Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.F[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][N:16]=1.[H-].[Na+]>C1COCC1.CN(C=O)C.CCOCC>[F:21][C:20]1[C:15]([O:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[N:16][CH:17]=[C:18]([F:22])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Fc1cnc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ncc(F)cc2F)C1
Temperature: 40 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a stirred solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.10 g, 5.89 mmol) and 2,3,5-trifluoropyridine (0.86 g, 6.48 mmol) in dry THF (20 mL) and dry DMF (4 mL), at rt was added 60% NaH in oil (0.35 g, 8.84 mmol). The mixture was stirred in a 40° C. oil bath overnight, cooled to rt, diluted with ether (175 mL), washed with water (25 mL) and brine (25 mL), and dried over Na2SO4. Removal of the solvent left a dark oil (1.94 g) which was purified by chromatography on a 40-g silica cartridge eluted with a 0-100% EtOAc in hexanes gradient to afford (R)-tert-butyl 3-(3,5-difluoropyridin-2-yloxy)pyrrolidine-1-carboxylate (0.83 g, 47%). LC-MS Method 1 tR=1.85 min, m/z=301.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[CH3:31])[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[CH3:31])[CH2:26][NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:6][CH2:7]1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: Cc1ccc(C=O)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccc(CNC2CCN(CCn3c(=O)cnc4ccc(F)cc43)CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To 10 mL of a chloroform solution containing 383 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 160 mg of 3-fluoro-4-methylbenzaldehyde, 76 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 437 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=1:1] to give 429 mg of 1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: C#CCC.[Li][CH2:6][CH2:7][CH2:8][CH3:9].Cl[C:11]1([C:24]([F:27])([F:26])[F:25])[C:16]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:23])[O:12]1>C1COCC1>[C:6]([C:11]1([C:24]([F:26])([F:27])[F:25])[C:16]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:23])[O:12]1)#[C:7][CH2:8][CH3:9]
Reactant: COc1ccc2c(c1)C(Cl)(C(F)(F)F)OC(=O)N2
Reactant: [Li]CCCC
Agent: C#CCC
Solvent: C1CCOC1
Product: CCC#CC1(C(F)(F)F)OC(=O)Nc2ccc(OC)cc21
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 48 %

Procedure:
To a stirred, cooled(−78° C.) solution of 0.5 g(excess) of 1-butyne in 3 mL of anhydrous THF was added 1.6 mL(4.0 mmol) of a 2.5M solution of n-BuLi in hexanes over 3 min. The solution was stirred 5 min. and charged with 266 mg(1.00 mmol) of 4-chloro-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a single portion. The solution was warmed to −10° C. over 20 min., whereupon it was quenched with 20% aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed with saturated aq. NaHCO3 then brine. The solution was concentrated under reduced pressure, and the crude product was recrystallized from ethyl acetate-hexanes to afford 144 mg(48%) of 4-(1-butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, mp 161-162° C. 1H NMR(300 MHz, CDCl3) δ8.81(br. s, 1H); 7.07(d, 1H, J=2 Hz); 6.94(dd, 1H, J=9, 2 Hz); 6.81(d, 1H, J=8 Hz); 3.82(s, 3H); 2.34(q, 2H, J=7 Hz); 1.22(t, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[CH2:23][CH2:24][CH:25]=[O:26])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:27]([Mg]Br)[CH:28]=[CH2:29]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[CH2:23][CH2:24][CH:25]([OH:26])[CH2:29][CH:28]=[CH2:27])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=CCCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 65.7 %

Procedure:
A solution of 3-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-yl]-propionaldehyde (1.79 g, 4.47 mmol) in THF (45 mL) at −78° C. was treated with allylmagnesium bromide (1 M in Et2O, 5.8 mL, 5.8 mmol) and warmed to 0° C. over 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl, and extracted with EtOAc (2×). The combined organic extracts were washed saturated aqueous NaHCO3, brine, dried over MgSO4 and concentrated in vacuo. Flash chromatography (2→10% EtOAc/CH2Cl2) afforded the title compound (1.3 g, 66%): 1H NMR (CDCl3 400 MHz) δ 7.71 (dd, J=8.1, 1.5 Hz, 2H), 7.53 (dd, J=8.1, 1.5 Hz, 2H), 7.03 (m, 1H), 6.41 (m, 1H), 5.76 (m, 1H), 5.16-5.08 (m, 2H), 4.93 (ddd, J=11.7, 2.9, 2.9 Hz, 1H), 4.32 (dd, J=12.4, 2.2 Hz, 1H), 4.31 (s, 1H), 3.59 (m, 1H), 2.85 (m, 1H), 2.29-2.10 (m, 2H), 1.68-1.43 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([CH3:9])[C:7]=1Cl.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([CH3:9])[C:7]=1[O:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[Cl:14]
Reactant: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Cl
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Oc1ccc(Cl)cc1Cl
Temperature: 100 °C
Yield: 45.6 %

Procedure:
Into a 250 milliter three-necked round bottom reaction flask equipped with a magnetic stirrer and nitrogen inlet was charged 10.0 grams (45.44 mmol) of 3,4-dichloro-2,5-dimethylnitrobenzene, 7.95 grams (48.81 mmol) of 2,4-dichlorophenol, 9.41 grams (68.11 mmol) of potassium carbonate and 60 milliliters dimethylformamide. The reaction mixture was stirred and heated at a temperature of 100° C. for a period of 20 hours and then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was diluted with methylene chloride and the organic layer was washed with 4% NaOH solution (2x) and brine, dried through Na2SO4 and concentrated under reduced pressure to afford the crude product as a dark brown, viscous liquid. The addition of hexane and ethyl acetate afforded a light brown solid which was subjected to Kugelrohr distillation (about 180° C. and about 0.1 mm mercury) to give pure 3-chloro-4-(2,4-dichlorophenoxy)-2,5-dimethylnitrobenzene (7.17 grams, 20.7 mmol, 45%) as a yellow solid having a melting point of 118° C.-121° C. NMR spectroscopic analysis indicated the following: H'-NMR (CDCl3) 7.76 (br S, 1H), 7.53 (d, J=2 Hz, 1H), 7.12 (d,d; 2.9 Hz; 1H), 6.34 (d, J=9 Hz, 1H), 2.45 (S, 3H), 2.24 (S, 3H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[N:24]=[C:23]2[S:25][C:26]([NH2:28])=[N:27][C:22]2=[CH:21][CH:20]=1>S(Cl)(Cl)=O.C1COCC1.N1C=CC=CC=1>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:28][C:26]2[S:25][C:23]3[C:22]([N:27]=2)=[CH:21][CH:20]=[C:19]([O:18][CH3:17])[N:24]=3)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc2nc(N)sc2n1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccccc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2nc(NC(=O)[C@H](CC3CCCC3)c3ccccc3)sc2n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The title D compound, (R)-3-cyclopentyl-2-phenyl-propionic acid (1.66 g, 7.605 mmol) is dissolved in thionyl chloride (15 mL) and heated at 50° C. for 1.5 h. The reaction is then cooled to RT and concentrated to afford a yellow oil. This is dissolved in anhydrous THF (10 mL) and added dropwise to a solution of the title E compound, 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (1.38 g, 7.605 mmol) in anhydrous pyridine (10 mL) at 0° C. The reaction is allowed to stir and warm to RT. After 2 h, the reaction is concentrated to remove the THF and most of the pyridine. The resulting brown oil is dissolved in ethyl acetate (250 mL)/1 N HCl (250 mL) and extracted further with ethyl acetate. The combined organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product as a brown oil. This is chromatographed over silica eluting with 5→60% ethyl acetate in hexanes to afford (R)-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-phenyl-propionamide as a yellow foam: 1H NMR (400 MHz, DMSO-D6) 1.1 (m, 2 H) 1.4 (dd, J=7.2, 4.7 Hz, 2 H) 1.6 (m, 3 H) 1.7 (m, 3 H) 2.1 (m, 1 H) 3.9 (m, 4 H) 6.9 (d, J=8.8 Hz, 1 H) 7.3 (m, 1 H) 7.4 (m, 4 H) 8.0 (d, J=8.6 Hz, 1 H) 12.5 (s, 1 H); LC/MS 382.1 (M+1), 380.2 (M−1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>ClCCl>[CH3:27][S:28]([N:15]1[CH2:16][CH2:17][CH:12]([CH:3]([O:4][Si:5]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:10][CH3:11])[C:2]([F:18])([F:1])[F:19])[CH2:13][CH2:14]1)(=[O:30])=[O:29]
Reactant: CC[Si](CC)(CC)OC(C1CCNCC1)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(C1CCN(S(C)(=O)=O)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
4-[2,2,2-Trifluoro-1-(triethylsiloxy)ethyl]piperidine (303 mg, 1.02 mmol) was dissolved in dichloromethane (6 mL). To this, triethylamine (0.213 mL, 1.53 mmol) and methanesulfonyl chloride (0.118 mL, 1.53 mmol) were added at 0° C. and the mixture was stirred at room temperature for 30 minutes. The reaction was stopped by addition of water to the reaction mixture, and extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 1-methanesulfonyl-4-[2,2,2-trifluoro-1-(triethylsiloxy)-ethyl]piperidine (302 mg, yield: 79%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]([C:18]1[CH:22]=[C:21]([NH2:23])[O:20][N:19]=1)([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:23][C:21]2[O:20][N:19]=[C:18]([C:15]([CH3:17])([CH3:16])[C:14]([F:25])([F:24])[F:13])[CH:22]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: CC(C)(c1cc(N)on1)C(F)(F)F
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(c1cc(NC(=O)Cc2ccc(Br)cc2F)on1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.2 %

Procedure:
To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (360 mg, 1.545 mmol) in DCM (50 mL) was added 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (300 mg, 1.545 mmol), HATU (881 mg, 2.317 mmol) and triethylamine (0.645 mL, 4.63 mmol). Then the mixture was stirred at 25° C. for 12 h. The mixture was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to yield a yellow oil of 2-(4-bromo-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (600 mg, 1.1 mmol, 71% yield): 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=6.8 Hz, 1H), 7.34-7.29 (m, 1H), 7.21 (s, 1H), 6.64 (d, J=6.8 Hz, 1H), 6.43 (s, 1H), 3.75 (s, 2H), 1.52 (s, 6H); ES-LCMS m/z 409 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]N(C)C=O.CI>O>[CH3:20][N:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]=1)[C:15](=[O:17])[CH3:16]
Reactant: CN(C)C=O
Reactant: CC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Reaction time: 1 h

Procedure:
A mixture of 2.25 g of N-[3-(6-chloro-3-pyridazinyl)-phenyl]acetamide, 0.48 g of sodium hydride (50% in oil) and 100 ml of dimethylformamide was stirred under argon for 1 hour. To the mixture was added 0.6 ml of methyl iodide and after stirring 5 hours, an additional 0.6 ml of methyl iodide. After stirring overnight, 0.3 g of sodium hydride (50% in oil), then 0.6 ml of methyl iodide were added and stirring continued for 2 hours. The mixture was poured into water, filtered and the filtrate extracted with 60 ml portions of dichloromethane. The extracts were combined, evaporated in vacuo and the residue triturated with hexane. The resulting solid was chromatographed as described in Example 26 to give 1.45 g of product which was recrystallized from dichloromethane-ether to give the desired compound as crystals, mp 118°-120° C.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[O:5]=[CH:6][C@@H:7]([C@H:9]([C@H:11]([C@@H:13]([CH2:15][OH:16])[OH:14])[OH:12])O)[OH:8].[Sb](Cl)(Cl)(Cl)(Cl)Cl.N1C=C[CH:26]=[CH:25][CH:24]=1>>[CH3:1][C:2]1([CH3:4])[O:12][C@H:11]2[C@H:9]([C@@H:7]([CH2:6][OH:5])[O:8][C@@H:15]3[O:16][C:25]([CH3:26])([CH3:24])[O:14][C@@H:13]32)[O:3]1
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: CC(C)=O
Reactant: c1ccncc1
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Product: CC1(C)O[C@H]2[C@@H](O1)[C@@H](CO)O[C@@H]1OC(C)(C)O[C@@H]12
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To 200 ml of acetone were added 10.0 g of D-galactose and 89.7 mg of antimony pentachloride, and the mixture was refluxed with stirring in a water bath of 60° C. for 8 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the condenser. After completion of the reaction, a small amount of pyridine was added to the reaction mixture, and the acetone was distilled off under reduced pressure. The residue was dissolved in benzene, and the solution was washed with aqueous sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. The benzene was distilled off, and the resulting residue was distilled under reduced pressure to give 11.97 g (82.9%) of 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose as a fraction having a boiling point of 129°-133° C./0.2 mmHg.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[CH3:16])[CH3:2]>C(OCC)(=O)C.[Ni]>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[CH3:16])[CH3:18]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1C
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(N)cc1C
Reaction time: 36 h

Procedure:
3.10 g (12.3 mmol) of diethyl[2-(2-methyl-4-nitrophenoxy)ethyl]amine is dissolved in 250 mL of ethyl acetate, 0.55 g of Raney nickel is added, and the mixture is hydrogenated for 36 hours at 50 psi and ambient temperature. The catalyst is filtered off and the filtrate is evaporated down in vacuo. Yield: 2.70 g (99% of theory); C13H22N2O (M=222.33); calc.: molecular ion peak (M+H)+: 223; found: molecular ion peak (M+H)+: 223; Rf value: 0.35 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[C:11]([Cl:14])(=[O:13])[CH3:12]>>[ClH:14].[CH2:11]([O:13][C:6](=[NH:7])[C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][C:4]=1[F:10])[CH3:12]
Reactant: CC(=O)Cl
Reactant: N#Cc1ccc(Br)cc1F
Product: CCOC(=N)c1ccc(Br)cc1F
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
A suspension of 4-bromo-2-fluorobenzonitrile (25.0 g, 125 mmol) in IMS (88 mL) at 0-5° C. and treated dropwise with acetyl chloride (71 mL, 1 mol) maintaining the temperature below 10° C. The reaction vessel was sealed and the mixture stirred at RT for 18 h before concentrating in vacuo. The resultant residue was triturated in diethyl ether to give 4-Bromo-2-fluoro-benzimidic acid ethyl ester hydrochloride as a white solid (20.3 g, 57%). 1H NMR δ (ppm, DMSO-d6): 7.93-7.88 (1H, m), 7.85-7.76 (1H, m), 7.72-7.64 (1H, m), 4.60 (2H, q, J=7.02 Hz), 1.47-1.38 (3H, m).
Reaction SMILES: [C:1]1([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19]C(=O)OCC3C=CC=CC=3)[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.CO.C(Cl)(Cl)Cl>C(O)C.C(Cl)(Cl)Cl.[C].[Pd]>[C:1]1([C@H:13]2[CH2:14][CH2:15][C@H:16]([NH2:19])[CH2:17][CH2:18]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: O=C(N[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: N[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5% Palladium-carbon (5.00 mg) was added to benzyl [trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]carbamate (7.00 mg, 0.0180 mmol) in a mixture of ethanol (1 mL) and chloroform (1 mL) under an argon atmosphere, and after the reaction system was flushed with hydrogen, the reaction mixture was stirred at room temperature for one day and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (NH-PLC05 plate manufactured by Fuji Silysia Chemical Ltd.: methanol/chloroform=1/19 (v/v)) to give the title compound as a colorless solid (0.35 mg, yield 8.0%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13](OC)(=[O:17])[CH:14]([CH3:16])[CH3:15].C(O)(=O)C>C1COCC1.O>[CH3:15][CH:14]([CH3:16])[C:13](=[O:17])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COP(=O)(CC(=O)C(C)C)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Dimethyl methylphosphonate (8.8 g, 0.071 mol) was dissolved in anhydrous THF (100 ml) under argon atmosphere. To the solution stirred at -78° C. was added dropwise n-butyl lithium (1.58N, 45 ml, 0.071 mol) over 30 minutes and then a solution of methyl isobutyrate (2.9 g, 0.0284 mol) in anhydrous THF (5 ml) was added dropwise over 30 minutes. The reaction mixture was warmed to room temperature. After 30 minutes, acetic acid (4.3 ml) and water (10 ml) were added with ice cooling. After concentration, water (20 ml) was added to the residue and the mixture was extracted with ethyl acetate (50 ml×2). The ethyl acetate layers were washed with water (20 ml×1) and with brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. Distillation of the residue gave dimethyl 3-methyl-2-oxo-butylphosphonate (4.8 g, 0.025 mol, yield 88%, b.p.= 82°-84° C./0.31 mmHg). The structure was identified by the following data.
Reaction SMILES: C1(COC2C=CC(S(C)(=O)=O)=CC=2[C:16]2[C:17]3[O:26][C:25]([CH3:27])=[N:24][C:18]=3[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)CC1.[F:28][C:29]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])=[CH:34][C:33]=1B1OC(C)(C)C(C)(C)O1>>[F:28][C:29]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH2:42][CH3:43])(=[O:40])=[O:41])=[CH:34][C:33]=1[C:16]1[C:17]2[O:26][C:25]([CH3:27])=[N:24][C:18]=2[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1
Reactant: Cc1nc2c(=O)n(C)cc(-c3cc(S(C)(=O)=O)ccc3OCC3CC3)c2o1
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3nc(C)oc23)c1

Procedure:
7-bromo-2,5-dimethyl-[1,3]oxazolo[4,5-c]pyridin-4-one prepared in Example 238 and N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamide prepared in Example 240 were reacted in a manner similar to Example 237, step 6 to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=6.95 Hz, 3H) 2.45 (s, 3H) 3.13 (d, J=7.83 Hz, 2H) 3.58 (s, 3H) 6.95 (d, J=8.59 Hz, 1H) 7.03-7.30 (m, 3H) 7.30-7.48 (m, 2H) 7.91 (s, 1H) 9.86 (s, 1H). LCMS: 476 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1cccc(Br)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 3-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][N:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].C(O)C.Cl>O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([N:11]=[N:12][N:13]=2)[CH:4]=1)(=[O:10])[CH3:9]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc2nnnn2c1

Procedure:
To a stirred solution of 8.4 gm. (51.6 mmoles) of 2-chloro-5-acetylpyridine and 8.4 gm. (129 mmoles) of sodium azide in 150 ml. of ethanol and 150 ml. of water was added 75 ml. of 10% HCl over a period of 20 min. The reaction mixture was then heated to reflux for 18 hours, cooled in an ice bath and the resulting crystals filtered off to give a first crop of 6.0 gm. A second crop of 1.0 gm. was obtained for a total of 7.0 gm. of A, (84.% yield), m.p. 159°-160° C.