Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21](=[O:40])[C:22]([C:25]1[N:30]=[CH:29][C:28]([O:31][C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)([F:24])[F:23].C(=O)(O)[O-].[Na+]>C1COCC1.CS(C)=O.C1COCC1.[Cl-].[Na+].O>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1([C:22]([F:23])([F:24])[C:25]2[N:30]=[CH:29][C:28]([O:31][C:32]3[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)[CH2:7][O:40]1
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)C(=O)c3ccc(F)cc3F)nc2)cc1
Agent: C[S+](C)(C)=O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2ccc(C(F)(F)C3(c4ccc(F)cc4F)CO3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
To a magnetically stirred solution of trimethylsulfoxonium iodide (6.4 g, 29.42 mmol) in dry THF/DMSO (10:6) was added potassium tert-butoxide (3.302 g, 29.42 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 1 h and then cooled to 0° C. 4-((6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2oxoethyl)pyridin-3-yl)oxy)benzonitrile (8.737 g, 22.63 mmol) in THF (40 mL) was added slowly to maintain the temperature below 5° C. The reaction mixture was maintained at 0° C. for 30 min and saturated sodium bicarbonate was added to quench the reaction. Brine was added and the mixture was extracted with Et2O. The combined organic phases were diluted with hexanes and washed with brine and water, dried (Na2SO4) and concentrated to give the title compound as an amber oil (4 g, 44%): 1H NMR (300 MHz, CDCl3) δ 8.46 (d, J=2.7 Hz, 1H), 7.73-7.62 (m, 2H), 7.52 (dd, J=8.6, 0.6 Hz, 1H), 7.48-7.35 (m, 2H), 7.13-7.02 (m, 2H), 6.92-6.80 (m, 1H), 6.75 (ddd, J=10.0, 8.9, 2.5 Hz, 1H), 3.46 (d, J=5.1 Hz, 1H), 3.03-2.96 (m, 1H); ESIMS m/z 401 ([M+H]+).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]1[CH2:24][C:23]2([CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[O:22][CH2:21][CH2:20]1)=[O:18]>C(Cl)Cl>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]1[CH2:24][C:23]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:22][CH2:21][CH2:20]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(=O)c1nc3ccccc3s1)CCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1nc2ccccc2s1)N1CCOC2(CCNCC2)C1
Reaction time: 0.42 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 4-(benzo[d]thiazole-2-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 106, step a) (0.83 g) in DCM (15 mL) and the resulting mixture was stirred for 25 minutes. The solvent was evaporated in vacuo. The residue was dissolved in DCM:methanol (1:1) (5 mL) and applied to a SCX cartridge pre-wetted with DCM:methanol (1:1). The cartridge was washed with methanol (60 mL) and eluted with 2M ammonia in methanol solution (40 mL). The eluent was evaporated in vacuo to give the subtitled compound as a colourless oil. Yield 0.57 g.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][Cl:14])[CH:8]=1)[CH3:5].[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[ClH:14].[ClH:1].[ClH:14].[CH3:3][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][NH:18][C:16](=[NH:15])[SH:17])[CH:8]=1)[CH3:5]
Reactant: CN(C)Cc1ccnc(CCl)c1
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: CN(C)Cc1ccnc(CNC(=N)S)c1

Procedure:
4-Dimethylaminomethyl-2-chloromethylpyridine dihydrochloride is reacted with thiourea in ethanol under reflux. Removal of the ethanol yields 4-dimethylaminomethyl-2-pyridylmethyl isothiourea trihydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[F:39][C:40]1([F:45])[CH2:44][CH2:43][NH:42][CH2:41]1>CN(C=O)C>[F:39][C:40]1([F:45])[CH2:44][CH2:43][N:42]([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]([CH3:15])[CH3:14])[CH2:41]1
Reactant: FC1(F)CCNC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (1.1 g, 5.06 mmol), which is commercially available, and TBTU (1.63 g, 5.06 mmol) was mixed in DMF (10 mL). The mixture was cooled to 0° C. and TEA (2.105 mL, 15.19 mmol) was added. After 10 min was 3,3-difluoropyrrolidine hydrochloride (0.872 g, 6.08 mmol) added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue dissolved in DCM (50 mL). The organic phase was washed with HCl (1M aq. solution, 100 mL), NaHCO3 (saturated, 2×100 mL) and brine (100 mL), filtered through a phase separator and concentrated under reduced pressure to give the title compound (1.54 g, 99%). The obtained crude product was used without further purification. 1H NMR (400 MHz, CD3OD) δ 0.77-1.09, 1.21, 1.43, 1.84-2.08, 2.22-2.69, 3.52-4.40. Total no of protons: 24. LCMS (M+H)+: 307.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[C:11]2[C:18]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=3)=[CH:17][N:16]([CH:27]([CH3:29])[CH3:28])[C:12]=2[N:13]=[CH:14][N:15]=1>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[NH2:9][C:10]1[C:11]2[C:18]([C:19]3[CH:20]=[CH:21][C:22]([CH:23]([OH:24])[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:25][CH:26]=3)=[CH:17][N:16]([CH:27]([CH3:29])[CH3:28])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: CC(C)n1cc(-c2ccc(C=O)cc2)c2c(N)ncnc21
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)n1cc(-c2ccc(C(O)c3ccccc3)cc2)c2c(N)ncnc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Phenylmagnesium chloride (1.5 ml of a 2M solution in THF) was added dropwise with stirring under nitrogen to a solution of 4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzaldehyde (0.25 g) in toluene/THF (1:1, 16 ml) at minus 78° C. under nitrogen. After the addition the mixture was allowed to warm 0° C. and maintained at this temperature for 40 minutes. The reaction was quenched by the dropwise addition of saturated ammonial chloride solution (4 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stood overnight at this temperature. The solvent was removed under reduced pressure and the solid residue obtained was washed with water and filtered. The residue was triturated with hot ethyl acetate, collected by filtration and identified by LCMS as ∝-[4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]benzyl alcohol, m.p. 279-281° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=2)(=[O:29])=[O:28])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Product: Cc1cccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 3-methylbenzene-1-sulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]=[O:11].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:51])[CH2:43][C:44]([CH3:50])([CH3:49])[C:45]([O:47][CH3:48])=[O:46])=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=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.O>[F:1][C:2]1[CH:7]=[C:6]([C:36]2[CH:37]=[CH:38][C:39]([C:42](=[O:51])[CH2:43][C:44]([CH3:49])([CH3:50])[C:45]([O:47][CH3:48])=[O:46])=[CH:40][CH:41]=2)[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]=[O:11]
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(Br)cc1
Reactant: O=CNc1ccc(I)cc1F
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(NC=O)c(F)c2)cc1
Temperature: 80 °C
Yield: 45.7 %

Procedure:
A suspension of 2-fluoro-4-iodophenylformamide (1.94 g, 7.35 mmol, prepared as described above), bis(pinacolato)diboron (1.86 g, 7.35 mmol), potassium acetate (2.16 g, 22.1 mmol), and palladium acetate (49.4 mg, 0.22 mmol) in N,N-dimethylformamide (50 mL) was degassed by bubbling a flow of argon through the mixture for 30 minutes. The mixture was then heated at 80° C. for 3 h. After the mixture was cooled to rt, methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate (2.2 g, 7.4 mmol), tetrakis(triphenylphosphine)palladium(0) (254.8 mg, 0.22 mmol), and cesium carbonate (3.59 g, 11.0 mmol) were added, and the reaction mixture was heated at 80° C. for 16 h. The mixture was then cooled to rt and water was added. The mixture was extracted with ethyl acetate and the combined extracts were dried over sodium sulfate. The mixture was concentrated under reduced pressure and the crude was purified by flash chromatography (Biotage Flash 40M, 1:1 ethyl acetate/hexane) to afford methyl 4-[3′-fluoro-4′-(formylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate (1.2 g, 46%). LC-MS ret. time 2.80 min, m/z 358.1 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 1.19 (s, 6H), 3.36 (s, 2H), 3.51 (s, 3H), 7.56 (d, 1H), 7.69 (dd, 1H), 7.82 (d, 2H), 7.99 (d, 3H), 8.21 (t), 10.25 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[N:6][C:7]=1C.O.[C:14](=[O:17])([O-])[O-:15].[K+].[K+].[Mn]([O-])(=O)(=O)=O.[K+]>N1C=CC=CC=1>[C:10]([NH:9][C:5]1[N:6]=[C:7]([C:14]([OH:15])=[O:17])[C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:12])[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1ccc(Br)c(C)n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc(Br)c(C(=O)O)n1
Temperature: 90 °C
Yield: 603.8 %

Procedure:
To a solution of N-(5-bromo-6-methyl-pyridin-2-yl)-acetamide 48.46 g in pyridine 250 ml was added water 250 ml and the mixture warmed to 90° C. and potassium carbonate 2.2 g was added. Potassium permanganate was added portionwise over 10 h and the mixture allowed to cool slowly overnight. The reaction mixture was re-heated to 90° C. for 2 h, cooled slightly and filtered to remove manganese dioxide. The filtrate was evaporated in vacuo and the residue partitioned between water 1 L and ethyl acetate 500 ml. The aqueous solution was washed with ethyl acetate. The organic solutions were combined, washed with brine, dried MgSO4 and evaporated in vacuo to recover unchanged starting materials 12.6 g. The aqueous solution was acidified with concentrated hydrochloric acid (circa 80 ml) and the solid product filtered off, washed with a minimum of water, sucked dry and then dried at 80° C. (vac) to give 6-acetylamino-3-bromo-pyridine-2-carboxylic acid 24.9 g
Reaction SMILES: [N:1]([CH:4]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][CH2:6][C@@H:7]1[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[C:10](=[O:23])[CH2:9][CH2:8]1)=[N+:2]=[N-:3].CO.O.[OH-].[K+].Cl>CCOCC>[N:1]([CH:4]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][CH2:6][C@@H:7]1[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:10](=[O:23])[CH2:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)N=[N+]=[N-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)O)N=[N+]=[N-]

Procedure:
A suspension of 880 mg. of ethyl 15-azido-9-oxoprostanoate (Example 110) in 15 ml. of methanol-water (1:1) containing 360 mg. of potassium hydroxide is stirred at ambient temperature for 18 hours. The resulting solution is acidified with dilute hydrochloric acid and the oily layer is taken up in ether. The ether is washed with saturated sodi sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 797 mg. (98%) of an oil; λmax. 3.0-3.5 broad (acid group), 4.88 (azido group), 5.78 and 5.90 (carbonyl groups).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:19]([NH:21][NH:22][C:23](=[O:36])[CH2:24][NH:25]C(OCC1C=CC=CC=1)=O)=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:19]([NH:21][NH:22][C:23](=[O:36])[CH2:24][NH2:25])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)C[C@@H](C(=O)NNC(=O)CNC(=O)OCc1ccccc1)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NNC(=O)CN)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Yield: 98.4 %

Procedure:
A solution of 2.95 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-2′-[N-(benzyloxycarbonyl)-glycinyl]-4-methylvalerohydrazide in 30 ml of methanol was hydrogenated in the presence of 0.300 g of 5% palladium-on-carbon for 0.5 hours. The mixture was filtered and evaporated to give 2.2 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-2′-glycinyl-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH3:8])=[CH:3][CH:4]=[O:5].[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH3:8])(=[O:11])[CH3:10]
Reactant: CCCC(C)=CC=O
Reactant: CC(=O)OC(C)=O
Product: CCCC(C)=CCOC(C)=O
Temperature: 100 °C

Procedure:
3-methylhex-2-enal (as a 40/60 Z/E isomers mixture) (112 g, 1 mol.), acetic anhydride (107 g, 1.05 mol) and (ethylenediamine)[1,2-bis(diphenylphosphino) ethane]ruthenium(bispivalate) (76 mg, 0.1 mmol, 0.01 mol.%) were loaded altogether in a 300 ml autoclave equipped with a mechanical stirring device. Sealed autoclave was then purged to under stirring with nitrogen (3 times 5 bars) and hydrogen (3 times 5 bars) before being pressurized to 50 bars hydrogen. It was then heated to 100° C. and hydrogen pressure was maintained to 50 bars during all the reaction to afford desired product with 96% selectivity as a 40/60 WE isomers mixture. Upon reaction completion (checked by both hydrogen consumption and GC), autoclave was then cooled down to 25° C. It was then depressurized and purged with nitrogen (3 times 5 bars) and reaction mixture was then transferred to a round-bottomed flask and concentrated under vacuum. After initial flash distillation followed by further fractional distillation, pure 3-methylhex-2-en-1-yl acetate was obtained in 90% yield.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C2OC(=O)CC2)=CC=1.[C:19]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:24]=[CH:23][C:22]([C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:21][CH:20]=1.[BH4-].[Na+]>C(O)(=O)C>[C:19]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:20]=[CH:21][C:22]([CH:25]([OH:26])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][CH:24]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2)cc1
Agent: O=C1CCC(c2ccc(-c3ccccc3)cc2)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)CCC(O)c1ccc(-c2ccccc2)cc1

Procedure:
The compound 5-(4-biphenylyl)dihydro-2-(3H)-furanone may be prepared by treating 3-(4-biphenylylcarbonyl)-propionic acid in basic medium with sodium borohydride. The addition of acetic acid precipitates a solid which is again treated with sodium borohydride in basic medium, and precipitated with glacial acetic acid giving 4-(4-biphenylyl)-4-hydroxybutyric acid. This product is treated with a mineral acid and then neutralized with sodium acetate giving the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:11])[CH2:10][O:9]2)=[CH:4][CH:3]=1.Br[C:13]1[NH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=1>C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:11])[O:9][C:13]3=[N:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]3[CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Br)[nH]1
Reactant: CC1(c2ccc(Br)cc2)CO1
Solvent: CCN(CC)CC
Product: CC1(c2ccc(Br)cc2)Cn2cc([N+](=O)[O-])nc2O1

Procedure:
2-(4-Bromo-phenyl)-2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazole was synthesized according to the scheme shown in FIG. 6. 2-(4-Bromo-phenyl)-2-methyl-oxirane (213 mg, 1 mmol), 2-bromo-5-nitroimidazole (191 mg, 1 mmol) and triethylamine (0.4 mL) were stirred in a sealed tube at 80° C. for 6 hours Column chromatography (EtOAc/Hexanes, v/v, 1/1 to 3/1) gave 330 mg yellow solid. The solid was dissolved in 5 mL DMF with Cs2CO3 (780 mg, 2.4 mmol). The resulting mixture was stirred at 50° C. for 24 hours and then partitioned in EtOAc/water (200 mL, 1/1, v/v). The organic layer was washed with brine and dried over Na2SO4 Column chromatography (EtOAc/Hexanes, v/v, 1/1 to 3/1) gave the titled compound (178 mg, 55% yield in two steps) as yellow solid. ESI MS m/z 324, 326 (M+H). 1H NMR (400 MHz, Acetone-d6) δ 7.66 (s, 1H), 7.76 (s, 1H), 7.52 (d, J=8.2 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 4.58 (d, J=10.8 Hz, 1H), 4.47 (d, J=10.8 Hz, 1H), 1.89 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([F:13])[CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([F:13])[CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OCC1Cc2cc(F)cc(Br)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(Br)c3O2)cc1
Yield: 66.3 %

Procedure:
Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol (11.5 g, 0.047 mol) with p-toluenesulfonyl chloride (9.76 g, 0.051 mol) generally according to the procedure described for Intermediate 10 gave 12.50 g (66%) (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.44 (silica, ethyl acetate:hexanes 1:4); mp 84-86° C.; Anal. calcd. for C16H14BrFO4S: C, 47.89; H, 3.52. Found: C, 47.65; H, 3.63.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:21]([O:23][C:24]([C:26]1[C:27](=[O:49])[C:28]2[CH:33]=[N:32][C:31](S(C)(=O)=O)=[N:30][C:29]=2[N:38]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[CH2:45][CH2:44][CH2:43]3)[CH:39]=1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1[C:27](=[O:49])[C:28]2[CH:33]=[N:32][C:31]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:19][CH:18]=3)=[N:30][C:29]=2[N:38]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[CH2:45][CH2:44][CH2:43]3)[CH:39]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N4CCNCC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (52 mg, 0.19 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 70 mg, 0.17 mmol). A yellow solid was obtained (75 mg, 86%) after a preparative HPLC (32 mL min 5-100% MeCN/H2O gradient over 10 min) purification. The Boc group was removed by treatment with TFA in CH2Cl2 (1:1 v/v) to give the title compound. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.25 (s, 1H), 8.45 (s, 1H), 7.61 (br, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.21 (s, 1H), 7.14 (br, 2H), 7.10 (d, J=7.9 Hz, 1H), 6.57 (br, 2H), 4.30 (q, J=7.1 Hz, 2H), 3.02-2.90 (m, 12H), 2.15 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]([NH2:17])([CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Br:18][CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](Cl)=[O:21]>C(N(CC)CC)C>[CH3:16][C:8]([NH:17][C:20](=[O:21])[CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[Br:18])([CH3:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: Cc1ccccc1C(C)(C)N
Reactant: CC(C)(C)C(Br)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(C)(C)NC(=O)C(Br)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (150 ml), α,α,2-trimethylbenzylamine (7.5 g) and triethylamine (6 g), and α-bromo-tert-butylacetyl chloride (10.2 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. The benzene layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 13.8 g of N-(α,α,2-trimethylbenzyl)-α-bromo-tert-butylacetamide. M.P., 166.5°-168° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([O:15][CH2:16][C@@H:17]2[CH2:22][O:21][CH2:20][CH2:19][N:18]2CC2C=CC(OC)=CC=2OC)=[CH:13][C:12]([C:34]#[N:35])=[CH:11][C:10]=1[NH:36][C:37]1[N:42]=[C:41]([N:43]([CH:53]2[CH2:55][CH2:54]2)CC2C=CC(OC)=CC=2)[C:40]2=[N:56][CH:57]=[C:58]([C:59]#[N:60])[N:39]2[N:38]=1.C1(OC)C=CC=CC=1>ClC(Cl)C>[Cl:8][C:9]1[C:14]([O:15][CH2:16][C@@H:17]2[CH2:22][O:21][CH2:20][CH2:19][NH:18]2)=[CH:13][C:12]([C:34]#[N:35])=[CH:11][C:10]=1[NH:36][C:37]1[N:42]=[C:41]([NH:43][CH:53]2[CH2:54][CH2:55]2)[C:40]2=[N:56][CH:57]=[C:58]([C:59]#[N:60])[N:39]2[N:38]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(OC[C@@H]4COCCN4Cc4ccc(OC)cc4OC)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(Cl)Cl
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(OC[C@@H]2COCCN2)c1
Temperature: 60 °C
Yield: 68.9 %

Procedure:
50% TFA in dichloroethane (1 ml) was added to a solution of (S)-2-((2-chloro-5-cyano-3-((4-(2,4-dimethoxybenzyl)morpholin-3-yl)methoxy)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (80 mg, 0.109 mmol) and anisole (0.095 ml, 0.869 mmol) in a 1-dram vial and the reaction mixture was heated at 60° C. for 4 hours. The reaction mixture was concentrated and residue was dried under vacuum overnight. The crude was dissolved in acetonitrile (2 ml) and neutralized with 2N ammonia in methanol (2 ml); white precipitate formed and was collected by filtration. This material was further purified by flash chromatography on silica gel using an automated ISCO system (24 g gold column, eluting with 1-6% 2 N ammonia in methanol/dichloromethane). (S)-2-((2-chloro-5-cyano-3-(morpholin-3-ylmethoxy)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (35 mg) was obtained as a white solid.