmol) in ethanol (100 mL) under nitrogen atmosphere was charged with platinum oxide (800 mg). A balloon of hydrogen was attached and the mixture was stirred vigorously at ambient temperature over night. After removal of excess hydrogen, the catalyst was removed by filtering mixture through a pad of Celite and the resulting solution was evaporated to afford 3-(3,5-dichlorophenyl)-propionic acid tert-butyl ester as an oil. 1H-NMR (CDCl3, 400 MHz): δ 7.18 (s, 1H), 7.08 (s, 2H), 2.85 (s, 2H), 2.52 (s, 2H), 1.41 (s, 9H).
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[C:7]([Cl:13])[CH:6]=1>O.CS(C)=O>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:1]#[N:2])=[C:7]([Cl:13])[CH:6]=1
Reactant: [C-]#N
Reactant: Clc1cc(Br)ccc1CBr
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc(Br)cc1Cl
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Potassium cyanide (587 g) was dissolved in a mixed solution of water (1408 mL) and dimethyl sulfoxide (767 g), and a solution of 4-bromo-2-chlorobenzyl bromide (512 g) of Reference Example 13 in dimethylsulfoxide (1663 g) was added dropwise at an inside temperature of 90° C. After stirring at the same temperature for 1 hr, the reaction mixture was poured into water. After partitioning and extraction with ethyl acetate, the organic layer was washed 4 times with 25% brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (383 g) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(Br)cc2)CC1
Temperature: 75 °C
Reaction time: 5 h
Yield: 73.7 %

Procedure:
To a mixture of 1-bromo-4-(3-bromopropoxy)benzene (300 mg, 1.02 mmol) and tert-butyl piperazine-1-carboxylate (144 mg, 1.02 mmol) in acetonitrile (6.0 mL) was added Cs2CO3 (365 mg, 1.10 mmol). The mixture was stirred at 75° C. for 5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give the title compound (300 mg, 75% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.40 (d, 2 H), 6.75 (d, 2 H), 3.95 (m, 2 H), 3.42 (m, 4 H), 2.54 (t, 2 H), 2.40 (m, 4 H), 2.01-1.89 (m, 2 H), 1.50-1.40 (s, 9 H).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:22]=[CH:21][C:7]([C:8](=[O:20])[CH2:9][N+:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.C(=O)(O)[O-].[Na+].[C:37](#[N:40])[CH:38]=[CH2:39]>CN(C)C=O>[C:37]([C:38]1[CH:39]=[C:9]([C:8](=[O:20])[C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:22][CH:21]=2)[N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]=12)#[N:40]
Reactant: C=CC#N
Reactant: COc1ccc(C(=O)C[n+]2cccc3ccccc32)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cc(C#N)c3ccc4ccccc4n23)cc1

Procedure:
The title compound was prepared from 1-(4-methoxy-phenacyl)-quinolinium bromide (110 mg, 0.307 mmol), tetrapyridinecobalt(II) dichromate (202 mg, 0.332 mmol), sodium bicarbonate (66.2 mg, 0.788 mmol), acrylonitrile (110 μL, 1.67 mmol), and N,N-dimethylformamide (2.0 mL), similar to Example 1b, and yielded 26.6 mg (26%) as a yellow solid. 1H NMR (CDCl3): 8.08 (dd, J=9.15, 2.20 Hz, 2H), 8.02 (d, J=8.52 Hz, 1H), 7.83 (dd, J=7.55, 1.78 Hz, 1H), 7.70 (d, J=9.34 Hz, 1H), 7.66 (d, J=9.06 Hz, 1H), 7.59 (td, J=7.83, 1.83 Hz, 1H), 7.52 (td, J=7.48, 1.19 Hz, 1H), 7.38 (s, 1H), 7.05 (dd, J=9.25, 2.33 Hz, 2H), 3.94 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[OH:14].[CH3:16][CH:17](O)[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH-].[Na+]>O1CCCC1>[CH:17]([O:14][C:5]1[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:15])([CH3:18])[CH3:16]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1O
Reactant: CC(C)O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 500 mg (2.271 mmol) 2-hydroxy-4-trifluoromethyl-benzoic acid methyl ester (CAS: 345-28-8), 209 ul (2.725 mmol) 2-propanol and 706.2 mg (2.612 mmol) triphenylphosphine in 6.5 ml tetrahydrofuran under nitrogen at 0° C., was added dropwise a solution of 575.2 mg (2.498 mmol) di-tert-butyl azodicarboxylate in 1 ml tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. 8 ml (15.9 mmol) 2N NaOH was added and the reaction mixture was warmed at 80° C. for 5 hours. The reaction mixture extracted twice with 5 ml ether. The aqueous layer was acidified under ice bath cooling with a 5N HCl solution to pH 1. The resulting precipitate was filtered and dried in vacuo to provide 444 mg (y: 78.8%) of the expected compound as a white solid. MS (m/e): 247.0 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH3:18][NH:19]C(=O)C1C=CC(C(C)(C)C)=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O.C(OCC)C.C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:18][NH2:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: CNC(=O)c1ccc(C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1ccc(CCN)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.9 %

Procedure:
Chloroform (100 ml), was mixed with 10.1 g (56.6 mmol), of p-tert-butylbenzoic acid and 20.2 g of thionyl chloride, and the mixture was refluxed for 5 hours. The solvent and excess thionyl chloride were distilled off under reduced pressure and the residue was dissolved in a small amount of methanol. The solution was dropped to 17 ml of a 40% methylamine-methanol solution cooled on an ice bath. After dropping, the solution was taken out of the ice bath and stirred at room temperature for 48 hours. Then, 100 ml of 2N hydrochloric acid was added to the reaction mixture, which was extracted with dichloromethane, and after washing with water and saturated saline, respectively, the organic layer was dried with magnesium sulfate. After distilling off the solvent under reduced pressure, the resulting white crystals were dissolved in dichloromethane and the solution was washed with 1 liter of a saturated aqueous sodium hydrogen carbonate solution to remove p-tert-butylbenzoic acid, raw material. After the organic extract was dried with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 8.15 g (yield: 74.9%), of N-methyl-4-tert-butylbenzamide as white crystals. This was mixed with 110 ml of diethyl ether, 8.15 g (42.6 mmol), of N-methyl-4-tert-butylbenzamide and 2.88 g (85.2 mmol), of lithium aluminum hydride, and refluxed in nitrogen atmosphere for 6 hours. After the reflux, the reaction mixture was ice cooled and water was added thereto to decompose excess lithium aluminum hydride. Aluminum hydroxide deposited was filtered off and the filtrate was extracted with diethyl ether. After washing with water and saturated saline, respectively, the organic extract was dried with magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting yellow oily substance was distilled under reduced pressure (115 to 118°C./10 mmHg), to obtain 3.69 g (yield: 48.9%), of the target compound as yellow oily substance.
Reaction SMILES: C([CH:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1)#N.[O-:20]C#N.[K+].OO.[Mn]([O-])(=O)(=O)=O.N>CC(C)=O.O>[C:3]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#C[O-]
Reactant: N#CC(c1ccccc1)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: N
Agent: OO
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1ccccc1)c1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 15 °C

Procedure:
Five hundred forty eight grams (2 moles) of 2-(cyanophenylmethyl)-3-nitro-6-chloropyridine were suspended in 3 liters of acetone and these were simultaneously dropped in at 37°C. a solution of 325 grams of potassium cyanate (4 moles) in 1 liter of water and a solution of 435 ml of 30% H2O2 (4.05 moles) in 800 ml of water. The reaction vessel was cooled with ice water. Both solutions were added within 45 minutes. After the end of the addition the color of the solution turned from the initial permanganate color (violet) solution to a light yellow. The solution was cooled in an ice bath to 15°C., then 600 grams of ice, 300 ml of 25% aqueous ammonia and 1 liter added with stirring. Yellow crystals separated out. They were filtered off with suction after 1 hour and washed with water. After boiling with 4 parts of methanol per part of crystals, cooling and filtering with suction there was obtained the pure 2-benzoyl-3-nitro-6-chloropyridine, M.P. 107°C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([CH:24]2[CH2:27][C:26]([F:29])([F:28])[CH2:25]2)=[CH2:23])[N:16]=3)=[C:9]([F:30])[CH:8]=1.[I-].[CH3:32][S+](C)(C)=O.CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([CH:24]4[CH2:27][C:26]([F:29])([F:28])[CH2:25]4)[CH2:32][CH2:23]2)[N:16]=3)=[C:9]([F:30])[CH:8]=1
Reactant: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CC(F)(F)C1
Reactant: C[S+](C)(C)=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(C4CC(F)(F)C4)CC3)nc2s1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(3,3-difluoro-cyclobutyl)vinyl)thiazolo[5,4-b]pyridine (299.1 mg, 0.692 mmol) in THF (13.33 mL) was added a solution of trimethylsulfoxonium iodide (913 mg, 4.15 mmol) and potassium 2-methylpropan-2-olate (466 mg, 4.15 mmol) in DMSO (8.0 mL) under argon, and the resulting solution was stirred at 60° C. for 2.5 h. The reaction mixture was then cooled to 25° C., THF was removed in vacuo, and the residual mixture was diluted with DCM (200 mL). The resulting solution was sequentially washed with sat. aq. NH4Cl and brine). The combined aqueous layers were extracted with DCM, and the combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-70% EtOAc/hexanes) furnished 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(3,3-difluoro-cyclobutyl)cyclopropyl)thiazolo[5,4-b]pyridine as a light yellow solid. MS (ESI) m/z: Calculated: 446.1; Observed: 447.1 (M++1).
Reaction SMILES: C([C:4]1([O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:6]1[F:36])[OH:5])(=O)C.C(O)(=O)C.NN>CN(C=O)C.ClCCl>[F:36][C@@H:6]1[C@@H:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@@H:25]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:26][CH:4]1[OH:5]
Reactant: CC(=O)C1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1F
Agent: NN
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
Acetyl-2-deoxy-2-fluoro-3,4,6-tri-O-benzyl-glucopyranose (750 mg) was dissolved in anhydrous DMF (7.5 mL). Hydrazine acetate (300 mg) was added and the reaction mixture was stirred for 3 hours at room temperature until most of the starting material was converted into product. The solution was diluted with dichloromethane (150 mL) and the organic layer was washed with water (3×150 mL), dried over sodium sulfate, filtered and evaporated. Chromatography of the material on silica gel using hexane-ethyl acetate (5:1) as eluent provided 2-deoxy-2-fluoro-3,4,6-tri-O-benzyl glucopyranose (500 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH3:17])[N:13]=[C:12](Cl)[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(Cl)Cl.[K+].[Br-]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH3:17])[N:13]=[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CNc1nc(Cl)nc(Nc2cc(Cl)cc(Cl)c2)n1
Reactant: Nc1ccc(O)cc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1nc(Nc2ccc(O)cc2)nc(Nc2cc(Cl)cc(Cl)c2)n1
Yield: 74 %

Procedure:
The title compound was synthesized from 2-(3,5-dichlorophenylamino)-4-methylamino-6-chloro-1,3,5-triazine and 4-aminophenol using a similar procedure to the one used in 8. Yield: 74%; Tg 83° C., Tc 155° C., Tm 187° C.; FTIR (CH2Cl2/KBr) 3401, 3282, 3180, 3112, 2952, 2918, 2850, 1572, 1514, 1503, 1421, 1400, 1366, 1258, 1227, 1168, 1114, 1080, 1011, 993, 937, 833, 807, 737, 703, 668, 632 cm−1; 1H NMR (300 MHz, DMSO-d6, 298K): δ 9.43 (br s, 0.5H), 9.29 (br s, 0.5H), 9.00 (br s, 0.5H), 8.83 (br s, 0.5H), 7.90 (br d, 2H), 7.43 (br s, 2H), 7.06 (s, 1H), 7.00 (br s, 1H), 6.70 (d, 3J=8.8 Hz, 2H), 2.81 (d, 3J=4.1 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6): δ 165.9, 164.0, 163.6, 152.7, 143.0, 133.6, 131.1, 122.6, 120.0, 117.1, 114.9, 27.2 ppm; HRMS (EI) calcd. for C16H14Cl2N6O (m/e): 376.0606. found: 376.0601.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5].Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH2:31])=[O:30]>>[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5])(=[O:30])[NH2:31]
Reactant: NC(=O)CCCCBr
Reactant: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1O
Product: NC(=O)CCCCOc1ccc(OCC(F)(F)F)cc1C(=O)NCc1ccccn1
Yield: 66.9 %

Procedure:
Using the general method of Example I Part A, 4.7 g (0.014 mole) of 2-hydroxy-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide was reacted with 2.3 g (0.013 mole) of 5-bromovaleramide to give 3.7 g of white powdery 2-(4-carbamoylbutoxy)-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide, m.p. 178°-180° C. Analysis: Calculated for C20H22F3N3O4 : %C, 56.5; %H, 5.2; %N, 9.9; Found: %C, 56.7; %H, 5.2; %N, 9.9.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:18])=[CH:14][NH:15]2)=[CH:11][CH:10]=1.[C:19]1(=[O:24])[O:23][CH2:22][CH2:21][CH2:20]1.O>CC(N(C)C)=O.C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:18])=[CH:14][N:15]2[CH2:22][CH2:21][CH2:20][C:19]([OH:24])=[O:23])=[CH:11][CH:10]=1
Reactant: COc1ccc2c(C)c[nH]c2c1
Reactant: O=C1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(C)cn(CCCC(=O)O)c2c1
Reaction time: 12 h
Yield: 73.6 %

Procedure:
Anhydrous potassium carbonate (34.5 g, 0.25 mmol) was added to a solution of 6-methoxy-3-methylindole (16.1 g, 0.1 mol) and γ-butyrolactone (43 g, 0.5 mol) in dimethylacetamide (750 mL). Under mechanical stirring and protected with a drying tube, the reaction mixture was refluxed for 18 hours, more γ-butyrolactone (21.5 g, 0.25 mol) was added, and the reflux was continued for 12 hours. A final portion of γ-butyrolactone (21.5 g, 0.25 mol) was added and the thick suspension was refluxed for another 12 hours, cooled to ~30° C., and poured into water (600 mL). Toluene (600 mL) was added and the 2 layer system was stirred for 15 minutes. The aqueous layer was separated and acidified with concentrated hydrochloric acid. The product was extracted with toluene (3×250 mL). The combined extracts were washed with water (600 mL), dried over MgSO4, filtered, evaporated, and the dark oily residue was chromatographed on silica gel (480 g). Elution with chloroform/hexane (1:1) afforded 18.2 g (74%) of the title compound as a yellowish oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:26][CH3:27])=[C:7]([CH:13]([N:15]3[C:19]4=[N:20][CH:21]=[N:22][C:23]([NH2:24])=[C:18]4[C:17]([Br:25])=[N:16]3)[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=2[CH3:11])[CH2:2]1.[CH2:28]([N:30](CC)CC)[CH3:29].BrCC#N>C(#N)C.CN(C=O)C>[NH2:24][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:15]([CH:13]([C:7]3[C:6]([O:26][CH3:27])=[C:5]([CH:3]4[CH2:4][N:1]([CH2:29][C:28]#[N:30])[CH2:2]4)[C:10]([CH3:11])=[C:9]([Cl:12])[CH:8]=3)[CH3:14])[N:16]=[C:17]([Br:25])[C:18]=12
Reactant: COc1c(C(C)n2nc(Br)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: CCN(CC)CC
Agent: N#CCBr
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(Br)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(CC#N)C1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.2 mmol) and triethylamine (37 μL, 0.27 mmol) in acetonitrile (3 mL) was added bromoacetonitrile (19 μL, 0.27 mmol). The resulting mixture was stirred at room temp. After an hour, the reaction mixture was still cloudy with not all of the material in solution. Several drops of DMF were added which allowed for a clear solution. The mixture was stirred overnight at room temperature and then most of the solvents were evaporated. The resulting residue was purified on silica gel (eluted with 0-10% MeOH in dichloromethane) to give 29 mg (30%) of the desired product. LCMS calculated for C20H22BrClN7O (M+H)+: m/z=490.1; Found: 490.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([N:18]([CH3:20])C)=[O:17])=[N:11][C:10]([OH:21])=[C:9]([OH:22])[C:8]=2[C:7]1=[O:23].C[O-].[Mg+2].C[O-].Br[CH2:34]CNC(=O)OC(C)(C)C>CO.CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]3[CH2:34][CH2:20][NH:18][C:16](=[O:17])[C:12]3=2)[C:7]1=[O:23]
Reactant: CN(C)C(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: C[O-]
Agent: [Mg+2]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1NCCn2c1c1c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide (1.00 g, 2.63 mmol; Example 1, Step 9) and magnesium methoxide in methanol (13.1 mL, 6-10% methanol solution available from Aldrich) in DMSO (26 mL) was heated at 60° C. for one hour. Methanol was exhaustively removed under vacuum over 45 minutes. The resulting DMSO solution was treated with tert-butyl (2-bromoethyl)carbamate (2.94 g, 13.13 mmol) and stirred at 60° C. under an atmosphere of nitrogen for one hour. The reaction mixture was diluted with ethyl acetate and washed successively with 10% sodium thiosulfate and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reverse phase high pressure liquid chromatography. Collection and lyophilization of appropriate fractions provided the title compound.